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Cancer Research & APP Development

MD Anderson study evaluates need for biopsies during follow-up care in women with early breast cancer

Findings first to address this key concern of patients

MD Anderson Cancer Centre -- January 31, 2018

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HOUSTON - In an analysis of more than 120,000 women diagnosed with and treated for early-stage breast cancer, researchers from The University of Texas MD Anderson Cancer Center determined the rate of additional breast biopsies needed for these patients during their follow-up care.

The findings, reported in JAMA Surgery, are the first comprehensive nationwide population-based study regarding the need for breast biopsies performed during follow up after treatment for invasive breast cancer.

According to the American Cancer Society, 252,710 women will be diagnosed with breast cancer in 2017, and of those, 63,410 will have early-stage disease.

Research and data help physicians counsel women about breast cancer recurrence rates, how often cancer in one breast develops in the second breast. However, in a thorough review of the literature, no data offered clues about how often a patient, after having had breast cancer, will require a biopsy, explains Henry Kuerer, M.D., Ph.D., the study's corresponding author.

"This is a genuine concern for patients. Many feel very anxious over the future need for biopsies and the potential of another diagnosis," explains Kuerer. "Women will often choose a mastectomy rather than have the fear and stress associated with future biopsies or another cancer diagnosis."

To gather information that could shed light on the need for follow-up biopsies, the researchers analyzed two national databases. They looked at 41,510 breast cancer patients in MarketScan (the national database of patients with private insurance, age 64 years and younger), and 80,369 breast cancer patients in SEER-Medicare (patients age 65 years and older). All had Stage I - III disease, and were diagnosed between 2000 and 2011. Diagnosis and procedural codes were used to identify biopsy rates during follow up.

Five- and 10-year overall incidence of breast biopsy was 14.7 percent and 23.4 percent, respectively in the MarketScan cohort, and 11.8 percent and 14.9 percent, respectively, in the SEER-Medicare cohort. Adjuvant chemotherapy use, patient age, and endocrine therapy were independently associated with biopsy in both cohorts.

Of note, say the researchers, the five-year incidence of breast biopsy was higher in women treated with brachytherapy, compared to those treated with whole-breast radiation: 16.7 percent in the MarketScan cohort and 15.1 in the SEER-Medicare cohort. Also, after a mastectomy in one breast, the estimated five-year breast biopsy rates for the other breast were 10.4 and 7.8 in the MarketScan and SEER-Medicare cohorts, respectively.

Of the patients who underwent a breast biopsy, 29.8 percent in the MarketScan cohort and 23.2 in the SEER-Medicare cohort underwent subsequent cancer treatment.

Kuerer notes that the study is not without limitations, including that it's based on claims data. Also, he and his colleagues note that both imaging and targeted therapy treatment for early-stage breast cancer may have improved since 2011, when the study concluded.

Still, he says, the research addresses an important issue that will allow surgeons to have more meaningful conversations with their patients.

"This information is something I can use daily when discussing breast cancer treatment options," said Kuerer. "The important message is that the rate of biopsy for patients is relatively low and the overwhelming majority of the biopsy results will be benign and not require further treatment."

This research also serves as a complement to another MD Anderson study led by Kuerer that evaluates the need for surgery in early-stage breast cancer patients who achieve a pathologic complete response to chemotherapy or targeted therapy. That study is ongoing and actively accruing patients.

In addition to Kuerer, other authors on the all-MD Anderson study include: Raquel F.D. van la Parra, M.D., Ph.D., Breast Surgical Oncology; Kaiping Liao, Ph.D., Health Services Research; Benjamin D. Smith, M.D., Ph.D., Radiation Oncology and Health Services Research; Wei T. Yang, M.D. and Jessica W.T. Leung, M.D., both of Diagnostic Radiology; and Sharon H. Giordano, M.D., Health Services Research.

The study was funded by the Dutch Cancer Society Clinical KWF Fellowship, the PH and Fay Etta Robinson Distinguished Professorship in Cancer Research Endowment, a Cancer Center Support Grant from the National Institutes of Health (CA16672) and the MD Anderson Clinical Research Funding Award Program.

Regarding disclosures, Kuerer reports publishing patents, royalties and other intellectual property from the New England Journal of Medicine Group and McGraw-Hill Publishing, serving on the speaker's bureau for PER and former research funding from Genomic Health. Dr. Leung reports serving on the Scientific Advisory Board for Hologic Inc.

© 2018 The University of Texas MD Anderson Cancer Center

TARGET Study Finds Major Differences between Childhood and Adult AML

by NCI Staff

The National Cancer Institute -- January 30, 2018

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    UPDATE: Content about a related study, published February 28 in Nature, has been added to this post. See the box at the bottom of the page.

An NCI-funded study has found that, at the genetic level, acute myeloid leukemia (AML) differs greatly between younger and older patients.

"AML in younger patients and AML in older patients are entirely distinct diseases," said the study's senior investigator, Soheil Meshinchi, M.D., Ph.D., of Fred Hutchinson Cancer Research Center. "It's almost like comparing breast cancer to colon cancer."

The findings, published in the January 2018 issue of Nature Medicine, come from a genomic analysis of nearly 1,000 children and young adults with AML. The study is part of the Therapeutically Applicable Research To Generate Effective Treatments (TARGET) initiative, a collaborative effort between NCI and the Children's Oncology Group (COG) to better understand the biology of several high-risk or hard-to-treat pediatric cancers.

"This [study] can inform where therapeutic development should focus in order to better target pediatric AML," said Yana Pikman, M.D., a pediatric oncologist at Dana-Farber/Boston Children's Cancer and Blood Disorders Center, who was not involved in the study.

Therapies that are tailored to the biology of AML in children may be the best hope for treating the disease, the researchers believe. They have already used some of the early study findings to influence clinical trials of potential targeted therapies for AML.

Challenging Assumptions about AML

Acute myeloid leukemia, a cancer of the bone marrow and blood, occurs most frequently in adults over the age of 60. Though it is rare, AML also develops in younger adults and children, sometimes as early as a few days after birth.

The treatment options for young patients with AML include intensive chemotherapy and bone marrow transplantation. In the early 1980s, approximately 30% of children with AML survived 5 years after their diagnosis, and in more recent years, the rate has increased to around 65%.

Despite this improvement, there has been limited progress in identifying effective targeted therapies due to "an inadequate understanding of the biology of childhood AML," the TARGET investigators wrote.

"Generally, people think that AML in children is the same disease as in older adults, just less common," explained Dr. Meshinchi. "So, until now, most of the studies, discoveries, and treatments [for AML] have been developed in older patients. The assumption is that whatever we find in an older population can be used to treat younger patients," he continued.

But earlier studies by Dr. Meshinchi and his colleagues showed that some of the most common genetic features of adult AML are completely absent in childhood AML, suggesting that the biological characteristics of this leukemia may differ by patient age.

Toward a Better Understanding of Childhood AML

For the TARGET project, the researchers analyzed the genomic (DNA, RNA, and epigenetic) features of cancer cells from infants (less than 3 years old), children (3-14 years old), and adolescents and young adults (15-39 years old) with AML.

In addition to identifying small DNA mutations, the investigators also took note of big changes in chromosome structure (known as structural alterations), such as the loss, amplification, or relocation of a chunk of a chromosome.

The genomic characteristics of childhood AML differed broadly among study participants, the researchers discovered. For example, only a handful of the same mutations and structural alterations were present in more than 5% of patients in the study.

The low frequency of recurring mutations and alterations represents "a substantial challenge to advancing therapies for pediatric AML," noted Andrew Brunner, M.D., and Timothy Graubert, M.D., of Massachusetts General Hospital, in a commentary that accompanied the TARGET study.

Because the genetic features of each child's AML are unique, "no single treatment strategy is likely to be effective for all pediatric AML [patients]," the TARGET researchers wrote.

The team also identified many fusion genes, which can form when chromosome pieces shift and have been found to drive the growth of many blood cancers. The fusion proteins produced by such fusion genes are ideal drug targets because they are exclusive to cancer cells, so drugs that target them are less likely to harm normal cells, Dr. Meshinchi explained.

"The critical question is: Is it possible to target these fusion proteins directly?" he asked. Dr. Meshinchi and his team are exploring this possibility, as well as the potential for targeting fusion proteins indirectly by going after the genes and proteins that they regulate.

Same Name, Different Disease

When the team compared the genomic characteristics of pediatric AML to those of adult AML, as identified by a study from The Cancer Genome Atlas (TCGA), they discovered significant differences.

The most critical difference, noted Dr. Meshinchi, was: Whereas mutations were much more common than structural alterations in adults with AML, the opposite was true in children. For example, the researchers found nearly ten times more structural alterations than DNA mutations in infants with AML.

The finding suggests that, in young children, structural alterations are potent enough to cause cancer on their own, he explained. In adults, AML is caused by the accumulation of multiple mutations and alterations over the course of a lifetime.

The researchers also found that the few DNA mutations that were present in pediatric AML were different from those in adult AML-both in terms of where and how frequently the mutations occurred. For example, mutations in the NRAS gene (a gene that controls cell growth and death) were much more common in pediatric AML than adult AML. There was some overlap in DNA mutations identified in adult and pediatric AML patients, however, particularly between the adolescent and young adults group and older adults.

Said Dr. Pikman, "people often say that kids are not little adults, and I think that this [study] very clearly shows that."

Together, the study results underscore the fact that many AML treatments that are developed for adults with the hope that they can "trickle down" to children and young adults may not be effective for pediatric AML, Dr. Meshinchi stressed.

The study findings provide a "better understanding of what initiates or sustains these cancers," which will help guide the development of new treatments, said study investigator Daniela S. Gerhard, Ph.D., of NCI's Office of Cancer Genomics.

In fact, TARGET and COG researchers are already planning several clinical trials based on these findings. For example, the researchers found high levels of a protein called mesothelin-which is sometimes expressed by lung cancer cells-in some younger patients with AML. Dr. Meshinchi and his colleagues are working with Bayer to bring a mesothelin-targeting drug the company has developed for lung cancer into clinical trials for children and young adults with relapsed AML.

Researchers at COG are also planning a clinical trial that will investigate whether comprehensive genetic tests such as those used in the TARGET study can help guide treatment selection and improve patient outcomes.

The next step is to continue "mining the data" from the TARGET study to identify patterns, associations, and potential drug targets, Dr. Gerhard said. And because the data are available to qualified researchers (in ways that protect patient privacy), more researchers have the opportunity to build on these initial results.

Dr. Pikman, who leads a multi-institutional study investigating the efficiency of genomic tests for matching patients with leukemia to targeted therapy, is already using some of the data to guide her research.

    Differences between Childhood and Adult Cancers Found in Multiple Cancer Types

    A study published February 28 in Nature by many of the same TARGET researchers has found that several cancer types are genetically different in children and adults.

    According to the study authors, the findings reinforce the belief among some researchers that drugs developed and approved to treat cancers in adults may not always be effective or appropriate for children with the same cancer types.

    To perform the "pan-cancer" study, Jinghui Zhang, Ph.D., of St. Jude Children's Research Hospital, and her colleagues analyzed samples from nearly 1,700 patients, aged 20 or younger, looking at all noninherited, or somatic, genetic alterations. Patients in the TARGET study had common childhood cancers, including acute lymphoblastic leukemia, acute myeloid leukemia, neuroblastoma, Wilms tumor, and osteosarcoma.

    The researchers identified 142 altered genes that drive the development of these cancers (driver mutations), of which only 45% are found in adult cancers. Most of the genetic alterations (62%) fell into two categories: copy number variants and structural alterations.

    The findings "provide a comprehensive genomic architecture for [pediatric] cancers and emphasize the need for [pediatric] cancer-specific development of precision therapies," the researchers wrote.

    This study, and a similar one published in the same issue of Nature, provide "a remarkably complete picture of childhood cancer," NIH Director Francis Collins, M.D., Ph.D., wrote in a recent blog post.

© 2018 The National Cancer Institute

Olaparib Approved for Treating Some Breast Cancers with BRCA Gene Mutations

by NCI Staff

The National Cancer Institute -- January 29, 2018

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The drug olaparib (Lynparza) has become the first treatment approved by the Food and Drug Administration (FDA) for patients with metastatic breast cancer who have inherited mutations in the BRCA1 or BRCA2 genes.

On January 12, FDA granted regular approval to olaparib for patients with metastatic breast cancer who have a BRCA gene mutation and have received chemotherapy previously.

"This is an important advance for women with germline BRCA mutations who have breast cancer," said Elise Kohn, M.D., head of Gynecologic Cancer Therapeutics in NCI's Division of Cancer Treatment and Diagnosis.

"We are always in need of new and better, more active treatments for the women we serve," Dr. Kohn continued. "The approval allows us to move forward in a new direction for treating breast cancer associated with BRCA mutations."

The BRCA1 and BRCA2 genes produce tumor suppressor proteins that help repair damaged DNA in cells. Mutations in these genes cause about 75% to 80% of hereditary breast cancer and 5% to 10% of all breast cancers, Dr. Kohn noted.

Patients are selected for treatment with olaparib using a companion diagnostic test called BRACAnalysis CDx, which the FDA approved for detecting mutations in BRCA genes in blood samples from patients with breast cancer who may be eligible for olaparib.

Olaparib belongs to a class of drugs known as PARP inhibitors. These agents block the actions of PARP proteins, which, like BRCA proteins, help repair DNA damage in cells. Blocking PARP proteins in breast cancer cells that already have a defect in DNA repair-because of BRCA mutations-may lead to further DNA damage and cell death.

Olaparib is already approved for treatment of some patients with recurrent ovarian, fallopian tube, or primary peritoneal cancer, including those with advanced cancers who have BRCA mutations, and as a maintenance therapy for some patients with recurrent ovarian, fallopian tube, or primary peritoneal cancer.

Study Finds Improvement in Progression-Free Survival

FDA based its new approval on the results of the OlympiAD clinical trial, which enrolled 302 patients with HER2-negative metastatic breast cancer who carried a germline BRCA mutation. The trial included some patients with triple-negative breast cancer, which can be aggressive and for which there are few treatment options.

Patients were randomly assigned to receive olaparib or a standard chemotherapy selected by the patient's physician. All patients had previously received chemotherapy.

The primary endpoint of the trial-which was funded by olaparib's manufacturer, AstraZeneca-was progression-free survival.

In the study, median progression-free survival was 7.0 months for patients in the olaparib group compared with 4.2 months for patients in the standard-therapy group. In the olaparib group, 59% of the patients responded, compared with 28.8% of the standard-therapy group.

The authors also found that the median time until a patient responded was similar for olaparib and standard therapy. "This finding is an important consideration for symptomatic or rapidly progressing patients," they added.

The rate of grade 3 or higher adverse events was 36.6% in patients receiving olaparib and 50.5% in patients receiving standard therapy.

Common side effects included low levels of red blood cells (anemia), low levels of certain white blood cells (neutropenia, leukopenia), nausea, fatigue, and vomiting. Severe side effects included the development of certain blood or bone marrow cancers (myelodysplastic syndrome/acute myeloid leukemia) and inflammation in the lungs (pneumonitis).

"It is striking that nearly every parameter assessed in the study-from the primary endpoint to toxicity-was better with olaparib," said Dr. Kohn, adding that longer follow-up is needed to assess overall survival. "This is progress for patients."

Additional clinical trials of olaparib for breast cancer are under way. For example, a randomized phase 3 trial is testing the drug in patients with triple-negative breast cancer, and another study, which includes some patients with triple-negative breast cancer, is evaluating olaparib in combination with the drug onalespib.

© 2018 The National Cancer Institute

Presurgical targeted therapy delays relapse of high-risk stage 3 melanoma

First-of-its-kind study indicates pretreatment improves outcomes over standard-of-care surgery

MD Anderson Cancer Center -- January 17, 2018

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Watch to learn more about the trial results from Dr. Amaria

HOUSTON - A pair of targeted therapies given before and after surgery for melanoma produced at least a six-fold increase in time to progression compared to standard-of-care surgery for patients with stage 3 disease, researchers at The University of Texas MD Anderson Cancer Center report in Lancet Oncology. Patients who had no sign of disease at surgery after combination treatment did not progress to metastasis.

Early results of the study comparing surgery to pre- and post-surgical treatment with the BRAF inhibitor dabrafenib and the MEK inhibitor trametinib were so strikingly positive that MD Anderson's data safety monitoring board ordered the randomized, prospective phase II trial halted and changed to a single-arm using the combination.

"These results are encouraging for patients with surgically resectable stage 3 melanoma, who face a high rate of relapse and progression to metastatic disease," said lead author Rodabe Amaria, M.D., assistant professor of Melanoma Medical Oncology. "Our proof-of-concept study strongly supports further assessment of neoadjuvant (presurgical) therapy for this high-risk population, which has a five-year survival rate of less than 50 percent."

The targeted combination is approved by the U.S. Food and Drug Administration for stage 4 metastatic melanoma that features a BRAFV600 mutation. Amaria, senior author Jennifer Wargo, M.D., associate professor of Surgical Oncology and Genomic Medicine, and colleagues hypothesized that the combination could help patients with stage 3 BRAF-mutant disease.

Trial launched through Moon Shots Program

In October 2014, the investigator-initiated clinical trial was launched through the Melanoma Moon Shot, co-led by Wargo and part of MD Anderson's Moon Shots Program to accelerate improvement of cancer treatment and prevention. It was the first prospective, randomized neoadjuvant clinical trial for stage 3 melanoma.

The trial was designed to enroll 84 patients randomized to either up-front surgery or to eight weeks of the targeted combination followed by surgery and another 44 weeks of combination treatment. An interim data analysis occurred after 21 patients were treated.

At a median follow-up time of 18.6 months:

  • All seven treated with standard of care surgery had their disease progress, with median time to progression at 2.9 months.
  • Of 14 randomized to the neoadjuvant combination, four progressed, with median time to progression of 19.7 months.
  • Of the seven patients who achieved a pathological complete response after presurgical therapy, none experienced distant disease relapse.
  • Median overall survival had not been reached in either arm.

Most melanoma is detected at early stages and treated successfully with surgery, but about 15 percent of patients progress to stage 3, when the disease has spread to lymph nodes.

Importance of pathological complete response

Reaching pathological complete response (pCR) - no evidence of live cancer found by pathology at surgery - appears to be a powerful indicator of treatment success, Amaria said. Twelve patients in the neoadjuvant group proceeded to surgery, with seven achieving pCR. Only one relapsed, with a small tumor in the same area as the original tumor. Three patients who reached a partial pathological response relapsed, with all developing brain metastases, a common risk in BRAF-positive disease.

"As we accumulate more data, we can further explore the importance of pathological complete response," Wargo said. "If we can prove that pathologic complete response is important in achieving superior outcomes, then the next step is to ask 'what can you do to get to pCR?'"

Biopsies and blood samples taken in the trial allowed the team to begin to address those issues.

  • Patients that did not reach pCR had tumors with high levels of phosphorylated ERK, a growth-promoting protein in the MEK pathway, before combination treatment began.
  • Research has shown evidence of an immune response in successful treatment with BRAF inhibitors, even though these drugs are not explicitly immunotherapies. The team found penetration of tumors by CD8-positive T cells in pCR patients, but evidence of T cell exhaustion in tumors of patients who did not reach pCR. Two checkpoint proteins that stifle immune response, TIM3 and LAG3, were found in abundance on T cells in those patients.
  • Whole exome sequencing revealed no significant difference in mutational load or copy-number alterations at baseline between responders and non-responders. However, those who did not reach pCR often had known genetic aberrations that cause resistance to the combination.

These differences provide pathways for larger, additional studies and point to possible combination therapy approaches. Since the original trial was halted, 11 patients have enrolled in the neoadjuvant study.

Toxicities from the combination were primarily grade 1 and 2 side effects expected with dabrafenib and trametinib, most commonly chills, headache and fever. There were eight grade 3 events, no grade 4 events and no deaths related to treatment. Two patients in the surgical arm and one in the neoadjuvant arm died from disease progression.

Those in the standard-of-care surgery arm were offered a variety of adjuvant (post-surgical) therapies, including interferon-alpha, the checkpoint blockade drug ipilimumab, biochemotherapy or observation. Existing adjuvant therapies at the time the trial was enrolling had extremely low response rates as well as harsh side effects, Amaria said. Only one patient chose to have post-surgical therapy in that arm.

The targeted combination and immune checkpoint blockade drugs have shown promise as adjuvant therapies in recent clinical trials.

MD Anderson researchers have developed an international neoadjuvant melanoma consortium to develop larger clinical trials needed to further explore this approach.

Novartis Pharmaceuticals provided drugs and funded the clinical aspects of the study, but played no role in study design, execution, data collection, analysis or interpretation. Correlative studies of tumors and blood samples were funded by the Cancer Prevention and Research Institute of Texas, MD Anderson's Melanoma Moon Shot and the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation.

Co-authors with Amaria and Wargo are: Isabella Glitza M.D., Ph.D., Wen-Jen Hwu, M.D., Hussein Tawbi M.D., Ph.D., Sapna Patel M.D., Lauren Simpson, R.N., Rosalind Mouton, Haifeng Zhu Ph.D., Patrick Hwu, M.D., Adi Diab, M.D., Michael Wong, M.D., Ph.D., Jennifer McQuade, M.D., Scott Woodman, M.D., Ph.D., and Michael Davies, M.D., Ph.D., all of Melanoma Medical Oncology; co-first author Peter Prieto, M.D., Alexandre Reuben, Ph.D., Miles Andrews, Ph.D., Merrick Ross, M.D., Janice Cormier, M.D., Jeffrey Lee, M,D., Jeffrey Gershenwald, M.D., Vancheswaran Gopalakrishnan, Ph.D., Zachary Cooper, Ph.D., Richard Royal, M.D., Anthony Lucci, M.D., and Elizabeth Burton, M.B.A., all of Surgical Oncology; Michael Tetzlaff, M.D., Courtney Hudgens, Khalida Wani, Ph.D., and Alexander Lazar, M.D., all of Pathology; Christine Spencer, Li Zhao, Ph.D., and Andrew Futreal, Ph.D., all of Genomic Medicine; Roland Bassett of Biostatistics; Sangeetha Reddy, M.D., of Cancer Medicine; and Padmanee Sharma, M.D., Ph.D., and Jim Allison, Ph.D., of Immunology.

© 2018 The University of Texas MD Anderson Cancer Center

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Cabozantinib Approval Expands Initial Treatment Options for Advanced Kidney Cancer

by NCI Staff

The National Cancer Institute -- February 27, 2018

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For patients with the most common type of kidney cancer, there is now a new approved use of the targeted therapy cabozantinib (Cabometyx). In December 2017, the Food and Drug Administration (FDA) approved use of the drug as an initial, or first-line, treatment for patients with advanced renal cell carcinoma (RCC).

Cabozantinib was initially approved in 2016 for patients with metastatic RCC whose tumors did not respond to their first treatment or who had relapsed after previous treatment. (In 2012, a different formulation of the drug was approved under the trade name Cometriq for the treatment of patients with medullary thyroid carcinoma.)

More than 60,000 people in the United States develop RCC each year. The overall incidence of kidney cancer has been increasing in the United States, while the mortality rate has decreased recently. Still, approximately 15,000 people in the United States are expected to die from this disease in 2018.

"Unfortunately, it's a very lethal cancer," said W. Marston Linehan, M.D., chief of the Urologic Oncology Branch in NCI's Center for Cancer Research.

Over the last 13 years, however, FDA has approved numerous drugs, both targeted therapies and immunotherapies, to treat patients with various stages of RCC, Dr. Linehan pointed out.

"Patients now have a number of options to treat this aggressive disease," he said.

A Deadly Silencing

The most common subtype of RCC, called clear cell RCC, accounts for 75% of cases. Ninety percent of clear cell RCC is caused by mutation or silencing of a gene called VHL, Dr. Linehan explained.

Twenty-five years ago, Dr. Linehan and his colleagues at NCI identified the VHL gene and demonstrated its critical role in kidney cancer. VHL is a tumor suppressor gene, and its silencing triggers a domino effect, resulting in the increased expression of genes and proteins that promote tumor cell survival and growth.

"Before we knew the genetic basis of this cancer, there were no effective therapies for patients with metastatic disease," he said. As recently as 2005, "aside from Interleukin 2, very few targeted systemic therapies existed for metastatic RCC, and those that did were largely ineffective."

But the past decade or so has seen an encouraging increase in the number of drugs targeting the underlying genetic mechanisms of kidney cancer, he continued.

"We now have numerous drugs, including cabozantinib, targeting the VHL pathway that are FDA approved for patients with advanced kidney cancer," Dr. Linehan said.

Cabozantinib Delays Cancer Growth

The new approval of cabozantinib was based on data from an NCI-sponsored randomized phase 2 trial in which 157 patients with metastatic kidney cancer were randomly assigned to receive either cabozantinib or sunitinib (Sutent), a drug commonly used as first-line treatment for advanced RCC. Both drugs are pills taken by mouth.

The trial, called CABOSUN, compared each drug's ability to prevent RCC from worsening, an outcome called progression-free survival. Patients treated with cabozantinib had a median progression-free survival of 8.6 months, compared with 5.3 months for patients taking sunitinib.

Patients taking cabozantinib were also more likely to respond to treatment, with 33% having a partial or complete response compared with 12% for those taking sunitinib. Those taking cabozantinib were also more likely than those taking sunitinib to have stable disease as a best response: 46% versus 42%.

Manageable Side Effects

Almost all patients in the trial experienced side effects and, in about two-thirds of them, those side effects were considered serious. The most common serious side effects experienced by patients treated with cabozantinib included diarrhea, high blood pressure, and hand-foot syndrome. Other side effects included fatigue, nausea, decreased appetite, and painful mouth sores.

There were three treatment-related deaths in each arm of the trial. Dose reductions were more common in patients treated with cabozantinib, but the rate of treatment discontinuation was the same, with about 20% of patients in each arm stopping treatment because of side effects.

Despite the prevalence of adverse events, the side effects of cabozantinib are comparable to other drugs in this class, said Dr. Linehan, "and they are manageable."

That perspective is supported by the recent publication of quality of life results from the phase 3 METEOR trial that formed the basis for cabozantinib's initial approval for RCC in 2016. Patients in that trial experienced a similar quality of life and a longer period before deterioration of quality of life compared to patients treated with everolimus (Afinitor).

Drugs Block Blood Vessel Growth

Cabozantinib and sunitinib are members of a group of drugs called tyrosine kinase inhibitors (TKIs), which block the action of various proteins involved in cell signaling, growth, and division.

Both drugs block a protein called VEGF that promotes angiogenesis, the formation of new blood vessels that feed the growth of tumors. The VEGF gene is part of the genetic pathway activated by the mutated VHL gene that leads to RCC. To date, FDA has approved nine angiogenesis inhibitors for patients with kidney cancer, although not all are TKIs.

"The approval of cabozantinib provides another option for patients and doctors," said Brian Rini, M.D., a kidney cancer expert at the Cleveland Clinic Taussig Cancer Institute.

Although all the drugs block angiogenesis, he pointed out, they are not identical. They may inhibit their targets in different ways, or they may inhibit different molecular targets. All the TKIs approved for RCC inhibit VEGF, but cabozantinib also inhibits several other gene pathways that are important in kidney cancer development.

"There may be good and bad in that," Dr. Rini said. Some drugs may have "better clinical activity for some patients, but there may also be additional toxicity" caused by inhibiting those pathways. "There are good and bad characteristics of each one, so it's always good to have more options," he said.

One benefit of having more options is that it allows doctors to address a common problem with anti-angiogenesis therapy: drug resistance. In most patients, tumors treated with VEGF-targeted agents eventually develop resistance to the drugs, and the disease then progresses.

However, "it's very common for doctors treating patients with advanced kidney cancer to start with one agent and then, if the treatment is no longer benefiting the patient, to switch to another agent or add an agent to the regimen," explained Dr. Linehan.

Combination Therapies: The Future of Kidney Cancer Treatment?

While the approval of cabozantinib adds another TKI to the available options for patients with advanced kidney cancer, combination therapy involving TKIs and other agents is likely to be the future for these patients, according to Dr. Rini.

"There are a lot of trials of drug combinations that are beginning to report results," Dr. Rini said. "We expect this whole landscape is going to change in the next year or so. We won't be giving single TKIs to patients with metastatic RCC as front-line therapy for very long."

Dr. Linehan echoed Dr. Rini's prediction.

"There is a lot of excitement about the potential of combining immunologic agents with these targeted TKIs," he said.

    TKI-Checkpoint Inhibitor Combination Shows Promise in Advanced RCC

    Results from an ongoing early-stage clinical trial suggest that patients with newly diagnosed advanced kidney cancer may benefit from treatments that combine a TKI and immune checkpoint inhibitor. Patients in the trial were treated with axitinib (Inlyta), an angiogenesis-inhibiting TKI, and pembrolizumab (Keytruda), which blocks the checkpoint protein PD-1. Results from the trial-which was sponsored by Pfizer, the maker of axitinib-were presented February 10 at the Genitourinary Cancers Symposium in San Francisco and published simultaneously in The Lancet Oncology.

    At a median follow-up of approximately 20 months, 73% of patients in the study experienced an objective response, meaning their tumors shrank by 30% or more. Four of these patients experienced a complete response. The median progression-free survival was almost 21 months, and patients had not been followed long enough to determine the median overall survival. Nearly two thirds of patients experienced serious side effects and 52% eventually discontinued treatment.

    A randomized phase 3 trial, sponsored by pembrolizumab's manufacturer, Merck, is underway comparing the combination to single-agent sunitinib in previously untreated patients with locally advanced or metastatic RCC.

© 2018 The National Cancer Institute

MD Anderson and RaySearch announce strategic alliance to advance radiation therapy of cancer

MD Anderson Cancer Center -- February 26, 2018

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HOUSTON - The University of Texas MD Anderson Cancer Center and RaySearch Laboratories today announced a strategic alliance with the aim of enhancing cancer radiation therapy through several initiatives, including more precisely targeting of tumors, and improving upon, and making more available, an existing radiation therapy called adaptive radiation therapy (ART), which is currently only used at highly specialized care centers.

Successful radiation therapy depends on the ability to delineate the precise tumor location. Since most radiation treatments are delivered over several weeks, a number of variables can compromise treatment accuracy. Traditionally, additional margins are set around the target area to allow for tumor movement and variations in how patients are positioned during treatment.

However, these margins do not always compensate for unexpected changes in the tumor and surrounding normal tissue over the full course of radiation treatment. ART uses frequent imaging to give an up-to-date assessment of physical changes and enable precisely tailored treatment for each patient.

The alliance builds upon a previously established relationship between RaySearch and MD Anderson centered on RayCare, RaySearch's new oncology information system. This new collaboration combines MD Anderson's clinical data and expertise with the latest technology and platforms available through RaySearch and will focus on the following areas:

  • Integration of advanced imaging into the treatment planning process to help define the tumor targets better.
  • Management of changes in the tumor that may occur during treatment, and monitoring and adjusting treatment to accommodate each patient's individual circumstances at any point during therapy.
  • Building software components with the aim of creating a new standard of care in radiation therapy.

"The technology to perform ART has been around for a number of years and studies have demonstrated its advantages," said Caroline Chung, M.D., assistant professor of Radiation Oncology at MD Anderson. "However, it is a complex process that has not yet been broadly adopted in clinical practice and is largely limited to highly specialized care centers. The goal of this collaboration is to establish a methodology and workflow, clinically tested at MD Anderson, which can be streamlined and automated to enable adaptive radiation therapy on a larger scale."

The combination of advanced imaging data, with platforms such as RayCare and the treatment planning system RayStation, will be vital to improving the delineation of tumors. Together, they provide a novel opportunity for more personalized treatment. The development of digital workflows has the potential to improve patient care at MD Anderson and other cancer care facilities.

"This strategic alliance between MD Anderson and RaySearch is a very significant milestone for RaySearch," said Johan Lof, Ph.D., CEO and founder of RaySearch. "It is one of the most ambitious collaborations that we have ever engaged in. With RayStation and RayCare as the technological platforms, paired with the expertise of MD Anderson, I believe that we can make tremendous progress toward our vision of a world where cancer is conquered."

About RaySearch RaySearch Laboratories AB (publ) is a medical technology company that develops innovative software solutions for improved cancer treatment. RaySearch markets the RayStation treatment planning system to clinics all over the world and distributes products through licensing agreements with leading medical technology companies. The company recently launched the next-generation oncology information system, RayCare*, which comprises a new product area for RaySearch. RaySearch's software is used by over 2,600 clinics in more than 65 countries. The company was founded in 2000 as a spin-off from Karolinska Institute in Stockholm and the share has been listed on Nasdaq Stockholm since 2003. To learn more about RaySearch, go to: www.raysearchlabs.com

* Subject to regulatory clearance in some markets.

© 2018 The University of Texas MD Anderson Cancer Center

Kinase inhibitor larotrectinib shows durable anti-tumor abilities in patients of all ages with 17 unique cancer diagnoses

Tumor mutation studies reported overall response rates of 75 percent and minimal side effects

MD Anderson Cancer Center -- February 21, 2018

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HOUSTON - Three simultaneous safety and efficacy studies of the drug larotrectinib reported an overall response rate of 75 percent for patients ages four months to 76 years with 17 different cancer diagnoses. All patients had tumors with tropomyosin receptor kinase (TRK) fusions, gene mutations that switch on TRK genes, allowing cancer growth. The studies indicate larotrectinib as a potentially powerful new treatment approach for the approximately 5,000 patients with these forms of cancer.

Findings from the multi-center investigation were published in the Feb. 21 online issue of the New England Journal of Medicine (NEJM). Co-principal investigators were David Hong, M.D., professor of Investigational Cancer Therapeutics at The University of Texas MD Anderson Cancer Center, and David Hyman, M.D., chief of Early Drug Development at Memorial Sloan Kettering Cancer Center.

"In this series of studies, larotrectinib had rapid, potent and durable anti-tumor activity in children and adults who had solid tumors with TRK fusions without regard to patient age, tumor tissue and fusion status," said Hong. "Our data not only validated TRK fusions as therapeutic targets, but also showed the potential for larotrectinib as a therapeutic agent for TRK-fusion-positive cancers."

The three protocols included a Phase I study of adults, a Phase I-II study of children, and a Phase II study with adolescents and adults. The investigators followed 55 patients who demonstrated minimal low-grade adverse effects.

Eligible patients had previously been diagnosed with locally advanced or metastatic solid tumors, received standard-of-care therapy and had functioning major organs. The study encompassed 17 unique cancer diagnoses including infantile fibrosarcoma (seven patients); mammary analogue secretory carcinoma of the salivary gland (12 patients); thyroid, colon, lung and gastrointestinal stromal tumors (20 patients); and 16 patients with other cancers.

"TRK fusions defined a unique molecular subgroup of advanced solid tumors in children and adults in whom larotrectinib was highly active," said Hong. "Study results suggest that long-term administration of larotrectinib is feasible for patients with TRK-fusion-positive cancers. However, screening strategies that include assays with the ability to detect TRK fusions will need to be developed to better identify patients who may benefit from this therapy."

Hong added that while clinically meaningful durability of response was observed in study patients, continued follow up could provide further confirmation of the drug's benefit.

Other senior co-authors of the NEJM paper included Alexander Drilon, M.D., Memorial Sloan Kettering Cancer Center, New York, and Theodore Laetsch, M.D., The University of Texas Southwestern Medical Center, Dallas. Funda Meric-Bernstam, M.D., chair of Investigational Cancer Therapeutics at MD Anderson, also participated in the study.

Other study team institutions included Stanford Cancer Center, Palo Alto, Calif.; Children's Hospital of Los Angeles, Keck School of Medicine; and the University of California Los Angeles David Geffen School of Medicine, Los Angeles; Loxo Oncology, South San Francisco, Calif.; Dana-Farber Cancer Institute, and Massachusetts General Hospital, Boston; the Finsen Center, Righospitalet, Copenhagen; the University of Colorado, Aurora; St. Jude Children's Hospital, Memphis, and Vanderbilt University, Nashville, Tenn.; Cincinnati Children's Hospital Medical Center; University Hospitals of Cleveland; Cleveland Clinic's Taussig Cancer Institute; Perelman School of Medicine, Abramson Cancer Center and Fox Chase Cancer Center, Philadelphia; University of Washington-Seattle Cancer Care Alliance; Seattle Children's Hospital' Inova Schar Cancer Institute, Falls Church, Va.; START Madrid, Centro Integral Oncologico Clara Campal, Madrid; Memorial Cancer Institute-Florida International University, Miami; Oregon Health and Science University, Portland; and the West Virginia Cancer Institute, Morgantown, W.Va.

The studies were funded by Loxo Oncology, which developed larotrectinib; the National Institutes of Health (P30 CA008748, P30 CA006927, P30 CA016672, P20 CA046934, and P50 CA058187); the Cancer Prevention and Research Institute of Texas (RP110000584); Alex's Lemonade Stand Foundation Centers of Excellence Award; and the National Center for Advancing Translational Sciences (TR000371 and UL1 TR001881). Hong previously served in an advisory capacity for Loxo Oncology.

© 2018 The University of Texas MD Anderson Cancer Center

Can Oxygen "Microbubbles" Make Radiation Therapy More Effective?

by NCI Staff

The National Cancer Institute -- February 20, 2018

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A new study in mice raises the possibility that microscopic, oxygen-carrying bubbles may help to improve the treatment of breast cancer.

In the NCI-supported study, researchers used these "microbubbles" and ultrasound waves to increase the amount of oxygen within tumors. This treatment, they found, greatly improved the ability of radiation therapy to slow breast tumors growing in the mice. The approach also increased how long the mice lived without their disease progressing compared with mice that did not receive the microscopic bubbles prior to radiation treatment.

The new research was published January 21 in the International Journal of Radiation Oncology*Biology*Physics.

If the approach can be translated to humans, "we could potentially get a lot more 'bang for our buck' with radiation in terms of treating a tumor, without increasing toxicity," said the study's lead investigator, John Eisenbrey, Ph.D., of Thomas Jefferson University.

Supplying Oxygen to Boost Radiation Therapy

Radiation therapy is a mainstay of modern cancer treatment. For example, about half of all women with breast cancer will receive radiation at some point during treatment.

But many tumors are resistant to the cell-killing effects of radiation. Much of this resistance is caused by the low levels of oxygen often found in tumors: oxygen is required for radiation therapy to generate the molecules, called free radicals, that kill cancer cells. When oxygen levels in a tumor are low, radiation therapy is less effective.

For decades, researchers have tested different ways of increasing the amount of oxygen in tumors, said Eric Bernhard, Ph.D., chief of the Radiotherapy Development Branch in NCI's Division of Cancer Treatment and Diagnosis, who was not involved in the study.

These approaches range from putting patients in hyperbaric chambers before radiation therapy to using drugs that increase blood flow or the number of blood cells that carry oxygen, explained Dr. Eisenbrey.

Unfortunately, because the human body is programmed to keep blood oxygen levels steady, these systemic approaches have largely failed, he added. So his team decided to see if microbubbles-constructs the size of red blood cells that are used for medical imaging-could work in a localized, mechanical way to transport oxygen to tumors.

After manufacturing their microbubbles, the researchers first tested whether the bubbles, when triggered by an ultrasound pulse, could drive oxygen into tumor tissue of mice bearing human breast tumors. To do this, the team first injected the microbubbles into the bloodstream. After the bubbles had circulated throughout the body, ultrasound was aimed at the tumors to "pop" the bubbles and drive oxygen into the tumor tissue.

Verifying an Oxygen Boost

The team then used both a mechanical probe and a type of imaging, called photoacoustic imaging, to measure oxygen in tumors before and after microbubble injection and ultrasound.

Using the probe, they found that on average, after the ultrasound pulse, oxygen in tumors increased to a level that would render cells sensitive to radiation, and these levels were maintained for at least 2 minutes.

Photoacoustic imaging showed that transportation of oxygen in the tumors did not rely on a molecule in the bloodstream called hemoglobin. The researchers were not expecting this, Dr. Eisenbrey said. But, he continued, the lack of dependence on hemoglobin transport may explain how the oxygen molecules also reached parts of the tumor not immediately adjacent to the blood vessels carrying the microbubbles.

"Originally, the hypothesis was that we would only be delivering oxygen where there's active blood supply," he said. "But once the oxygen bubbles pop, [the oxygen] actually gets transported out of the blood supply and into the oxygen-depleted parts of the tumor," he added.

Approach Improves Outcomes

Next, the researchers tested whether the microbubble treatment made the tumors more sensitive to radiation therapy. For this analysis, they divided similar tumor-bearing mice into five groups.

One control group received radiation alone. A second control group received the oxygen microbubbles and ultrasound but no radiation therapy. The third control group received the oxygen microbubbles and radiation, but no ultrasound triggering. A final control group received nitrogen-containing microbubbles, ultrasound, and radiation therapy. The experimental group received the oxygen microbubbles and ultrasound plus radiation therapy.

The mice in the experimental group that received all three parts of the treatment had the best outcomes. Though the effect of the oxygen microbubbles varied between animals, on average, it delayed tumor growth by about a month and lowered the rate of growth compared with the four other groups. The mice in the experimental group also lived longer without showing any symptoms of progressing cancer.

Interestingly, the mice that received nitrogen microbubbles followed by radiation showed a slight reduction in tumor growth compared with the other three control groups. Previous studies have shown that the mechanical damage caused by microbubbles popping can, on its own, provide some sensitization to radiation, explained Dr. Eisenbrey.

Moving the Technique into Human Trials

A potential advantage of a microbubble-based approach for improving the response to radiation therapy, said Dr. Eisenbrey, is that many microbubble products have already been approved by the Food and Drug Administration for use in diagnostic imaging. That may make it easier to get approval from the agency to test them as part of cancer therapy in a human trial.

The team has already launched a microbubble trial in people with liver cancer, though this trial is only using the bubbles to cause mechanical damage to cancer cells, not to deliver oxygen.

A few kinks need to be worked out of the oxygen-carrying microbubble approach before it could be tested in people, Dr. Eisenbrey added. These include extending the time oxygen levels are raised in tumor tissue, to match the longer duration needed to deliver radiation therapy in the clinic.

The team would also like to test the system in models of other cancer types, including glioblastoma, liver cancer, and head and neck cancer.

"Combining oxygen-carrying microbubbles with ultrasound-triggered delivery to solid tumors is a novel approach to enhancing tumor oxygenation and sensitivity to radiation, and it deserves further study," concluded Dr. Bernhard.

© 2018 The National Cancer Institute

Melody Management

Cancer Research & APP Development

NIH-funded study shows sorafenib improves progression-free survival for patients with rare sarcomas

by NCI Staff

The National Cancer Institute -- March 28, 2018

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    Interim results from a randomized clinical trial for patients with desmoid tumors or aggressive fibromatosis (DT/DF) show that the drug sorafenib tosylate (Nexavar) extended progression-free survival compared with a placebo. Progression-free survival is the length of time patients lived before their disease worsened. Based on these interim results, the data and safety monitoring board overseeing the trial recommended that the primary results of the study be released.

    The trial was sponsored by the National Cancer Institute (NCI), part of the National Institutes of Health (NIH); designed and conducted by researchers with the Alliance for Clinical Trials in Oncology (Alliance); and supported by Bayer HealthCare AG, which provided the study drug.

    "Sorafenib is a novel way of treating this rare cancer," said lead investigator and study chair Mrinal M. Gounder, M.D., sarcoma medical oncologist at Memorial Sloan Kettering Cancer Center in New York City. "The promising results of this phase 3 trial represent a paradigm shift in the approach to treatment of patients with desmoid tumors."

    DT/DF are rare sarcomas estimated to occur in approximately 1,000 people each year in the United States, many of them relatively young. The sarcomas usually arise in the extremities or the abdomen and occasionally are associated with familial adenomatous polyposis or Gardner Syndrome. DT/DF are locally aggressive and can result in pain and decreased mobility, and they can invade vital organs or structures resulting in bowel obstructions and other serious complications.

    "Currently, there is no standard treatment for this rare disease, and the effectiveness of the treatments that are used for it-for example, surgery, radiation, and chemotherapy-is generally limited," said Jeff Abrams, M.D., clinical director of NCI's Division of Cancer Treatment and Diagnosis. "But the interim results of this trial are promising and may offer a new treatment alternative."

    Sorafenib is a targeted treatment, given in pill form, that interferes with the growth of cancer cells and new blood vessels that tumors need to grow. It is approved by the U.S. Food and Drug Administration for the treatment of some patients with advanced kidney, liver, and thyroid cancer. The drug was chosen for this trial because in earlier retrospective studies of patients treated with sorafenib, desmoid tumors shrank, and patients had a reduction in pain and other symptoms.

    The phase 3 double-blind clinical trial, designated as A091105, enrolled 87 patients with DT/DF between March 2014 and December 2016. To be eligible, patients had to have disease that could not be removed surgically, that had grown, or that was causing symptoms and met specific criteria. Patients were randomly assigned to one of two treatment arms: one group received sorafenib (400 mg/day), and the other received a matched placebo. Patients in both groups continued treatment until their tumors grew or they experienced adverse events from treatment. Patients whose tumors progressed while in the study were informed of their treatment assignment, and those who had been receiving a placebo were allowed to receive sorafenib.

    The primary endpoint was progression-free survival. The trial was designed to target an improvement in median progression-free survival from six months for placebo to 15 months for sorafenib. Based on an interim analysis of the first 75 patients enrolled, the observed improvement in progression-free survival exceeded the trial-design target.

    Patients who received sorafenib were more likely to experience drug-related adverse events than those who received placebo. However, these side effects-which included fatigue, rash, gastrointestinal complications, infection, and hypertension-were generally not severe.

    Full details from this study will be presented at an upcoming scientific meeting and in a peer-reviewed publication.

    Alliance is one of four adult network groups in the NCI National Clinical Trials Network (NCTN). Bayer, the drug's manufacturer, provided sorafenib for the trial and supported this study under a Clinical Trials Agreement with NCI for the clinical development of sorafenib.

    "This trial would not have been done without a large national network of investigators brought together through the NCI-supported NCTN program that was capable of enrolling patients with this very rare cancer," said Dr. Abrams.

    "The success of this study shows how a partnership between Alliance, NCI, and Bayer HealthCare AG was able to provide the infrastructure and scientific knowledge to conduct a transformative trial in this rare tumor in patients across the United States and Canada," added Gary K. Schwartz, M.D., co-chair of the Experimental Therapeutics and Rare Tumor Committee of Alliance and deputy director of the Herbert Irving Comprehensive Cancer Center of Columbia University in New York City.

    "We welcome the potentially practice-changing results from this NCI-sponsored trial in patients with desmoid tumors or aggressive fibromatosis and are looking forward to the full data presentation at an upcoming scientific congress," said Svetlana Kobina, M.D., Ph.D., head of Global Medical Affairs, Oncology, at Bayer.

    According to the data and safety monitoring board's recommendation, treatment assignments have been disclosed to patients still receiving treatment in the study and to their physicians. Patients who were receiving sorafenib in the trial can continue therapy, and those who were receiving placebo can receive sorafenib instead, if warranted, after these patients discuss treatment options with their physicians.

    For more information on the trial: http://clinicaltrials.gov/ct2/show/NCT02066181

    About the National Cancer Institute (NCI): NCI leads the National Cancer Program and NIH's efforts to dramatically reduce the prevalence of cancer and improve the lives of cancer patients and their families, through research into prevention and cancer biology, the development of new interventions, and the training and mentoring of new researchers. For more information about cancer, please visit the NCI website at cancer.gov or call NCI's Contact Center (formerly known as the Cancer Information Service) at 1-800-4-CANCER (1-800-422-6237).

    About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit nih.gov.

    © 2018 The National Cancer Institute

Forging Military Partnerships to Empower the Cancer Research Enterprise

by Norman E. Sharpless, M.D.

The National Cancer Institute -- March 27, 2018

companies img NCI Director Norman Sharpless, M.D. (left), tours the Murtha Cancer Center with the center's director, Colonel Craig Shriver, M.D.

Credit: US Navy / Mass Communication Specialist 2nd Class Kevin V. Cunningham

I'm very proud of the innovative research NCI supports and feel honored to be leading this world-renowned institution. The many partnerships and collaborations in which NCI is involved are an important component of the innovation and success of NCI's efforts. I'm a big believer in partnerships and I intend to facilitate more of them moving forward.

I'm particularly excited about the first partnership I signed since becoming director of NCI, which is with three of our country's military institutions. In fact, one of the first things I displayed in my new office at NCI is an enlarged copy of the memorandum of agreement (MOA).

This MOA-officially known as the Collaborative Efforts Statement, Multi-Federal Cancer Initiative-involves the US Department of Veterans Affairs (VA), the US Department of Defense's (DoD) Walter Reed National Military Medical Center, and the Uniformed Services University of the Health Sciences (USU). Signed on December 1, 2017, the MOA renews a prior agreement with DoD and USU signed by former NCI Director Harold Varmus, M.D., and extends the collaboration to now include the VA.

The partnership has numerous aims, including optimizing resources and expertise, developing and leveraging new technologies, collaborating on clinical trials, accelerating discoveries in cancer research, and increasing education and training opportunities.

The ultimate goal, as always, is to enhance patient care. Under this partnership, in fact, civilian patients with cancer being treated at the NIH Clinical Center can receive certain types of care at the John P. Murtha Cancer Center at Walter Reed, which is just across the road from the NIH campus in Bethesda, MD.

It was this past December, during my first visit to the Murtha Cancer Center, that I had the honor of signing the MOA. I've gone back to visit Walter Reed, the Murtha Cancer Center, and USU since then to learn more about, and view firsthand, the cutting-edge technology and the exceptional work being done on the campus.

With these visits, I can better appreciate the enormous potential of this strategic partnership and the benefits to our mutual scientific, educational, and clinical missions.

companies img An enlarged copy of the memorandum of understanding displayed in the NCI director's office.

Credit: National Cancer Institute

APOLLO Deepens our Understanding of Proteogenomics

One of the major initiatives that exemplifies what the MOA hopes to further is the Applied Proteogenomics OrganizationaL Learning and Outcomes (APOLLO) network, which was established in 2016 as part of the Cancer MoonshotSM.

APOLLO is led by Murtha Cancer Center Director Colonel Craig Shriver, M.D., who brings nearly two decades of experience directing DoD's congressionally mandated Clinical Breast Care Project (CBCP), a military-civilian coalition that provides cutting-edge breast cancer research and clinical care. CBCP, in fact, has amassed one of the world's most extensive human biorepositories of breast tumor and tissue samples.

APOLLO leverages the scientific and technical capabilities and resources of DoD's Murtha Cancer Center and USU's American Genome Center; the VA's Precision Oncology Program and hospital network; and NCI's Clinical Proteomic Tumor Analysis Consortium (CPTAC), The Cancer Imaging Archive (TCIA), and Genomic Data Commons (GDC).

This initiative is an excellent example of how different parts of the federal government can leverage each other's knowledge, resources, and infrastructure. The APOLLO network is bringing together NCI's expertise in both proteomics and genomics and applying it across the VA's and DoD's national health care systems, with the ultimate goal of creating the first nationwide program for systematically integrating proteogenomics into cancer care.

Under this program, tumor and other samples from patients being treated at VA hospitals, the Murtha Cancer Center, and the NIH Clinical Center-veterans, active-duty military, and civilians-will undergo comprehensive proteogenomic analysis. APOLLO initially focused on lung cancer, but it has now expanded to include ovarian, endometrial, prostate, and breast cancers.

Over the course of the 5-year initiative, DoD labs will perform deep molecular characterization of the DNA, RNA, and proteins in samples from 8,000 patients seen at these hospitals. In future phases of APOLLO, this information will be used to match patients to targeted therapies as part of nationwide clinical trials.

NCI's collaboration in this emerging proteogenomics field with the nation's two largest health systems, DoD and VA, is clearly more efficient than if each organization worked in separate silos.

In addition, the patients treated in the VA system and at the Murtha Cancer Center form a large and diverse population. As an example, the DoD active-duty population, in particular, includes a large number of older adolescents and young adults with cancer, a group that has unique challenges and has been underrepresented in cancer clinical trials.

Combining these military patient populations with the NIH Clinical Center patient population should result in more representative and meaningful data. We're hopeful that, ultimately, APOLLO can accelerate the clinical application of newer and more effective precision cancer treatments.

NAVIGATE Brings Clinical Trials to Veterans

NCI is also partnering with the VA on another important effort, the NCI and VA Interagency Group to Accelerate Trials Enrollment (NAVIGATE). The goal of this 3-year initiative is to offer veterans who have been diagnosed with cancer increased access to state-of-the-art care through participation in NCI-supported clinical trials.

As part of NAVIGATE, NCI is providing funding for up to 10 VA medical facilities to directly enroll patients on NCI-supported trials.

NAVIGATE is a win-win initiative. It will make it easier for veterans with cancer to receive the newest treatments and increase their participation in NCI-supported clinical trials. And the increased participation should allow the trials to be completed more quickly and new treatments to become available sooner.

BD-STEP Trains a New Generation of Clinical Data Scientists

Advancements in technology are providing us with more means to collect data. But, are we as a research community ready and able to take on the increasingly mounting data being collected?

In order to take advantage of the information we are amassing, the data must be harmonized, which means ensuring that the systems that store the data and the data speak the same language. And the data must be centralized and accessible to promote sharing and analysis among researchers.

NCI has been developing tools to help make this possible. For example, the GDC brings genomic and clinical datasets together in one virtual location, offering a unified knowledge base that any researcher can access. Much more than a data repository, the GDC also makes available to the broader cancer research community interactive Data Analysis, Visualization, and Exploration (DAVE) tools that can be used to customize the data the researchers wish to study.

But even with these and other new tools, we're still very much in the early stages of understanding how to use big data. I think it's incumbent on NCI to take a lead role in ensuring that the cancer research community understands how to gain insights from these data so that we can take this understanding and apply it to our patients.

That's the impetus for NCI partnering with the VA to launch a pilot training initiative called the Big Data Scientist Training Enhancement Program (BD-STEP).

The goal of BD-STEP is to teach data scientists-who typically have a background in computer science, modeling, statistics, analytics, and math-to use data sets, algorithms, and models for health outcome and patient care research.

As part of BD-STEP, NCI is identifying early-career scientists and engineers from accredited programs in engineering, chemistry, computer science, mathematics, physics, and other relevant disciplines, and placing them in VA medical centers, giving them an opportunity to work closely with VA clinicians.

The hope is to train a new generation of clinical data scientists who can work with the rapidly increasing amounts of data being generated and help to fill gaps in our understanding, with the goal of directly impacting clinical decisions and improving care outcomes. So far, six VA centers are participating in this pilot program and are actively recruiting new fellows.

A Long Tradition of Powerful Partnerships

It's a privilege to help advance cancer research and care that directly benefits American active-duty military and veterans.

But NCI's partnerships with VA, Walter Reed, and USU that are included in the renewed MOA are just one example of a long history of successful interagency partnerships. They are a continuation of successful collaborations the institute has engaged in over the years that emphasize innovation, convergence of scientific disciplines, integration of advanced technologies, and leveraging of resources.

Whether the partnerships are with other US federal agencies, national and foreign institutions, private philanthropic organizations, or industry, our ultimate goal is always to create and foster opportunities that otherwise might not be feasible-all as a means of further accelerating progress and benefiting patients. I'm confident that the partnerships created by this MOA will help to do just that.

© 2018 The National Cancer Institute

Higher Risk of Heart Failure Seen in Some Cancers

by NCI Staff

The National Cancer Institute -- March 26, 2018

companies img Credit: National Cancer Institute/Cancer.gov

Some people who have been treated for breast cancer or lymphoma have a higher risk of developing congestive heart failure than people who haven't had cancer, results from a new study show.

The study researchers retrospectively compared heart failure rates in people who were diagnosed with breast cancer or lymphoma with those in people who did not have cancer. Although the risk of developing heart failure was relatively low overall, people who had been treated for cancer had more than twice the risk of developing heart failure than those who had never had cancer, they found, and the risk was evident as early as one year after their cancer diagnosis. The increased risk persisted for at least 20 years.

"As more cancer patients live longer, they are living long enough to manifest the long-term cardiac effects of cancer treatment," said Lori Minasian, M.D., of NCI's Division of Cancer Prevention, who was not involved in the study. "Increasingly, cardiologists and cardiovascular investigators have seen the need to evaluate the short- and long-term cardiac effects of cancer treatment."

The bottom line, said study investigator Carolyn Larsen, M.D., of the Mayo Clinic, is that people who have been treated for breast cancer or lymphoma and their physicians should be aware of these risks, and patients should be assessed annually for signs of heart failure.

Dr. Larsen presented the study findings at the American College of Cardiology (ACC) Annual Scientific Session on March 10.

Some Cancer Treatments Can Damage the Heart

Congestive heart failure (also referred to as heart failure) is a condition in which weakened or damaged heart muscles are unable to effectively pump blood to the rest of the body. Heart disease, diabetes, and high blood pressure are all risk factors for heart failure, as are some cancer treatments such as chemotherapy, chest radiation, immunotherapy, and some targeted therapies.

To assess the long-term risk of heart failure in people with cancer, Mayo Clinic researchers analyzed data from the Rochester Epidemiology Project. They focused on participants who were diagnosed with breast cancer or lymphoma from 1985 to 2010 and compared them with matched controls-people without cancer who were the same age and sex, and who had similar risk factors for heart disease.

Some people with breast cancer or lymphoma are "treated with therapies that can be toxic to the heart, particularly anthracyclines," explained Dr. Larsen. Among the patients with cancer included in the analysis, nearly all had been treated with chemotherapy and 84% had received an anthracycline.

Within 5 years of their cancer diagnosis, the risk of heart failure was three times higher in people treated for breast cancer or lymphoma than in people without cancer, the researchers found. Within 20 years, 10% of the cancer survivors had developed heart failure, compared with 6% of control subjects.

The risk of heart failure was even higher for certain people with cancer. For example, people who were diagnosed with cancer at age 80 or older had three times the risk of heart failure as those who were diagnosed at a younger age. And heart failure risk was twice as high for survivors who had diabetes compared with those without diabetes.

In addition, they found that the risk of heart failure was two times higher for patients who were treated with doxorubicin (an anthracycline-based chemotherapy drug) compared with patients who received other cancer treatments.

What the Results Mean for People with Cancer

The study findings "add more information about the long-term risk after chemotherapy to the existing knowledge base and provide that data in an epidemiology study rather than a clinical trial-so the findings may be more applicable to a general population of breast cancer and lymphoma patients," Dr. Larsen said.

Many clinical trials exclude patients with heart disease from participating, Dr. Minasian explained. Consequently, data from clinical trials may not reveal the extent to which heart failure risks are increased in those with pre-existing risk factors.

Nevertheless, Dr. Larsen stressed that "not every breast cancer or lymphoma patient is going to develop heart failure."

Overall, 7% of those in the study treated for cancer developed heart failure, compared with approximately 3% of those in the control group. "It's the minority" of people who develop heart failure, she said.

The researchers' main goal, she added, "is to raise awareness of the risk of heart failure and to encourage a heart-healthy lifestyle in cancer survivors." A heart-healthy lifestyle includes healthy eating, managing weight and stress, maintaining physical activity, and quitting smoking.

In addition, breast cancer and lymphoma survivors should be assessed for signs or symptoms of heart failure and for additional risk factors such as high blood pressure, diabetes, and smoking, Dr. Larsen said. Treating or controlling those risk factors may mitigate heart failure risk.

Patients should also "be mindful that the risk of heart failure doesn't end when they finish their cancer treatment," Dr. Minasian added.

Ongoing Cardiotoxicity Research

Researchers are actively investigating approaches to lessen or prevent heart damage from cancer treatments. One trial-sponsored by NCI and the National Heart, Lung, and Blood Institute-is testing the cholesterol-lowering medication atorvastatin for reducing heart damage in women with breast cancer who are receiving anthracycline treatment.

Along the same lines, two studies presented at the ACC conference found that cardiac drugs may protect women with breast cancer from cardiotoxicity of cancer treatment.

In one study, the drugs lisinopril and carvedilol both prevented cardiotoxicity in women with breast cancer who were receiving the targeted therapy trastuzumab and who had been previously treated with anthracycline chemotherapy. In the other study, carvedilol reduced some measures of heart damage in women with breast cancer who were receiving anthracycline chemotherapy.

Organizations such as the ACC are also helping to better educate cardiologists and oncologists about heart failure risk factors in people with cancer "so we're better able to take care of these patients," Dr. Minasian said.

Earlier this year, for example, the American Heart Association published its first-ever statement on breast cancer and heart disease.

In it, the organization stressed the importance of managing cardiac risk factors in older women who have been treated for breast cancer, "because [cardiovascular disease], if not recognized and treated, can pose a greater health risk than the cancer itself."

© 2018 The National Cancer Institute

The Imperative of Addressing Cancer Drug Costs and Value

by Barbara K. Rimer, Dr.P.H.

The National Cancer Institute -- March 15, 2018

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    The President's Cancer Panel is an independent panel that was established under the National Cancer Act of 1971. The panel's charge under the law is to identify high-priority issues that are impeding progress against cancer, engage the relevant stakeholders, and develop recommendations for addressing each respective issue. The recommendations are included in a report that is submitted to the President.

    Barbara K. Rimer, Dr.P.H., dean of the University of North Carolina's Gillings School of Global Public Health, is the panel's chair.

This week, the President's Cancer Panel released its latest report to the White House and the public, Promoting Value, Affordability, and Innovation in Cancer Drug Treatment.

The report recommends six critical actions to maximize the value and affordability of cancer drug treatment and to support investments in science and research that will drive future innovation.

I've been member and chair of the panel since 2011. The topic of drug costs and value was, in many ways, the most challenging we have taken on during my tenure.

As a panel, we began discussing the possibility of focusing our next report on cancer drug prices because it seemed that, everywhere we turned, we heard stories-some heartbreaking-about the impact of the rising cost of cancer care and the escalating costs of cancer drugs.

From 1995 to 2014, in fact, there was a sharp increase in the launch price of new cancer drugs-that is, the cost of a new drug being introduced to the market for the first time. Most cancer drugs launched between 2009 and 2014 were priced at more than $100,000 per patient for one year of treatment. More recently, we've seen launch prices of more than $400,000 for a year of treatment.

As a consequence of these increasing prices, according to one recent analysis, some patients may face out-of-pocket costs of nearly $12,000 a year for one drug.

On one hand, thanks to investments in research on immunology, genomics, and related areas, some of the new cancer drugs that have reached the clinic are truly transformative for some patients, offering the hope of long-term remissions, if not cures, for previously refractory cancers.

On the other hand, many patients fear that these new drugs will be out of reach given their high price tags.

As the panel considered the topic of drug prices, we recognized that the issues are incredibly complex and there are no simple solutions.

In the end, though, we concluded that these issues were so urgent, so high-stakes, and so consistent with our legislatively mandated task of reporting to the President on the barriers to progress against cancer in the United States that we could not ignore the rising price of cancer drugs.

Patients at the Head of the Stakeholder Table

Although the debate around the cost of cancer drugs can often be contentious and seek to place blame, we were determined to approach this topic without any biases and to bring all of the key stakeholders to the table to help inform our recommendations.

We invited participants to several workshops with specific themes, where we discussed and debated important questions about the cost of cancer drugs and cancer care more broadly.

Participants included patients, health care providers, representatives from academia and government (including NCI, the Food and Drug Administration, and the Centers for Medicare and Medicaid Services), leaders from the pharmaceutical and insurance industries, and others.

They all came to these workshops with their own analyses of the problem and their own proposed solutions.

It was essential that patients be at the table. They brought a range of viewpoints and circumstances, and they all shared stories that were poignant and painful.

    Ide Mills introduced herself as a woman who has worn many hats: lung cancer patient, retired pediatric oncology social worker, and caregiver to her mother, whom she lost to lung cancer more than 30 years ago. Ide spoke of the challenges faced by patients who are burdened by financial distress; who routinely have to choose between paying for their medicines or their mortgages; who skip doses of their medications to stretch prescriptions longer, potentially reducing the effectiveness of their treatments.

    Andrew Schorr leads an advocacy organization called Patient Power and is on long-term maintenance therapy to manage two different cancers. As Andrew introduced himself, he held up a tiny white pill that carries a price tag of $10,000 a month. He will have to take this medication, along with others, for the rest of his life. He worries, he told us, about the day his doctor tells him he needs to start taking another high-priced drug.

    Heather Block, who has worked overseas for the State Department and United Nations helping those in need, said that she worries about potential bankruptcy from treatment costs as much as she worries about her metastatic breast cancer. "[This is] the reality of what it's like to live day to day and to stay in treatment forever," Heather told us.

Financial Toxicity: Harmful Side Effects of Cancer Treatment

Those stories are just a sampling of many that we heard. The financial distress caused by the cost of cancer care can cause patients to lose their homes or jobs. For patients, it can affect the livelihood of their families and, often, can leave debt as their legacy long after their deaths.

One patient talked about having to leave her job and move to another city temporarily to undergo a bone marrow transplant. Others talked about family members who have had to stop working to care for them or others.

The negative and often profound impact that cancer treatment costs can have on patients and their families and caregivers has come to be called financial toxicity.

During our workshops, it became clear to the panel that the challenges presented by financial toxicity raise serious questions about who we are as a country: Will we be a society that shares the fruits of our scientific enterprise so that all may benefit, or will innovative therapies be available only to those who can pay?

If drug prices continue on their current trajectory, we concluded, then as a country we will be on the path to making decisions about who will live and who will die.

Report Recommendations: Promoting Cancer Drug Value, Affordability, and Innovation

While the panel found no easy solutions, we did arrive at several key recommendations.

First and foremost, we recommend developing ways to better align drug costs with their value to patients. Some cancer drugs are both highly effective and very expensive. Those drugs can be a good value, and they should be available to all patients who can benefit. Some drugs, on the other hand, provide only small benefits-such as extending life by only days or weeks-and, perhaps, with a diminished quality of life. Those drugs are not a good value.

Of course, perspectives on the value of a given treatment can differ. But the panel concluded that addressing drug costs and financial toxicity will require a concerted and coordinated effort to better define drug value. And those conversations should always keep in mind the people most affected by these deliberations: patients.

We also recommend that patients and their families be offered conversations about the potential costs of treatments, including both the direct (e.g., drugs, surgery) and indirect (e.g., managing side effects, travel) costs. The most appropriate individuals to initiate these discussions, however, remain to be determined.

We also conclude that investments in science are critical to support a robust drug pipeline. Biomedical research is the foundation of innovative drug development, and support for regulatory science and infrastructure is essential to ensure that drugs are efficiently and effectively evaluated.

Promoting healthy competition in the generics and biosimilars markets is another key recommendation. Limiting competition can lead to troubling spikes in prices and drug shortages and even cause some manufacturers to leave markets. A functioning generics market is key to providing patients affordable access to needed drugs.

Role for the Cancer Research Community

Many unanswered questions remain regarding the best ways to prevent, detect, and address financial toxicity among individuals with cancer. In our recommendations, we stress the important opportunity for researchers to close these knowledge gaps.

Ann Geiger, Ph.D., M.P.H., of NCI's Healthcare Delivery Research Program, provided invaluable input as we planned the series of workshops and prepared the report.

Dr. Geiger offered the critical research perspective and highlighted the role that research can play in ensuring that patients have affordable access to high-value drugs.

The panel believes that research is essential to determining how best to equip patients and clinicians with the information and communication skills they need to balance financial considerations with other treatment risks and benefits.

Urgent Action Needed to Ensure Affordable Access to Cancer Drugs

Ide Mills died in April 2017, only months after we met her. Patients like Ide, Andrew, Heather, and countless others don't have the luxury of time to wait for drugs that could extend their lives at prices they can afford.

With this report, we've added a voice to the growing chorus of stakeholders who are deeply concerned that escalating cancer drug prices are straining societal resources, putting clinicians in difficult ethical positions, and risking serious financial distress for patients and their families.

Collaborative efforts to guarantee value in cancer drug treatment, better communication about treatment options and costs, a robust biomedical research enterprise, and a healthy generic drug market will move us closer to the goal of affordable access to high-value cancer drugs for all patients who need them.

Reaching that goal will require us, as a society, to make hard choices.

Summarizing the Research on Financial Toxicity

Financial toxicity has become an increasingly important area of research. The findings from these studies have been captured in NCI's Financial Toxicity and Cancer Treatment (PDQ) summary. The publication describes the growing evidence that cancer patients are at higher risk of financial difficulty than individuals without cancer, and the impact it is having on patients and patient care.

© 2018 The National Cancer Institute

Drug Combination Reduces Number of Colorectal Polyps in Patients with Hereditary Cancer Syndrome

by NCI Staff

The National Cancer Institute -- March 14, 2018

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In a new analysis of a prevention clinical trial, a two-drug combination substantially decreased the number of precancerous colorectal polyps in people with a very high hereditary risk of developing colorectal cancer.

In the trial, people with this hereditary condition-called familial adenomatous polyposis (FAP)-who were randomly assigned to receive the combination of erlotinib (Tarceva) and sulindac (Aflodac) had less than a third the number of polyps after 6 months of treatment than patients who received placebos. The new analysis was published February 8 in JAMA Oncology.

Earlier results from the same randomized clinical trial showed that treatment with these two drugs decreased the number of polyps in the duodenum (the first part of the small intestine) by about 70%. Reduction in duodenal polyps was the primary goal of the trial. However, the researchers had also planned to look at colorectal polyp reduction as a secondary endpoint.

The initial results were "remarkable, as no other drug has shown efficacy in reducing duodenal polyp burden," commented Asad Umar, D.V.M., Ph.D., chief of the Gastrointestinal and Other Cancers Research Group in NCI's Division of Cancer Prevention. "The new analysis shows that the combination has a potential cancer preventive effect on colorectal polyps, as well."

However, Dr. Umar cautioned, whether the two drugs together work dramatically better than either one alone in those with FAP cannot be determined from this trial, since it only tested the combination.

And while the results are exciting, many questions about chemoprevention in people with FAP remain unanswered, explained Jewel Samadder, M.D., of the Mayo Clinic in Phoenix, Arizona, who led the trial.

"But the goal, we hope, is that ultimately we can come up with a chemopreventive regimen that will markedly reduce the risk of cancer in patients with FAP," said Dr. Samadder.

Targeting Aggressive Cell Growth

People with FAP have an inherited mutation in a gene called APC, which normally is involved in suppressing cell growth in the digestive tract. Mutations in APC disrupt its activity, which can lead to the formation of hundreds to thousands of polyps during a person's lifetime.

People with FAP have a nearly 100% risk that such polyps will progress to colorectal cancer, and up to 12% of FAP patients also develop duodenal cancer.

Consequently, people with FAP undergo regular endoscopic monitoring and polyp removal. But when the number of polyps in the colon and rectum becomes too great to control in this way, they typically have a colectomy-the removal of all or part of the colon. Although this procedure almost completely reduces the risk of colorectal cancer, it can have a dramatic effect on a person's quality of life, explained Dr. Samadder.

In addition, duodenal cancer is much harder to prevent or treat surgically, he continued, which is why the main goal of the trial was to see if the two-drug combination reduced the burden of duodenal polyps in patients with FAP.

Much has been learned about how APC mutations lead to the development of gastrointestinal polyps. Two of the proteins involved in this process, EGFR and COX2, can be blocked with existing drugs, and researchers have long suggested that combining drugs that target both proteins might reduce polyp formation.

In the current trial, erlotinib-an EGFR inhibitor that is already used to treat lung and pancreatic cancer-was combined with sulindac, which targets COX2.

Major Reduction in Polyp Number

The trial enrolled 92 people with FAP beginning in 2010. The participants were randomly assigned to receive daily treatment with either erlotinib and sulindac pills or two identical-looking placebo pills. The number of polyps in both the duodenum and colorectum were measured using endoscopy before and after 6 months of treatment.

After the first 67 participants had finished 6 months of treatment, the trial's Data and Safety Monitoring Board recommended stopping enrollment, due to the dramatic reduction in duodenal polyps seen in the patients who had received erlotinib and sulindac.

During follow-up, patients who had received 6 months of erlotinib and sulindac also experienced a net drop of approximately 70% in the number of colorectal polyps from the start of the study, compared with the placebo group.

This effect was observed even though almost three-quarters of the patients given the two drugs had to have their dose of erlotinib reduced because of side effects, most often a painful rash. About half of participants receiving the two drugs also had a reduction in sulindac dose, for side effects including nausea and diarrhea.

There was no correlation between the total amount of either drug taken and the reduction in colorectal polyp burden-which, the trial leaders believe, suggests that the doses chosen were more than enough to interfere with the harmful molecular signaling in patients with FAP.

Future Questions

Unanswered questions about using such a drug regimen widely in people with FAP include whether it can reduce the number of duodenal and colorectal polyps long-term, as well as reduce the risk of polyps progressing to cancer. The researchers would also like to know if the drugs can reduce the need for colectomy in people with FAP, said Dr. Samadder.

In addition, they want to explore whether chemopreventive drugs for duodenal or colorectal cancer have to be taken continuously, or whether they could be taken intermittently to reduce the side effect and cost burden on patients.

And if preventive drugs need to be taken for a long period of time, the types and amount of the drugs would likely have to be tweaked, Dr. Samadder explained, because some people cannot tolerate the side effects of erlotinib. The research team is currently enrolling patients into a new trial that is looking at whether a reduced dose of erlotinib alone, given less often, would be as effective but less toxic than the combination used in this trial.

"We're not treating cancer, we're trying to prevent it, so you need to have a drug [regimen] that's highly tolerable," said Dr. Samadder.

It would also be interesting to test lower doses of both drugs in combination, commented Jason Zell, D.O., from the University of California, Irvine, who is working on a different clinical trial of colorectal cancer chemoprevention.

"If there is a lower effective dose of erlotinib that would work synergistically with sulindac in this population and would give similar efficacy results, that would be outstanding," he commented.

    Preventing High-Risk Adenomas and Second Cancers in Colorectal Cancer Survivors

    There is growing interest in testing drugs to prevent the development of high-risk precancers (called adenomas) or a second primary colorectal cancer in people who have already been treated for the disease.

    People who have been treated successfully for colorectal cancer are at higher risk of developing adenomas or a new colorectal cancer than the general population. But because their risk is much lower than that of people with FAP, a chemoprevention regimen would have to come with very few side effects to have any appeal, explained Dr. Zell, who is leading a chemoprevention clinical trial in colorectal cancer survivors called PACES.

    That trial, sponsored by NCI's Division of Cancer Prevention and open at more than 500 hospitals across the country, is enrolling patients who have been treated within the previous year for localized colorectal cancer. Participants are being randomly assigned to one of four groups: a combination of sulindac and eflornithine; sulindac plus a placebo; eflornithine plus a placebo; or two placebos.

    Eflornithine inhibits the activity of a class of enzymes known as polyamines, which may promote cancer formation in the colon and rectum, explained Dr. Zell. Sulindac, in addition to targeting COX2, also inhibits polyamine activity. Participants will take their pills for 3 years and be followed by the researchers for a total of 8 years. The hope is that one or both drugs will reduce the risk of adenomas and second primary colorectal cancers by about half during that time, Dr. Zell said.

© 2018 The National Cancer Institute

Drug May Help Prevent Resistance to Toxin-Based Leukemia Therapy

by NCI Staff

The National Cancer Institute -- March 12, 2018

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Previous clinical studies have suggested that an experimental cancer drug that includes a bacterial toxin may hold promise for treating the most common cancer in children, B-cell acute lymphoblastic leukemia (ALL). But the benefits of the therapy, which was developed at NCI, were limited because patients quickly developed resistance to the drug.

Now a new study has identified a possible strategy for improving the efficacy of this drug, moxetumomab pasudotox, or Moxe, in patients with relapsed and chemotherapy-resistant (refractory) ALL.

In the new study, NCI researchers and their colleagues showed that, in mouse models of this cancer, combining the drug 5-azacytadine (azacitidine or AZA)-which is already used to treat some types of blood cancer-with Moxe helped overcome resistance to the toxin-based therapy.

The findings suggest that AZA might improve the responses to Moxe in children with ALL, said the study's lead investigator Ira Pastan, M.D., of NCI's Center for Cancer Research.

The new findings were published February 20 in Proceedings of the National Academy of Sciences.

The study provides evidence to support a clinical trial of this drug combination in patients with leukemia, said Andrew Lane, M.D., Ph.D., of Dana-Farber Cancer Institute, a leukemia researcher who was not involved in the study.

Targeting Cell Surface Molecules to Treat Leukemia

Moxe (pronounced moxie) has shown promise for treating adults with hairy cell leukemia who have received at least two prior lines of therapy. A pivotal phase 3 single-arm trial of Moxe to treat adult patients with relapsed/refractory hairy cell leukemia who have had at least two prior lines of therapy met its primary endpoint (durable complete response).

Relapsed and chemotherapy-resistant childhood ALL is relatively uncommon, but when the cancer does come back it is difficult to treat. In addition, the current initial, or first-line, treatments for childhood ALL have serious side effects. So, researchers have been working to develop treatments that are more targeted and less toxic. One potential target is CD22, a molecule that is often found on the surface of tumor cells in ALL and that Moxe binds to.

"Targeting cell surface molecules that are found at unusually high levels in acute leukemias is considered an important addition to standard chemotherapy," said ALL researcher Marina Konopleva, M.D., Ph.D., of the University of Texas MD Anderson Cancer Center, who was not involved in the new study. And Moxe is just one of many such treatments being developed, Dr. Konopleva noted.

Moxe is an immunotoxin that consists of two fused components: a piece of an antibody that targets CD22, and a piece of a toxin from Pseudomonas bacteria. Moxe kills cancer cells by binding to CD22, entering the cell, and releasing the toxin, which blocks the cell's ability to make proteins.

In a previous early-stage clinical trial of Moxe in younger patients with ALL that had relapsed after initial treatment or was resistant to chemotherapy, only about one-third of patients had a reduction in the extent of their disease. And among those who initially responded to Moxe, their cancer soon became resistant to the treatment and their cancer returned, Dr. Pastan said.

Moxe is one of several microbial toxin fusion drugs under development that have shown promise, Dr. Lane said, "so it is critical to understand more about why they work or don't work in certain cancer cells."

Studying How Resistance Develops and How to Overcome It

Previous studies by Dr. Pastan's team identified the mechanism of Moxe resistance in lab-grown human ALL cell lines and showed that AZA can prevent or partially reverse that resistance.

For their new study, the researchers developed a mouse model for studying Moxe resistance in ALL, which they speculated would more closely resemble resistance in patients. They showed that immune-deficient mice injected with human ALL cell lines developed leukemia in the blood and bone marrow. The mice initially responded to Moxe but they quickly became resistant, Dr. Pastan said.

The Moxe-resistant cells, the researchers found, survived in distinct locations in the animals' bone marrow and then spread to other parts of the body. The resistant cells had reduced levels of CD22, Moxe's cell-surface target. They could no longer grow in the lab and contained major gene expression and chromosome changes.

The finding that CD22 levels are lower in Moxe-resistant cells "is interesting because in other leukemias where there are targeted therapies [that have] targets like CD22, what we've seen in patients is that...equently at the time of relapse the patients' tumor cells lose the target," Dr. Lane said.

Dr. Pastan's team showed that mice pretreated with AZA had greatly improved responses to Moxe. In one mouse model, AZA prevented resistance to Moxe from developing and the regimen completely eradicated the leukemia.

Identifying a drug "that prevents resistance so efficiently" in an animal model is "pretty amazing," Dr. Pastan said.

In the second mouse model, created with a different human ALL cell line, AZA delayed Moxe resistance and prolonged survival.

But how AZA might work to overcome resistance in the mice remains unclear, Dr. Konopleva said.

Clinical Trials Needed to Follow Up on Mouse Studies

"AZA is commonly combined with other novel agents in clinical trials in leukemia because it's well tolerated," said Dr. Lane. He is leading an early-stage clinical trial of AZA and another toxin fusion drug, DT(388)IL3 fusion protein SL-401, in patients with relapsed or refractory acute myeloid leukemia (AML).

That trial resulted from findings Dr. Lane and his colleagues reported at a conference late last year, which showed that, AZA reversed resistance to SL-401 in several different AML cell lines.

Dr. Konopleva said that, ideally, animal studies of cancer drug resistance should be done using patient-derived xenografts-tumor tissues from patients that are implanted into mice-rather than with lab-grown cancer cell lines. Dr. Lane agreed, although he said such studies can be difficult to do depending on the cancer type.

"We have leukemia patients who are in desperate need of new therapies," he continued. "When you have two drugs that have been shown to be safe in people, and then they show some additive effects in a [lab] dish and in a mouse model, you might want to move to clinical trials before knowing whether the lab model is perfect."

MedImmune, a subsidiary of AstraZeneca, licensed Moxe from NCI and has worked with NCI's Cancer Therapy Evaluation Program to further clinical development of the drug. The company has not said whether it will pursue clinical trials of the combination of Moxe and AZA.

Dr. Pastan said that Moxe alone or combined with other therapies could eventually be considered as a first-line treatment for hairy cell leukemia and possibly other cancers that have high CD22 levels. But the drug first must be shown to be safe and effective in patients whose cancer does not respond to standard therapies, he said.

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Gemtuzumab Receives New FDA Approval for Acute Myeloid Leukemia

© 2018 The National Cancer Institute

Targeted Therapy Larotrectinib Shows Promise in Early Trials, Regardless of Cancer Type

by NCI Staff

The National Cancer Institute -- March 9, 2018

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Initial results from a series of three small clinical trials of a targeted cancer therapy called larotrectinib suggest that it may be effective in patients-children and adults-with a wide variety of cancer types.

The drug disrupts the activity of TRK proteins caused by an alteration, known as a fusion, in a family of genes known as NTRK. In all three trials, larotrectinib treatment shrank tumors in many patients whose tumor cells overexpressed TRK fusion proteins.

And larotrectinib appeared to largely be safe, with little evidence thus far from the trials that it causes any serious side effects.

The trials were supported by Loxo Oncology (which developed larotrectinib), NCI and other NIH institutes, and several nonprofit groups.

Overall, among patients with the NTRK alterations who were treated in the trials, 75% experienced reductions in the size of their tumors (partial response) or their tumors stopped growing, the trials investigators reported February 22 in the New England Journal of Medicine (NEJM).

In seven patients, cancer was no longer detectable following treatment (complete response). And in a few patients, including several children with a rare form of sarcoma, tumors shrank enough that the patients were able to undergo surgery that could be potentially curative.

Although targeted therapies are now broadly used to treat cancer, most targeted agents are typically only effective in patients with one or two cancer types, said Alexander Drilon, M.D., a principal investigator of this trial at Memorial Sloan Kettering Cancer Center. With larotrectinib, that cancer type specificity isn't seen.

"Where the cancer originates doesn't seem to matter," Dr. Drilon said. As long as the patient's tumor has the appropriate molecular alteration, he continued, "there's a good chance it will respond."

Based on these early results, Loxo has already begun the process of applying for Food and Drug Administration approval of larotrectinib.

A Rare, But Shared, Alteration

There are three different NTRK genes, which code for TRK proteins (pronounced "track" or "trek"). Although they are active in-nervous system tissues in adults-having roles in areas like pain perception, memory, and appetite-TRK proteins' most critical role is promoting brain and nervous system development in embryos.

But NTRK genes also are prone to rearrangements-that is, swapping segments with other genes-creating fusion genes. These NTRK fusion genes, in turn, can produce TRK fusion proteins that can fuel the development and growth of tumor cells. In fact, tumor cells can become almost solely reliant on, or "addicted" to, the growth signals produced by TRK fusion proteins.

Only about 1% of solid cancers have NTRK fusions, according to current estimates. However, unlike some other genetic alterations that are targeted by cancer therapies, NTRK fusions are found in many different types of tumors, Dr. Drilon explained.

The trials included in the NEJM report, for example, included patients with 17 unique cancer types with NTRK fusions (including 5 types of sarcoma), and treatment responses were seen in patients with 13 of those 17 types.

But NTRK fusions seem to be most common in several rare cancer types, Dr. Drilon noted, including infantile fibrosarcoma and several other types of sarcoma, secretory breast carcinoma, and other cancers like papillary thyroid cancer to a lesser extent.

As more patients; tumors are tested, NTRK fusions will likely be found in an even larger number of cancer types, said Nita Seibel, M.D., head of Pediatric Solid Tumor Therapeutics in NCI's Cancer Therapy Evaluation Program.

Dr. Seibel pointed to the cases of other cancer-causing fusion genes like BCR-ABL and those involving the ALK gene, both of which were initially identified in a single cancer (chronic myelogenous leukemia and non-small cell lung cancer, respectively) and were successfully treated with a new targeted therapy. Both alterations were later found in one or two other cancer types and could be treated effectively with the targeted drug.

"That is why it will be important to screen many different types of tumors in large precision medicine studies such as the NCI-COG Pediatric MATCH trial," she continued. (See "Testing Larotrectinib in NCI-MATCH and Pediatric MATCH.")

So Far, Long-Lasting Responses

Most of the patients with NTRK fusions who responded to larotrectinib in the three trials had partial responses. In addition to the seven complete responses, seven other trial participants had stable disease, which is defined as no substantial reduction in tumor size, but no progression either.

Several children in the initial patient group had infantile fibrosarcoma, which, when it reaches more advanced stages, often requires limb amputations to treat the cancer. In two of the children, larotrectinib shrank their tumors enough that they were able to undergo surgery to remove the remaining tumor without the need for amputation; at the time of patient follow-up, there was no evidence that either child's cancer had returned.

Overall, at a median follow-up of approximately 9 months, 86% of the patients in the trial who responded to larotrectinib continued to receive the daily treatment or "had undergone surgery that was intended to be curative," the research team reported. In fact, the very first patient with an NTRK fusion to be treated with the drug was still taking it more than 2 years later.

Thus far, larotrectinib appears to be safe. No patients in the initial treatment groups had to stop treatment because of side effects, and only a handful had to have the dose of the drug reduced.

Among the more common side effects were anemia and elevated levels of enzymes that can indicate potential liver damage. None of the side effects seen in the initial patient group were clinically significant, the research team reported.

Dr. Drilon attributes larotrectinib's apparent safety to its design.

"It's a really clean drug. It only targets TRK [fusion proteins], so it has few of the off-target side effects" seen with some other targeted therapies, he said. "That's really important because it means patients can potentially take [larotrectinib] for a prolonged period of time."

Despite these initially promising results, some researchers voiced caution, noting the importance of seeing how the drug performs in a larger group of patients.

These early trials, said Margaret von Mehren, M.D., who heads the Division of Sarcoma Medical Oncology at Fox Chase Cancer Center, "may include a somewhat selected group of patients who...may have biologically less aggressive disease."

But even with the limited patient experience with larotrectinib, Dr. von Mehren continued, the results with the drug to date "reinforce the concept of targeted therapy and the benefits you can see when you target a tumor that is driven by a defined biologic process."

A "Practice-Changing" Opportunity in Some Childhood Cancers?

One of the three trials in the NEJM report, called SCOUT, enrolled only children (Loxo developed a liquid formulation of larotrectinib for use in children and older patients who can't take pills). Updated results from 17 patients in this trial were presented in December 2017 at the AACR Special Conference on Pediatric Cancer Research.

All but one of those 17 patients responded to larotrectinib, including several who had complete responses. One of the complete responses occurred in a child with glioblastoma, a highly fatal type of brain cancer. At the last follow-up point, many of the tumor responses were ongoing, including several that had lasted for more than a year.

The high response rates to larotrectinib, combined with the long duration of those responses, suggest that the drug is "likely to be practice changing" for children whose tumors have NTRK fusions, a lead investigator on the SCOUT trial, Brian Turpin, D.O., of the University of Cincinnati Children's Hospital Medical Center, said in a Loxo news release.

The experience with larotrectinib "speaks to one of the reasons for performing molecular profiling of patients' tumors-particularly for rare cancers, where you know these translocations can occur," Dr. von Mehren said. "Even in a small percentage of patients, you can have a significant impact with the right targeted therapy."

Larotrectinib's development can be a model for the development of other new targeted therapies, Dr. Drilon said. "I think there are other targets that we haven't completely explored yet that can work across many different types of cancer."

Testing Larotrectinib in NCI-MATCH and Pediatric MATCH

    Two NCI-supported clinical trials, NCI-MATCH and NCI-COG Pediatric MATCH, are enrolling patients regardless of their cancer type. In these studies, known as basket trials, participants are assigned to treatment based on the genetic alterations in their tumors. Larotrectinib is being studied in both trials.

    "Larotrectinib was the first drug we identified to be brought into Pediatric MATCH," Dr. Seibel explained, and Loxo was "very supportive" of having the drug be part of the study. The way in which larotrectinib has been developed has helped to accelerate its potential use in children with cancer. For example, she said, Loxo developed a pediatric formulation of the drug, identified an appropriate dose for children at the same time as they did for adults, "and started testing it very quickly in pediatric patients."

    NCI hopes to have discussions with the company about incorporating LOXO-195 into Pediatric MATCH, she added.

Next-Generation TRK Inhibitor Not Far Behind

Cancer returned in 10 of the 42 patients in these first three trials who initially responded to larotrectinib. When the research team analyzed tumor and plasma samples from these patients, the found that they had developed additional NTRK mutations that affect the drug's ability to bind to TRK fusion proteins.

Based on prior research, however, Loxo has already developed a second-generation drug that can work in tumors with these mutations.

Called Loxo-195, the drug is already being tested in a small clinical trial involving patients previously treated with a TRK-targeted drug but whose disease later progressed.

© 2018 The National Cancer Institute

FDA Approves Apalutamide for Some Men with Prostate Cancer

by NCI Staff

The National Cancer Institute -- March 8, 2018

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On February 14, the Food and Drug Administration (FDA) approved apalutamide (Erleada) for men with prostate cancer that has not spread (nonmetastatic) and is resistant to standard hormone therapy, also called androgen deprivation therapy (ADT).

Treatment with apalutamide decreased the risk of metastasis or death by more than 70% compared with placebo, the trial that led to the approval showed.

"These are very dramatic results and, in many ways, exceeded our expectations," said lead investigator Matthew Smith, M.D., Ph.D., of Massachusetts General Hospital Cancer Center. The treatment "will be an important option" for men with prostate cancer in this setting, he added.

"We're learning that using hormone therapy earlier in men with prostate cancer can delay metastasis and probably improve survival. But the balance of benefits and potential side effects will need to be evaluated on a patient-by-patient basis," said William Dahut, M.D., head of the Prostate Cancer Clinical Research Section of NCI's Center for Cancer Research.

A New Option After Hormone Therapy Resistance

Men with prostate cancer that has not spread may be treated with ADT. These treatments block the body's production and use of male sex hormones (known as androgens) that drive prostate cancer growth. But most prostate cancers eventually become castration resistant, meaning the tumor begins to grow again despite androgen deprivation.

In the past, men with nonmetastatic castration-resistant prostate cancer continued ADT and were carefully observed for signs that the cancer had spread, at which point they could receive therapies for metastatic prostate cancer.

"The prevention of metastases represents an important unmet medical need," trial co-investigator Eric Small, M.D., of the University of California, San Francisco, said at the 2018 Genitourinary Cancers Symposium.

In an earlier phase 2 trial funded by NCI, Dr. Smith and his colleagues found that apalutamide had anticancer activity against castration-resistant prostate cancer. Apalutamide prevents androgens from binding to androgen receptors on cells and triggering cell growth.

In the phase 3 trial (dubbed SPARTAN) that led to the FDA approval, men with castration-resistant prostate cancer and no metastatic disease detectable by standard imaging tests were randomly assigned to receive apalutamide or placebo in addition to ongoing ADT. All participants were at high risk of metastasis based on rapidly rising prostate specific antigen (PSA) levels. The study was sponsored by Janssen Pharmaceutical Companies, the manufacturer of apalutamide.

The median length of time from the start of treatment to when tumors spread or the patient died (metastasis-free survival) was 16 months in the placebo group and 40 months in the apalutamide group. Men treated with apalutamide also went longer without worsening symptoms of cancer progression. Even when their cancer progressed on apalutamide and they went on to receive another therapy, these men had longer time to progression with the subsequent treatment than men in the placebo group.

The median length of time patients were alive after the start of treatment (overall survival) was 39 months for those who received placebo and had not been reached at the time of the study analysis for those who received apalutamide. An early analysis suggests that apalutamide may reduce the risk of death from prostate cancer, but longer patient follow-up is needed before the researchers can confirm this.

More patients in the apalutamide group than the placebo group had weight loss, fatigue, rash, falls, and bone fractures. In the apalutamide group, approximately 11% of patients discontinued treatment due to side effects, compared with 7% in the placebo group. Serious side effects were associated with the death of 1 subject in the placebo group and 10 subjects in the apalutamide group.

The researchers found no differences in quality-of-life scores reported by participants between the groups, and the scores did not get worse during treatment.

Apalutamide is the first drug to be approved by FDA based on an improvement in metastasis-free survival. Traditionally, most approvals are based on an improvement in progression-free survival or overall survival.

"This new precedent for FDA approval may permit drugs to reach the clinic more quickly," Dr. Dahut explained.

Another Potential Option for Prostate Cancer

Results from a separate clinical trial that was also reported at the 2018 Genitourinary Cancers Symposium suggest that there may soon be another potential treatment option for men with nonmetastatic castration-resistant prostate cancer.

The PROSPER trial showed that enzalutamide (Xtandi), a hormone therapy that also counteracts castration resistance, reduced the risk of metastasis or death by 71% compared with placebo. Compared with placebo, enzalutamide delayed the median time before study subjects needed a different treatment because their cancer had gotten worse (18 months versus 40 months). At the time of analysis, patients were not followed long enough for the investigators to determine the median overall survival.

Enzalutamide caused side effects in a greater percentage of patients than did placebo (87% versus 77%). The most common serious side effects of enzalutamide were high blood pressure, fatigue, and blood in the urine. After the study treatment was completed, 32 patients who received enzalutamide died of unknown causes, compared with 4 patients who received placebo.

Enzalutamide is FDA-approved to treat metastatic castration-resistant prostate cancer but it is not currently approved to treat men with nonmetastatic castration-resistant prostate cancer.

Considering results from the SPARTAN and PROSPER trials, it is evident that "using these more intense hormonal therapies earlier can definitely prevent the development of metastasis," Dr. Dahut said.

"But treating asymptomatic patients carries a certain burden of proof wherein benefit must clearly outweigh risk," Philip Kantoff, M.D., of Memorial Sloan Kettering Cancer Center, noted in a discussion of the two trials at the symposium.

It is not clear whether longer metastasis-free survival translates to benefits such as fewer symptoms or longer overall survival in these men, Dr. Kantoff explained. While it seems that both apalutamide and enzalutamide may ultimately prolong overall survival, there is not yet enough data to know for sure. "To me the clinical benefit is not yet fully determined in both studies," he concluded.

New Imaging Techniques May Change Diagnoses

While apalutamide-and, potentially, enzalutamide-gives men with nonmetastatic castration resistant disease a new treatment option, this patient population may decrease in the future, Dr. Dahut noted. That's because traditional imaging techniques such as a CAT scan may not be able to detect tiny metastatic tumors, he explained. But a technique being used in research studies called molecular imaging can catch smaller tumors. If molecular imaging tests become part of clinical care, more men with prostate cancer might be classified as having metastatic disease.

"It's highly likely that apalutamide would be active" in men with metastatic castration-resistant prostate cancer, Dr. Dahut speculated. Trials to evaluate apalutamide in this patient population are already underway, Dr. Smith noted.

© 2018 The National Cancer Institute

MD Anderson and Berkeley Lights launch Optera Therapeutics to accelerate development of cell therapies for cancer

MD Anderson Cancer Center -- March 7, 2018

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HOUSTON and EMERYVILLE, Calif. - The University of Texas MD Anderson Cancer Center and Berkeley Lights, Inc. today announced the launch of Optera Therapeutics Corp, a biopharmaceutical company developing cell therapies with scalable manufacturing solutions for cancer.

Cell-based immunotherapies where patients are treated with their own immune cells, such as chimeric antigen receptors (CAR-T), T-cell receptors (TCR) engineered T cells, tumor-infiltrating lymphocytes (TIL) and endogenous T cells (ETC), have demonstrated promise for treating cancer. Optera Therapeutics will develop cancer cell therapies discovered at MD Anderson and apply Berkeley Lights' advanced cell therapy manufacturing systems with the goal of making these novel therapies accessible to all.

"MD Anderson is dedicated to improving the standard of care for our patients as we strive to realize our mission to end cancer," said Patrick Hwu, M.D., division head of Cancer Medicine. "Our hope is that - by combining our cell therapy research expertise with advanced automation capabilities - we will enhance our ability to deliver these treatments to every patient who needs them."

Optera Therapeutics is developing cell therapies under investigation at MD Anderson by leaders in the field of cellular immunology including Cassian Yee, M.D., professor of Melanoma Medical Oncology; Katy Rezvani, M.D., Ph.D., and Elizabeth Shpall, M.D., both professors of Stem Cell Transplantation and Cellular Therapy; Chantale Bernatchez, Ph.D., assistant professor of Melanoma Medical Oncology; Sattva Neelapu, M.D., professor of Lymphoma and Myeloma; and Greg Lizee, Ph.D., associate professor, of Melanoma Medical Oncology.

"Cell therapy is transforming the standard of care for cancer patients" said Yee. "Optera will capitalize on truly disruptive technology and allow us to extend our ability to treat more patients, for more cancers, in a shorter period of time."

Eric Hobbs, chief executive officer of Berkeley Lights, Inc., added, "the Berkeley Lights team is privileged and excited to join forces with our colleagues at MD Anderson who have devoted their lives to defeating cancer. We are absolutely driven to make their life-saving cell therapies accessible to all."

About Berkeley Lights:
Berkeley Lights is a digital cell biology company that develops and commercializes platforms for the acceleration of discovery, development, and delivery of cell based products and therapies. At the intersection of biology, technology and information, our platforms automate the manipulation, analysis and selection of individual cells, creating ultimate scalability and deep cell insights. The Beacon platform* is ideally suited for cell line development, antibody discovery (including direct B-cell workflows), gene editing, and antibody engineering workflows. Each workflow provides a100 fold increase in insights, 10 times faster, at a fraction of the cost. * For Research Use Only. Not for use in diagnostic procedures.

© 2018 The University of Texas MD Anderson Cancer Center

Testing an Interactive Approach to Promote Exercise in Young Cancer Survivors

by NCI Staff

The National Cancer Institute -- March 6, 2018

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An interactive website designed to promote physical activity among children and adolescents who have completed treatment for cancer may indeed help encourage them to get regular exercise, according to preliminary results from a pilot study.

The study tested an intervention that used an interactive website, wearable activity monitors, and small rewards to help kids become active after treatment for cancer.

"It's really important for young cancer survivors to be physically active," said Carrie Howell, Ph.D., of St. Jude Children's Research Hospital, who presented the study results on February 16 at the 2018 Cancer Survivorship Symposium in Orlando, Florida.

Studies have shown that survivors of childhood cancer are at an increased risk of obesity and other health problems that can occur months or years after treatment, explained Dr. Howell.

The pilot study included 78 cancer survivors between the ages of 11 and 15 who were no longer being treated for cancer and who had been getting less than 60 minutes of physical activity a day before enrolling in the 24-week study.

"The underlying premise of the study was to make the physical activity a game," said Dr. Howell. Participants in the intervention group had access to the interactive website and could earn small rewards, such as t-shirts and $5 gift cards, for reaching certain benchmarks of activity as measured by the wearable devices. Participants in the control group received the wearable activity monitors and educational materials about the benefits of physical activity.

For participants in the intervention group, the amount of moderate to vigorous physical activity increased by an average of nearly 5 minutes a week over the course of the study, whereas for participants in the control group it decreased by an average of more than 24 minutes a week.

In addition, patients in the intervention group but not the control group showed improvements in neurocognitive abilities and health-related quality of life.

Testing Ways to Reduce Obesity Risk

This study is a reminder "that we may need to be creative" in finding ways to motivate young survivors of childhood cancers to be physically active, said Timothy Gilligan, M.D., of the Cleveland Clinic, who moderated a press briefing on the study before the symposium.

Based on the pilot study, the researchers have launched a phase 3 randomized clinical trial, which is sponsored by NCI. It will test a similar intervention in children and adolescents who have completed treatment for acute lymphoblastic leukemia (ALL), which is the most common childhood cancer.

"Exercise is associated with every positive health outcome, including a stronger heart, stronger lungs, and being happier," said study coauthor Kirsten K. Ness, Ph.D., of St. Jude. But developing the habit of regular exercise "is hard, even for people who don't have a history of childhood cancer," she added.

In the pilot study, the control group steadily decreased their physical activity, which, unfortunately, is consistent with research on middle schoolers in general, noted Dr. Howell.

"That's why testing the intervention on this age group is so important," she said.

Larger Trial: Can Interaction Improve the Fitness of Younger Survivors?

The phase 3 trial, which is enrolling participants at more than 20 Children's Oncology Group sites around the country, is asking whether an interactive approach can not only cause children and adolescents who have just completed treatment for cancer to be more physically active but also improve their fitness.

The researchers aim to enroll 384 participants, and the intervention will last a year, with follow-up at 18 months.The researchers aim to enroll 384 participants, and the intervention will last a year, with follow-up at 18 months.

"We learned a lot in the pilot," said Dr. Ness. "The successful aspects of that study have been moved into the phase 3 trial, such as the interactive website and the small rewards."

Because the pilot study demonstrated that the interactive website could increase physical activity, the researchers decided to make it a standard feature of the larger trial. The study's control group will have access to a limited version of the website, which includes basic information about a participant's activity, for 6 months.

All participants will receive educational handouts about physical activity and be encouraged to increase physical activity to at least 7 hours per week. Participants will also wear an activity monitor daily and upload data at least once a week to an interactive website.

The intervention group will have access to the full version of the interactive website, where they can see their activity, earn activity points, see the activity of other players, and interact with other players for 6 months.

For example, players can send each other prewritten electronic messages of encouragement such as, "You're doing great!"

"We want to see if support from peers makes the intervention even better," said Dr. Ness.

Cancer Survivors "Taking Ownership" of Their Physical Activity

During the pilot study, some parents told the investigators that their children were taking ownership of their health and fitness for the first time, because "they now had something that engaged them," said Dr. Ness.

"When you have cancer, you don't have personal control over the disease-except, perhaps, to some degree by taking your medicine," she continued. "But if you want to improve your health, you can exercise."

A goal in developing the intervention was to make it widely available without the need for expensive resources, such as a counselor for one-on-one activities. "This intervention is available remotely to children across the United States and Canada," said Dr. Howell.

Just as important, the intervention was designed for children who have recently completed their treatment-the very time when they may begin to develop health and exercise habits that could last a lifetime.

"We view this point in time as a good teachable moment," said Dr. Ness.

Related Resources

Late Effects of Treatment for Childhood Cancer (PDQ)-Patient Version.

Physical Activity and Cancer

© 2018 The National Cancer Institute

Deeper look at biopsy exposes mutation ready to ambush drug combination

Discovery of pre-existing, rare variation points to new approach to treatment, biopsies

MD Anderson Cancer Center -- March 2, 2018

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HOUSTON - A powerful resistance mutation that appeared to emerge in melanoma after a patient received a targeted therapy combination, instead was lurking in the tumor all along, primed to thwart treatment before it began, researchers at The University of Texas MD Anderson Cancer Center report online at Cancer Discovery.

Researchers analyzed a series of biopsies taken before and during treatment to ferret out the pre-existing mutation and then developed a potential way to target its troublesome abilities.

The team, led by Lawrence Kwong, Ph.D., assistant professor of Translational Molecular Pathology, set out to find resistance mechanisms that arise against a combination of MEK and CDK4 inhibitors to treat melanoma that has a mutation in the NRAS gene.

The mutation, to a gene called PIK3CA, appeared initially to be an acquired resistance variation that arose after treatment. By re-analyzing the pretreatment biopsy, Kwong and colleagues were able to establish that it was rare but present from the start, hiding on one side of the tumor.

PIK3CA variant started rare, expanded rapidly

"Our study is the first to measure multiple regions in pre-treatment tumor biopsies at high resolution and then track the resistant mutation over years of treatment through six biopsies," Kwong said. "We are able to say that this mutation started out rare and then rapidly expanded as the MEK/CDK4 inhibitors killed off a large number of non-resistant cells."

This finding helps establish that such pre-existing mutations can lurk in a patient's tumor at 10 times the rarity than previously appreciated and still cause rapid drug resistance, raising the possibility that even more rare mutations exist in other patients, below the detection rate of current technology.

"Right now, when we detect a resistance mutation after treatment, we often don't know whether it came out of nowhere as a new mutation or was pre-existing but undetected in the original tumor," Kwong said.

Understanding the difference could guide treatment to make it more effective, earlier, Kwong notes, and identifying rare mutations that are geographically isolated on a tumor will require improving our approach to analyzing biopsies.

NRAS mutations occur in 15-20 percent of melanomas, and the MEK/CDK4 combination is often effective initially against these tumors, but resistance arises.

Initial response, then swift progression

A 59-year-old woman with stage III malignant melanoma was found to have an NRAS mutation in her tumor. She was enrolled in a clinical trial combining a MEK and a CDK4 inhibitor. After an initial partial response of a 39 percent reduction in tumor burden, resistance to the treatment arose swiftly and the disease progressed and spread.

Whole exome sequencing of the resistant tumor after treatment revealed a mutation to PIK3CA known to promote tumor growth. Since the mutation was detected only 16 days after treatment began, Kwong and colleagues decided to re-examine the pretreatment biopsy, which sampled a single region of the tumor and had not found a PI3KCA mutation.

By examining seven regions of the biopsy sample using an amplification method developed by co-author David Zhang, Ph.D., assistant professor of Bioengineering at Rice University, the team found PIK3CA mutations in three regions. The pre-existing mutation was both rare and geographically dispersed in the tumor, making it hard to detect by sampling a single region.

Their findings suggest multi-region sampling would expose pre-existing resistant cells, an approach that would not be cost-effective at present, Kwong said, but is likely to become more practical as technology develops.

The PIK3CA mutation could also be detected by isolating circulating cell-free DNA in the blood after resistance developed, making it a potential target for liquid biopsies that are under development.

S6 provides a common target

Simply adding a PIK3CA inhibitor to the MEK/CDK4 combination would likely be too toxic, so the team analyzed 300 proteins to find targets that might be present in more than one of the three pathways.

They found a protein called S6 to be the only spot where all three of these cancer-promoting pathways meet. Treating mice with an S6 inhibitor re-sensitized them to treatment with the MEK/CDK4 combination, restoring the drugs' ability to shrink the PIK3CA mutation-bearing melanomas.

Kwong said an optimized human version of the S6 inhibitor in mice has not yet been developed, but their findings point to a possible target for human drug development.

"One of the main questions in cancer drug resistance is how often it comes from a pre-existing or a completely new mutation" said Gabriele Romano, Ph.D., a postdoctoral fellow in Translational Molecular Pathology and the study's first author. "Our study helps define some of the parameters and tools that will be needed to answer this tricky question."

Co-authors with Romano, Kwong and Zhang are Roger Liang, Mingguang Liu, M.D., Dzifa Duose, Ph.D., Fernando Carapeto, Ph.D., and Alexander Lazar, M.D., Ph.D., of Translational Molecular Pathology; Pei-Ling Chen, M.D., Ph.D., Whijae Roh, Ph.D., Jun Li, Ph.D., Jianhua Zhang, Ph.D., Andrew Futreal, Ph.D., and Jennifer Wargo, M.D., of Genomic Medicine; Jennifer McQuade, M.D., Michael Davies, M.D., Ph.D., and Rodabe Amaria, M.D., of Melanoma Medical Oncology; Merry Chen, M.D., of Neuro-Oncology: Ping Song, Ph.D., of Bioengineering at Rice University; and Jessica Teh, Ph.D., and Andrew Aplin, Ph.D., of Thomas Jefferson University, Philadelphia

This research was funded by MD Anderson's Melanoma Moon Shot, part of the institution's Moon Shots Program, MD Anderson's Cancer Center Support Grant from the National Cancer Institute (CA-16672), the Cancer Prevention and Research Institute of Texas, the Dr. Miriam and Sheldon G Adelson Medical Research Foundation; and grants from the National Cancer Institute ((RO1CA203964, RO1CA182635, and 4PO1CA163222-04), the University of Texas Rising STARS Award and the Melanoma Research Alliance Young Investigator Award.

© 2018 The University of Texas MD Anderson Cancer Center

Melody Management

Cancer Research & APP Development

NCI study revises molecular classification for most common type of lymphoma

by NCI Staff

The National Cancer Institute -- April 11, 2018

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Subgroups of DLBCL by gene expression (left) defined several years ago. Genetic subtypes identified in the new study (right) that each share a group of genetic aberrations. Curved connectors indicate relationships between the subgroups and subtypes.

Credit: National Cancer Institute

In a new study, researchers identified genetic subtypes of diffuse large B-cell lymphoma (DLBCL) that could help explain why some patients with the disease respond to treatment and others don't. The study, led by researchers in the Center for Cancer Research (CCR) at the National Cancer Institute (NCI), part of the National Institutes of Health, with additional authors from several institutions around the world, was published online April 11, 2018, in The New England Journal of Medicine.

"These findings are the culmination of two decades of research at NCI and elsewhere, advancing our understanding of the effect of DNA mutations and gene expression on lymphoma biology and outcome," said NCI Director Ned Sharpless, M.D. "This refined molecular classification will be instrumental in predicting prognosis and tailoring therapy for patients with DLBCL going forward."

DLBCL is the most common type of lymphoma. Although it can be aggressive, it is potentially curable, and in some patients treatment eliminates the disease. However, researchers still don't have a full understanding of why some lymphomas of this type respond to treatment and others don't. The standard treatment for the disease is a combination of chemotherapy drugs plus rituximab, a drug known as a monoclonal antibody.

Several years ago, researchers defined two major subgroups of DLBCL that arise from different cells of origin and that have different patterns of gene activity. They found that patients with activated B-cell-like (ABC) DLBCL have about a 40 percent average survival rate, while those with germinal center B-cell-like (GCB) DLBCL have about a 75 percent average survival rate. But even in the GCB subgroup, many patients experience disease relapse after treatment.

"The first question we wanted to tackle was whether there were other molecular features of the tumors that could help us explain why some people were well-served by chemotherapy," explained Louis M. Staudt, M.D., Ph.D., of NCI's CCR, who led the new study. "And the second, related question was, if we could understand who was not responding well to treatment, could we understand the genetics of these tumors to suggest new potential therapies beyond chemotherapy? The answer to both questions was 'yes.'"

The investigators performed a multi-platform analysis of genomic alterations and gene expression on tumor samples from 574 patients with DLBCL. This analysis identified four prominent genetic subtypes that each share a group of genetic aberrations. Patients with two of the subtypes, called BN2 and EZB, respond well to treatment, while those with the other two, MCD and N1, do not. Some of these subtypes can be found in both ABC and GCB subgroups, so a patient could, for example, have ABC DLBCL, the gene expression profile with the lower survival rate, but the disease could also have the BN2 genetic subtype that responds well to chemotherapy.

"This shows we've gone beyond where we were," said Dr. Staudt. "Before, even with our most advanced molecular diagnosis, we would have said all ABC tumors are the 'bad' type and they need to be treated aggressively. Now we can implement this kind of classification and say that even if a patient has the 'bad' ABC type, they have the 'good' genetic type, BN2. So there's a much better chance of chemotherapy curing the disease." "This shows we've gone beyond where we were," said Dr. Staudt. "Before, even with our most advanced molecular diagnosis, we would have said all ABC tumors are the 'bad' type and they need to be treated aggressively. Now we can implement this kind of classification and say that even if a patient has the 'bad' ABC type, they have the 'good' genetic type, BN2. So there's a much better chance of chemotherapy curing the disease."

Data from the study will be shared through NCI's Genomic Data Commons to make it available for future research.

While the new findings relate to current treatment, Dr. Staudt said he and his colleagues hope the new molecular classification will be used in clinical trials, so, eventually, treatments can move away from chemotherapy as much as possible, toward more targeted therapies that have fewer side effects.

Research is already being done in this area. Results of a phase 2 clinical trial published in 2015, for example, demonstrated that patients with ABC DLBCL were more likely to respond to the targeted therapy drug ibrutinib than those with GCB DLBCL.

Precision medicine clinical trials could test tumors for the new genetic subtypes, Dr. Staudt explained, and then, based on the tumor's classification, the patient would be assigned to the most appropriate treatment arm of the study.

"The goal is to find the right drug for the right person at the right time," said Dr. Staudt. "And we feel this genetic understanding of diffuse lymphoma is a step forward in precision therapy."

About the National Cancer Institute (NCI): NCI leads the National Cancer Program and NIH's efforts to dramatically reduce the prevalence of cancer and improve the lives of cancer patients and their families, through research into prevention and cancer biology, the development of new interventions, and the training and mentoring of new researchers. For more information about cancer, please visit the NCI website at cancer.gov or call NCI's Contact Center (formerly known as the Cancer Information Service) at 1-800-4-CANCER (1-800-422-6237).

About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit nih.gov.


    1. Schmitz R, Wright GW, Huang D, et al. Genetics and Pathogenesis of Diffuse Large B-Cell Lymphoma. N Engl J Med 2018; 378:1396-407. DOI: 10.1056/NEJMoa1801445

© 2018 The National Cancer Institute

Interactive App Improves Colorectal Cancer Screening Rates

by NCI Staff

The National Cancer Institute -- April 9, 2018

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Although screening for colorectal cancer has been shown to decrease deaths from the disease, only about two-thirds of Americans are up to date with screening.

Now a new study suggests that giving people an easy way to order their own screening tests may help increase the number of people who get screened.

In the NCI-funded study, people waiting to see their doctors for routine checkups were given a tablet computer loaded with an interactive app that provides information about the need for colorectal cancer screening, helps patients make decisions about screening, and allows them to "self-order" their own screening test. People who used the app, the study showed, were twice as likely to be screened as those viewing a video that did not provide information about screening or the option to order a test.

The "interesting and innovative" aspect of the approach used in the new study is that "once patients made a choice about screening, they had the opportunity to order the test themselves," said health care delivery researcher Caitlin Murphy, Ph.D., M.P.H., of the University of Texas Southwestern Medical Center, who was not involved in the new study.

The findings were published March 13 in the Annals of Internal Medicine.

Clinical Trial Included Those Most Likely to Face Barriers to Screening

The US Preventive Services Task Force recommends screening for colorectal cancer for average-risk adults ages 50-75 with a colonoscopy once every 10 years or a stool-based test every year. People with an abnormal stool test result (signs of blood in the stool) are advised to undergo a colonoscopy to investigate the cause.

Many factors contribute to low screening rates in the United States, including fear of the procedure and/or the preparation; lack of awareness of the need for screening; and absent or inadequate doctor-patient discussions about screening. Screening rates are particularly low among people with less education or low incomes.

Researchers have tested different approaches to increasing colorectal cancer screening rates, such as small financial incentives and mailed invitation letters and free testing kits, and found varying levels of success.

In the new study, David P. Miller, Jr., M.D., of Wake Forest School of Medicine, and his colleagues tested the Mobile Patient Technology for Health-CRC (mPATH-CRC) app, which they designed for people with low health literacy and low computer literacy, at six community-based primary care practices in North Carolina.

Of the 450 study participants, 37% were assessed as having limited health literacy and 53% had annual incomes of less than $20,000. Most were non-Hispanic white (57%) or African American (38%). The study was limited to English speakers.

Participants were 50-74 years old, scheduled to see a primary care provider, and due for colorectal cancer screening.

The mPATH-CRC app tells patients about the two tests most commonly used to screen for colorectal cancer in the United States, colonoscopy and fecal occult blood testing, which looks for hidden (occult) blood in patient stool samples, and helps them decide which test to use.

Patients who had agreed to participate in the study were asked to arrive 45-60 minutes before their primary care appointment to use the app. They were then randomly assigned to use either the mPATH-CRC app or a control app that included a video about diet and exercise and did not give patients the option to self-order screening tests.

Primary care providers of patients who self-ordered a screening test with the app were notified and asked to approve or deny the test order. Patients who self-ordered a screening test received a series of automated follow-up email or text messages to help them follow through with the test.

App Improved Screening but Left Room for Improvement

Of the 223 participants assigned to the mPATH-CRC group, 30% completed a screening test within the study's 24-week follow-up period, compared with 15% of 227 people in the control group.

But the 30% screening rate "is still far from ideal," Dr. Miller said.

Dr. Murphy noted that it's also important to consider how many patients who chose a stool-based test went on to complete a diagnostic colonoscopy as recommended if they had an abnormal stool test result. Although the study team does not have complete data on this, Dr. Miller said, they know that at least some of the people who had an abnormal stool test result went on to have a colonoscopy.

And the researchers did look at detection of colon polyps (precancerous growths) and cancers in both groups. They found 15 people with polyps and one with cancer among those who used the app, compared with only 6 people with polyps in the control group.

"That suggests that for every 22 people who use the app, we'll find polyps in one extra person-and that's potentially one person we will prevent from getting colon cancer," Dr. Miller said.

The researchers were surprised to find that roughly half (53%) of patients in the mPATH-CRC group ordered a test for themselves via the app. This was a higher number than expected, Dr. Miller said.

"Clearly patients are willing to do the screening test, but something is happening on the [health-care] system or clinic side of things that's preventing some of them from completing it," Dr. Murphy said.

Further improving screening rates will require figuring out how to "incorporate system-level changes and practices that empower patients to play a more active role in their health care, and how to better support patients who fail to complete ordered tests," Dr. Miller said.

One simple, cost-effective approach could involve phone calls by patient navigators to patients most likely to need extra support to complete screening, he continued.

Dr. Miller's team recently received NCI funding for a follow-up trial to be conducted with partners at the University of Kentucky. The researchers plan to investigate the level of support that community-based health clinics need to implement mPATH-CRC and improve screening rates.

New Ways to Engage with Patients Are Needed

"When patients have the ability not just to choose the test but also to say, 'I want to order the test,' they're more likely to get screened," Dr. Murphy said.

A previous study of the decision aid by Dr. Miller's team did not allow patients to self-order tests, and in that study the decision aid did not have an effect on screening.

The new study also found that patients in the mPATH-CRC group were more likely than those in the control group to prefer a stool-based test.

Giving patients a choice of screening tests is important, Dr. Murphy said-not just in terms of personal preference but also for financial reasons, particularly for people who may not have health insurance or cannot easily take extra time off from work to have a colonoscopy.

"Our natural inclination to recommend colonoscopy [for screening] in the United States may be harmful, in that a patient may think, 'I can't afford a colonoscopy so I guess I can't get screened,' whereas if they knew a stool test was available, they might get screened," Dr. Miller said.

"Despite its success, this trial missed...opportunities that might have made it even more transformative," wrote David Asch, M.D., M.B.A., and Shivan Mehta, M.D., M.B.A., of the Center for Health Care Innovation at the University of Pennsylvania, in an editorial on the new study.

For one thing, they noted, encouraging colorectal cancer screening does not have to take place in the context of a clinic visit.

"In the end, the goal is not to get more primary care patients in the clinic screened, but to get more people screened-a goal that invites the use of smartphones, social networks, and other elements of daily life," Drs. Asch and Mehta wrote. "[T]he active ingredients of transformative change are likely to come from new ways to engage with patients outside of office visits and other traditional processes of care."

Related Resources

Colorectal Cancer Screening (PDQ)

© 2018 The National Cancer Institute

Findings from breast and gynecological cancer study may have potential for future clinical applications

Pan-cancer analysis of nearly 2,600 gynecologic and breast tumors reveals five previously unknown subtypes among other findings

MD Anderson Cancer Center -- April 5, 2018

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HOUSTON - Researchers from The University of Texas MD Anderson Cancer Center have found a startling amount of new information about molecular features of tumors as well as identified previously unknown cancer subtypes based on a comprehensive analysis of 2,579 tumors from breast and four different types of gynecologic cancers. These new findings potentially could serve as a launching pad for future therapeutic studies.

Results from the multi-institutional effort, led by Rehan Akbani, Ph.D., associate professor of Bioinformatics & Computational Biology were published this week in the online issue of Cancer Cell.

The study is part of the PanCancer Atlas, which aims to answer big overarching questions about cancer by examining the full set of tumors available via The Cancer Genome Atlas (TCGA), a joint effort of the National Cancer Institute (NCI) and the National Human Genome Research Institute (NHGRI). This study is one of several that conclude the PanCancer Atlas and TCGA missions of mapping key genomic changes in an array of cancer types, and providing a community resource that accelerates our understanding of the molecular basis of cancer.

"Our aims were to identify shared and unique molecular features, clinically significant subtypes and potential therapeutic targets," said Akbani. "We confirmed similarities previously identified in the five breast and gynecologic tumor types and discovered intriguing molecular relationships not observed in previous studies of these diseases. A number of the observations have possible prognostic and/or therapeutic relevance, although any clinical possibilities illuminated by this study would require extensive additional research before they would be ready for practical application."

Key results of the study included:

  • Using 16 key molecular features, the team identified five prognostic cancer subtypes and developed a decision "tree" that classified patients into the subtypes based on six features assessable in clinical laboratories.
  • Identifying other subtypes with high leukocyte counts, raising potential implications for immunotherapy treatment in the future.
  • Discovering the presence of significant estrogen receptor-regulated long non-coding RNAs (lncRNAs) and interaction "networks" between genes and lncRNAs.
  • Observing many genetic aberrations including 61 somatic copy-number alterations (SCNAs) and 46 significantly mutated genes (SMGs). Eleven each of the SCNAs and SMGs had not been identified in previous TCGA studies of five tumor types.

"This study presents a broad-based, curated atlas of gynecologic and breast cancer molecular features that we believe will be useful as a starting point for researchers in the field for many years to come," said Akbani.

John Weinstein, M.D., Ph.D., chair of Bioinformatics & Computational Biology, and a member of the research team added that "the study complements other integrative TCGA Pan-Cancer Atlas projects that have painted molecular portraits of about 11,000 patient tumors in 33 cancer types."

MD Anderson study participants included Anil Korkut, Ph.D.; Rupa Kanchi, Ph.D.; Apurva Hegde; Walter Lenoir; Wenbin Liu, Ph.D.; Yuexin Liu, Ph.D.; Visweswaran Ravikumar; Arvind Rao, Ph.D.; Andre Schultz, Ph.D.; Xubin Li; Keith Baggerly, Ph.D.; and John Weinstein, M.D., Ph.D., all of the Department of Bioinformatics & Computational Biology; Anil Sood, M.D., Gynecologic Oncology and Reproductive Medicine; Alexander Lazar, M.D., Ph.D., Pathology; Jason Roszik, Ph.D.,; Genomic Medicine; and Gordon Mills, M.D., Ph.D., and Christopher Vellano, Ph.D., Systems Biology.

Other participating institutions included the Broad Institute, Cambridge, Mass.; Van Andel Research Institute, Grand Rapids, Mich.; Baylor College of Medicine, Houston; Royal Institute of Technology, Solna, Sweden; Ghent University, Belgium; University of Houston; Buck Institute of Research on Aging, Novato, Calif.; University of California, San Francisco; Michael Smith Genome Sciences Centre, Vancouver, B.C.; University of Sao Paulo, Brazil; Mayo Clinic College of Medicine, Rochester, Minn.; Dana Farber Cancer Institute, Boston; The University of Kansas Medical Center, Kansas City; University of Washington, Seattle; Medical College of Wisconsin, Milwaukee; University of Oklahoma Health Sciences Center, Oklahoma City; University of Alabama, Birmingham; University of Maryland School of Medicine, Baltimore; Institute of Human Virology, Abuja, Nigeria; Chang Gung University, Taoyun, Taiwan; Wake Forest Baptist Health Center, Winston-Salem, N.C.; University of New South Wales, Sydney; Cedars-Sinai Medical Center, Los Angeles; Leukemia Therapeutics, LLC, Hull, Mass,; National Cancer Institute, Bethesda, Md.; and New York University Langone Health, New York.

The study was funded by the National Cancer Institute (U54 HG003273, U54 HG003067, U54 HG003079, U24 CA143799, U24 CA143835, U24 CA143840, U24 CA143843, U24 CA143845, U24 CA143848, U24 CA143858, U24 143866, U24 CA143867, U24 CA143882, U24 CA143883, U24 CA144025, U24 CA210949, U24 CA210950, P30 CA016672, and P50 CA136393).

© 2018 The University of Texas MD Anderson Cancer Center

Study of gene enhancers sheds light on how some cancers form and spread

Examination of nearly 9,000 tumor samples across 33 cancer types reveals enhancers as key regulators of therapy targets, including PD-L1

MD Anderson Cancer Center -- April 5, 2018

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HOUSTON - At the heart of any cancer diagnosis or treatment are cells. If one thinks of the cell components controlling gene activation as a Russian nesting-doll of gene regulatory layers, within those increasingly smaller tiers are short pieces of non-coding DNA called enhancers. A study at The University of Texas MD Anderson Cancer Center reveals enhancers as a significant area of research for diagnosing and/or treating many cancers.

Cancer researchers have been interested in enhancers due to their ability to turn genes off or on. Tens of thousands of enhancers can reside in a single cell, but in-depth understanding of how they work has eluded investigators. Findings from the study, which provides significant new knowledge about these cell components, were published in the April 5, 2018 online issue of Cell.

"Although the role of enhancers in cancer development has increasingly been recognized, genome-wide studies on enhancer activity over large patient cohorts have not been done," said Han Liang, Ph.D., study lead and associate professor of Bioinformatics & Computational Biology at The University of Texas MD Anderson Cancer Center. "Our study was able to illustrate, for the first time, the enhancer expression 'landscape' in a broad range of cancers."

In cancer cells, regulatory networks are often "rewired," leading to cancer; however, understanding of how this occurs has been limited. Liang's team revealed enhancers as a missing piece of the puzzle, indicating, among several key findings, their role as key regulators of therapeutic targets, including programmed death ligand-1 (PD-L1).

PD-L1, a protein that suppresses the immune system allowing cancer to form and grow, is an important target for many existing and emerging immunotherapies. Using RNA-sequencing data from The Cancer Genome Atlas (TCGA), Liang's team conducted a genome-wide analysis of 8,928 tumor samples across 33 cancer types, and identified a considerable number of enhancers in addition to PD-L1.

The study is part of the PanCancer Atlas, which aims to answer big overarching questions about cancer by examining the full set of tumors available via The Cancer Genome Atlas (TCGA), a joint effort of the National Cancer Institute (NCI) and the National Human Genome Research Institute (NHGRI). This study is one of several that conclude the PanCancer Atlas and TCGA missions of mapping key genomic changes in an array of cancer types, and providing a community resource that accelerates our understanding of the molecular basis of cancer.

"Our study provided a systematic view of enhancer activity in diverse tumors, suggesting a conceptually novel strategy to inhibit key therapeutic targets," said Liang.

The team also demonstrated how enhancers can serve as biomarkers, through examination of an enhancer that targets spleen tyrosine kinase (SYK), often linked to multiple types of late-stage cancer. In looking at patient survival times, the enhancer proved to be a marker of poor prognosis in several cancer types.

Based on their TCGA analyses, Liang's team additionally proposed a model in which chromatin - the "packaging" around DNA - could be a vital contributor to certain enhancer activation processes, which provides insights into how genetic mutation and cloning evolve into some cancers.

"Variations in chromatin organization in a single tumor progenitor cell could create striking differences among tumors if the variations occur over many generations of cell growth," said Liang. "Chromatin organization could be substantially remodeled by histone gene mutations, which are frequently seen in cancers."

The team's observation of enhancers' unique abilities to be both "on" and "off" switches throughout the cancer genome provided new data about tumor clonal evolution - the step-by-step cellular process by which cancer forms, and revealed a number of enhancers associated with genes tied to cancer. Liang adds that further efforts are required to investigate the potential of enhancers in clinical applications.

MD Anderson study team members included Han Chen, Ph.D.; Chunyan Li, Ph.D.; Xinxin Peng, Ph.D.; Zhicheng Zhou, Ph.D.; and John Weinstein, M.D., Ph.D., all of the Department of Bioinformatics & Computational Biology. The study was part of TCGA Program, a joint effort of the National Cancer Institute and the National Human Genome Research Institute.

Funding came from the National Institutes of Health (CA175486, CA209851 and CA016672) and the Cancer Prevention and Research Institute of Texas (RP140462).

© 2018 The University of Texas MD Anderson Cancer Center

NIH completes in-depth genomic analysis of 33 cancer types

by NCI Staff

The National Cancer Institute -- April 5, 2018

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Growing cancer cells (in purple) are surrounded by healthy cells (in pink), illustrating a primary tumor spreading to other parts of the body through the circulatory system.

Image credit: Darryl Leja, NHGRI

Researchers funded by the National Institutes of Health have completed a detailed genomic analysis, known as the PanCancer Atlas, on a data set of molecular and clinical information from over 10,000 tumors representing 33 types of cancer.

"This project is the culmination of more than a decade of groundbreaking work," said NIH Director Francis S. Collins, M.D., Ph.D. "This analysis provides cancer researchers with unprecedented understanding of how, where, and why tumors arise in humans, enabling better-informed clinical trials and future treatments."

The PanCancer Atlas, published as a collection of 27 papers across a suite of Cell journals, sums up the work accomplished by The Cancer Genome Atlas (TCGA) - a multi-institution collaboration initiated and supported by the National Human Genome Research Institute (NHGRI) and the National Cancer Institute (NCI), both part of NIH. The program, with over $300 million in total funding, involved upwards of 150 researchers at more than two dozen institutions across North America.

"TCGA was the first project of its scale to characterize - at the molecular level - cancer across a breadth of cancer types," said Carolyn Hutter, Ph.D., director of NHGRI's Division of Genome Sciences and the NHGRI team lead for TCGA. "At the project's infancy 10 years ago, it wasn't even possible, much less on such a scale, to do the types of characterization and analysis that were being proposed. It was a hugely ambitious project."

"The PanCancer Atlas effort complements the over 30 tumor-specific papers that have been published by TCGA in the last decade and expands upon earlier pan-cancer work that was published in 2013," said Jean Claude Zenklusen, Ph.D., director of the TCGA Program Office at NCI.

The project focused not only on cancer genome sequencing, but also on different types of data analyses, such as investigating gene and protein expression profiles, and associating them with clinical and imaging data.

The PanCancer Atlas is divided into three main categories, each anchored by a summary paper that recaps the core findings for the topic. The main topics include cell of origin, oncogenic processes, and oncogenic pathways. Multiple companion papers report in-depth explorations of individual topics within these categories.

In the first summary paper, the authors summarize the findings from a set of analyses that used a technique called molecular clustering, which groups tumors by parameters such as genes being expressed, abnormality of chromosome numbers in tumor cells, and DNA modifications. The paper's findings suggest that tumor types cluster by their possible cells of origin, a result that adds to our understanding of how tumor tissue of origin influences a cancer's features and could lead to more specific treatments for various cancer types.

The second summary paper presents a broad view of the TCGA findings on the processes that lead to cancer development and progression. Specifically, the authors noted that the findings identified three critical oncogenic processes: mutations, both germline (inherited) and somatic (acquired); the influence of the tumor's underlying genome and epigenome on gene and protein expression; and the interplay of tumor and immune cells. These findings will help prioritize the development of new treatments and immunotherapies for a wide range of cancers.

The final summary paper details TCGA investigations on the genomic alterations in the signaling pathways that control cell cycle progression, cell death, and cell growth, revealing the similarities and differences in these processes across a range of cancers. Their findings reveal new patterns of cancer's potential vulnerabilities that will aid in the development of combination therapies and personalized medicine.

The entire collection of papers comprising the PanCancer Atlas are available through a portal on cell.com. Additionally, as the decade-long TCGA effort wraps up, there will be a three-day symposium, TCGA Legacy: Multi-Omic Studies in Cancer, in Washington, D.C., September 27-29, 2018, that will discuss the future of large-scale cancer studies, with a session focusing on the PanCancer Atlas. The meeting will feature the latest advances on the genomic architecture of cancer and showcase recent progress toward therapeutic targeting.

About the National Human Genome Research Institute (NHGRI): NHGRI leads genomics research at the National Institutes of Health (NIH), providing technical expertise and guidance that benefit all institutes and centers. We share our groundbreaking science and vision with our colleagues in order to accelerate breakthroughs that improve lives. By collaborating with the scientific and medical communities, we catalyze the development of new genomic technologies and support the robust study and treatment of specific diseases throughout NIH. For more information about NHGRI and its programs, visit genome.gov.

About the National Cancer Institute (NCI): NCI leads the National Cancer Program and NIH's efforts to dramatically reduce the prevalence of cancer and improve the lives of cancer patients and their families, through research into prevention and cancer biology, the development of new interventions, and the training and mentoring of new researchers. For more information about cancer, please visit the NCI website at cancer.gov or call NCI's Contact Center (formerly known as the Cancer Information Service) at 1-800-4-CANCER (1-800-422-6237).

About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 institutes and centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit nih.gov.

© 2018 The National Cancer Institute

Cancer Immunotherapy Drug Simultaneously Targets Two Proteins that Block Immune Response

by NCI Staff

The National Cancer Institute -- April 4, 2018

companies img Top: Schematic of a Y-trap that binds TGF-beta, consisting of a targeting antibody fused to the extracellular domain of the TGF-beta receptor. Bottom: Crystal structure of the t?rap (green) binding to TGF-beta (red and blue).

Credit: Credit: Dr. Atul Bedi / Johns Hopkins Medicine

A growing number of patients with cancer have benefited from drugs that help the immune system fight cancer, such as immune checkpoint inhibitors. But most patients with cancers do not respond to these treatments.

To try to develop more effective immunotherapies, two groups of researchers, working independently, have developed a type of drug that simultaneously targets two proteins involved in suppressing the body's immune response against tumors.

The researchers created the drugs by fusing a receptor for a protein called TGF-beta to a monoclonal antibody that targets a checkpoint protein, such as PD-L1 or CTLA-4. The result is a single hybrid molecule that blocks two pathways used by tumors to evade the immune system.

TGF-beta is often found in the tumor microenvironment and may, like immune checkpoint proteins, regulate the activity of immune cells. The TGF-beta receptor portion of the new immunotherapy drug binds to TGF-beta, "trapping" the protein and rendering it useless.

"TGF-beta is well known to be a bad actor in the tumor microenvironment, because it inhibits immune cells called T cells, which are the good guys," said Jeffrey Schlom, Ph.D., of NCI's Center for Cancer Research (CCR), who has led several preclinical studies of the new immunotherapy drug.

The drug, which is a type of therapy called a bifunctional fusion protein or a Y-trap, may be more effective than an immune checkpoint inhibitor alone while not substantially increasing the side effects for patients, according to the results of several recent studies.

Based on the NCI preclinical studies, Julius Strauss, M.D., of CCR and his colleagues began to test the drug, which targets PD-L1, in clinical trials. Meanwhile, a new study from researchers at the Johns Hopkins School of Medicine has also demonstrated the potential of two Y-traps tested in mouse models of cancer, including one that, like NCI's drug, targets PD-L1.

"Targeting both a checkpoint inhibitor and other molecules, such as TGF-beta, gives you a much more effective way to block the immune suppression we so often see in tumors," said Jeffrey Sosman, M.D., of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University, who investigates immunotherapies but was not involved in the NCI clinical trials or the Johns Hopkins study.

Using a single drug to treat a patient's cancer has some advantages over using multiple drugs, such as reducing potential side effects, Dr. Sosman noted.

Encouraging Results from Clinical Trials

In January 2018, NCI researchers reported the results of a phase 1 clinical trial of this approach with a molecule called M7824 in 19 patients with advanced cancer that had been treated previously. Based on the findings, including one patient who had a complete response, the researchers have expanded the trial to include additional patients.

Inhibiting both PD-L1 and TGF-beta is a promising therapeutic strategy "because these key pathways have independent and complementary roles in suppressing the immune response," said CCR's James Gulley, M.D., Ph.D., an immunotherapy researcher who co-led the NCI clinical trial.

"This is a very exciting approach," he added, noting that in clinical trials the side effects of the new technology were similar to those of inhibitors that block the interaction of PD-1 and PD-L1 such as pembrolizumab (Keytruda) and nivolumab (Opdivo) and were largely manageable.

The researchers are also conducting early-phase clinical trials of M7824 in patients with pancreatic cancer and patients whose cancers are associated with the human papillomavirus. Additional phase 2 studies are in development, according to Dr. Schlom.

Testing Multiple Y-Traps in Mouse Models

In experiments with mice, the two Y-traps developed at Johns Hopkins were more effective than the corresponding immune checkpoint inhibitors, including the anti-CTLA-4 antibody ipilimumab (Yervoy) and the anti-PD-L1 antibodies atezolizumab (Tecentriq) and avelumab (Bavencio), the researchers reported in Nature Communications on February 21.

For example, a Y-trap targeting CTLA-4 and TGF-beta slowed the growth of tumors that did not respond to ipilimumab. Similarly, a Y-trap targeting PD-L1 and TGF-beta slowed the growth of tumors that did not respond to atezolizumab and avelumab.

"The antibody goes after CTLA-4 or PD-L1, and at the same time it can trap a molecule of interest, such as TGF-beta, that is helping to suppress the immune system," said Atul Bedi, M.D., who led the Johns Hopkins team.

The researchers initially became interested in targeting TGF-beta as a way to limit the production of regulatory T cells, a type of immune cell that suppresses the activity of the immune system. Regulatory T cells infiltrate many advanced cancers, and this infiltration is associated with a poor prognosis.

"You need a powerful set of tools to address this situation," he added. "With the Y-trap, we now have the ability to counteract a key mechanism of resistance to the immune response."

Developing a Family of Y-Trap

Dr. Bedi noted, however, that regulatory T cells are not the only way tumors evade the immune system. The Johns Hopkins team is developing a family of Y-traps that can be used to target multiple factors that play a role in the body's immune response to tumors.

Johns Hopkins has licensed the Y-trap technology to a new company that could begin to test the approach in patients, according to Dr. Bedi.

"The concept of using combined therapies for patients with cancer is a central theme in the development of new immunotherapies," said Dr. Sosman. "The beauty of this approach is that it combines multiple therapies in a single molecule."

The idea of using a single molecule for this purpose is not new, Dr. Sosman added. "But we now have examples of this approach that are getting into the clinic and showing activity in patients. We have molecules that clearly work."

© 2018 The National Cancer Institute

NCI Launches New Resource for Specimens and Data from Cancer Clinical Trials

by NCI Staff

The National Cancer Institute -- April 2, 2018

companies img Credit: National Cancer Institute

NCI announced the launch today of a new resource for cancer researchers interested in conducting studies using specimens and clinical data collected from cancer treatment trials in NCI's National Clinical Trials Network (NCTN) and former NCI Cooperative Group Program.

Known as NCTN Navigator, the resource includes information about specimens, such as tumor and blood samples, donated by patients in NCI-sponsored clinical trials. The clinical trials included in Navigator are published phase 3 studies that evaluated cancer treatments.

Investigators can use the NCTN Navigator website to search the inventory for specimens with specific characteristics. Investigators who develop proposals and get approval can use the specimens, along with the trial participants' clinical information, in their research.

"The optimal research proposals for this resource are those that capitalize on the large clinical trial study design and its associated specimens to develop ways to confirm how drugs work, select patients who benefit from a given treatment, and assess new methods to monitor treatment effectiveness," said Jeffrey S. Abrams, M.D., acting director for Clinical Research in NCI's Division of Cancer Treatment and Diagnosis (DCTD).

Hundreds of Thousands of Specimens from Clinical Trials

NCI has supported large cancer treatment trials for decades through what is now the NCTN. For many of the trials, donated specimens were collected and stored in NCI-funded specimen banks. The clinical data from the trials include detailed information about patient responses to treatments and their outcomes.

The NCTN Navigator inventory includes data from more than 80 trials, 50,000 patients, and 600,000 specimens.

"Navigator's strength, and what sets it apart from most other resources, is the combination of specimens and the associated clinical information collected over the course of a trial," said Irina Lubensky, M.D., of NCI's Cancer Diagnosis Program, which worked with NCI's Cancer Therapy Evaluation Program (CTEP) and NCTN specimen banks and researchers to develop Navigator.

Although the researchers who conducted these clinical trials have long been using the specimens and clinical data in studies, Navigator will now make the materials available to any investigators who submit research proposals that are approved by a scientific review board.

"Navigator will make NCTN trial specimens more visible and accessible to the broader translational cancer research community," said Mark Watson, M.D., Ph.D., of the Washington University School of Medicine in St. Louis. Dr. Watson directs one of the specimen banks where NCTN specimens are stored and was a member of the original Navigator project development team.

Proposals Undergo Peer Review

"Navigator is an amazing resource," added Lee Ellis, M.D., of the University of Texas MD Anderson Cancer Center.

Dr. Ellis also co-chairs a committee of scientific experts and patient advocates that will review proposals from investigators to use Navigator resources. "It will allow the cancer research community to develop new tools, such as predictive biomarkers, that will help us improve the care of our patients," he said.

To ensure the optimal use of the resources in Navigator, the scientific review committee will consider the importance of a proposed project with the value of the specimens in mind. "The standards are high because the specimens are a nonrenewable resource," said CTEP's Grace Mishkin, M.P.H., who helped develop Navigator.

In general, successful Navigator proposals will use the specimens and data to test a research question that builds on prior knowledge and has potential clinical implications, noted Mishkin. The specimens in Navigator will generally not be appropriate for studies that are more exploratory in nature, she added.

The Enduring Value of Large Clinical Trials

Before developing or submitting a research proposal to the Navigator program, investigators can perform searches on the program's website to ensure there are specimens and related data to meet their research needs.

If they would then like to move ahead, they can use the website to submit a proposal for how they would like to use the specimens.

"If their ideas are approved, they will receive the clinical data along with the specimens to conduct their analyses," said Dr. Abrams.

There is no charge for the specimens or clinical data in Navigator, but investigators with approved proposals will be responsible for the costs associated with processing and delivering the specimens and clinical data.

Although Navigator currently includes only specimens and information from adults, specimens and data from patients with pediatric cancers are expected to be added later this year.

Phase 3 clinical trials "remain an invaluable proving ground" for confirming findings from smaller studies, Dr. Abrams noted. The competitive process to obtain samples from Navigator will allow researchers to expand the value of these trials even further, he said.

Dr. Ellis agreed: "We hope that by making these specimens searchable on a user-friendly database, we can translate findings from these innovative research studies into better care for our patients."

© 2018 The National Cancer Institute

Melody Management

Cancer Research & APP Development

Preclinical MD Anderson study suggests ARID1a may be useful biomarker for immunotherapy

Alterations in commonly mutated gene may render tumors susceptible to immune checkpoint blockade

MD Anderson Cancer Center -- May 7, 2018

companies img Guang Peng, M.D., Ph.D.

HOUSTON - Functional loss of ARID1a, a frequently mutated tumor suppressor gene, causes deficiencies in normal DNA repair and may sensitize tumors to immune checkpoint blockade therapies, according to researchers from The University of Texas MD Anderson Cancer Center. The preclinical study suggests that mutations in ARID1a could be beneficial in predicting immunotherapy success.

The findings, published today in Nature Medicine, are the first to identify a role for ARID1a in regulating mismatch repair (MMR), a normal process for correcting DNA damage. Further, the study showed that treatment with immune checkpoint inhibitors targeting PD-1 successfully reduced tumor burden and prolonged survival in mouse models with ARID1a-deficient tumors relative to controls.

Mutations in ARID1a occur frequently in a wide spectrum of cancers, with particularly high mutation rates (15-50 percent) in clear cell ovarian cancer, endometrial cancer, gastric cancer and bladder cancer. However, most mutations lead to loss of ARID1a, making it a poor therapeutic target, explained senior author Guang Peng, M.D., Ph.D., associate professor of Clinical Cancer Prevention.

"Since this is a very highly mutated gene in cancer, we wanted to better understand the biological function of ARID1a and potential therapeutic vulnerabilities," said Peng. "We did a variety of molecular assays and demonstrated, for the first time, that ARID1a deficiency has a causative relationship with MMR deficiency."

The researchers performed a screen in cancer cells to identify proteins which interact with ARID1a and discovered a connection with MSH2, a protein with a key role in regulating MMR. Additional in vitro assays confirmed that ARID1a was essential to normal MMR function.

Tumors with deficiencies in MMR are known to accumulate large numbers of genetic mutations and corresponding mutant proteins, or neoantigens, as the disease progresses. These neoantigens are thought to stimulate an immune response, making them more susceptible to checkpoint blockade therapy.

The researchers therefore analyzed data across cancer types from The Cancer Genome Atlas (TCGA) and confirmed that tumors with ARID1a mutations indeed carried higher mutational loads. Further, ARID1a mutations were more common in tumors with microsatellite instability (MSI), another marker for MMR dysfunction.

"The FDA has approved MMR deficiency as a marker for the use of checkpoint-blockade immunotherapy," said Peng. "Therefore, we wondered whether ARID1a-deficient tumors would have increased sensitivity to checkpoint blockade because they have impaired MMR and increased mutation load."

Further analysis of TCGA data revealed that tumors with ARID1a mutations exhibited an activation of the immune system, according to gene expression levels of immune markers. Therefore, the researchers investigated the use of checkpoint blockade inhibitors in treating tumors with ARID1a mutations.

Using mouse models of both ovarian and colorectal cancer, the researchers compared the effectiveness of anti-PD-1 therapy in mice with ARID1a-mutant tumors relative to controls with functional ARID1a. Treatment with the checkpoint blockade therapy significantly improved survival in mice with ARID1a mutations, suggesting immunotherapy could be useful for patients with ARID1a-mutant tumors.

"Our findings link ARID1a mutations to MMR deficiency, thus providing a therapeutic target by immune checkpoint blockade," said Peng. "We hope that our data will contribute to clinical studies testing ARID1a as a new biomarker for checkpoint blockade therapies."

Future work will be necessary to confirm the researchers' findings in clinical patient samples. Peng hopes to initiate clinical studies to investigate the value of ARID1a mutations across cancer types as a predictor of response to checkpoint blockade inhibitors targeting PD-1.

In addition to Peng, MD Anderson authors include: Jianfeng Shen, Ph.D., Lulu Wang, Ph.D., and Yang Peng, Ph.D., all of Clinical Cancer Prevention; Zhenlin Ju, Ph.D., Wei Zhao, Ph.D., Jiyong Liang, M.D., Ph.D., and Gordon Mills, M.D., Ph.D., all of Systems Biology; Zhongqi Ge, Ph.D. and Han Liang, Ph.D., both of Bioinformatics and Computational Biology; Prabodh Kapoor, Ph.D. and Xuetong Shen, Ph.D., both of Epigenetics and Molecular Carcinogenesis; Shumei Song, M.D., Ph.D., and Jaffer Ajani, M.D., both of Gastrointestinal Medical Oncology; and Jinsong Liu, M.D., Ph.D., of Pathology. Additional co-authors include: Zachary Nagel, Ph.D. and Leona Samson, Ph.D., Massachusetts Institute of Technology, Cambridge, MA; Jun Zou, Ph.D., Chen Wang, Ph.D., Xiangyi Ma, Ph.D. and Ding Ma, Ph.D., Huazhong University of Science and Technology, Wuhan, China; and Guo-Min Li, Ph.D., University of Texas Southwestern Medical Center, Dallas, TX.

This study was funded the by National Cancer Institute (CA016672), the Department of Defense (OC140431), the National Institutes of Health (CA181663, GM093104) and the Cancer Prevention Research Institute of Texas (RP160242).

© 2018 The University of Texas MD Anderson Cancer Center

Rucaparib Approved as Maintenance Treatment for Some Recurrent Ovarian Cancers

by NCI Staff

The National Cancer Institute -- May 4, 2018

companies img PARP inhibitors work by blocking one method that cancer cells use to repair damaged DNA.

Credit: Adapted from Cancer Cell 2011. doi: 10.1016/j.ccr.2011.01.047. CC BY 3.0.

The Food and Drug Administration (FDA) has expanded the approval of the targeted therapy rucaparib (Rubraca) for the treatment of women with ovarian cancer.

The approval covers the use of rucaparib as a follow-on, or maintenance, treatment for women whose ovarian cancer has returned after their initial treatment and whose tumors then shrank, at least partially, during subsequent treatment with a platinum-based chemotherapy. The approval, announced on April 6, also includes women with fallopian tube or primary peritoneal cancer.

Rucaparib is a type of drug called a PARP inhibitor, which prevents cells from repairing damage to their DNA. Rucaparib joins olaparib (Lynparza) and niraparib (Zejula) as the third PARP inhibitor to be approved as a maintenance therapy for women with recurrent ovarian, fallopian tube, or primary peritoneal cancers that still respond to platinum-based chemotherapies.

What makes the rucaparib approval novel, explained Elise Kohn, M.D., head of Gynecologic Cancer Therapeutics in NCI's Division of Cancer Treatment and Diagnosis, is that it includes the approval of the first companion diagnostic test measuring possible indicators of PARP sensitivity. The test, called FoundationFocus CDxBRCA LOH, can help predict which tumors might be most likely to respond to the treatment.

Disrupting DNA Repair in Cancer Cells

Most cells have many molecular mechanisms for repairing DNA, and PARP proteins are part of just one of these mechanisms. That means that drugs like rucaparib, which work by blocking the activity of PARP proteins, are most effective in cancer cells that already have damage to other DNA repair mechanisms, explained Robert Coleman, M.D., of the University of Texas MD Anderson Cancer Center.

Earlier clinical trials of PARP inhibitors found that they worked best in patients with mutations in the BRCA1 and BRCA2 genes, both of which play important roles in DNA repair.

However, ongoing research has suggested that PARP inhibitors may also work in tumors with other types of DNA repair defects, including a broad category of defects called homologous recombination deficiency (HRD). The companion diagnostic test approved with rucaparib tests tumors for BRCA gene mutations and for HRD.

Less Repair, More Benefit

In the phase 3 randomized trial, called ARIEL3, that led to the new approval for rucaparib, researchers led by Dr. Coleman enrolled 564 women with recurrent ovarian, fallopian tube, or primary peritoneal cancer. ARIEL 3 was funded by Clovis Oncology, Inc., the manufacturer of rucaparib.

All the women in the trial were responding, either completely or partially, to platinum-based chemotherapy. After testing participants' tumors with the companion diagnostic test, the researchers randomly assigned 375 to receive rucaparib, which is given daily as a pill, and 189 to receive a placebo. Women continued treatment until their cancer progressed, they died, or they chose to discontinue treatment because of side effects or other reasons.

Overall, the women who received rucaparib had a longer time before their disease progressed (progression-free survival) than women in the placebo group: 10.8 months, compared with 5.4 months. The benefit of rucaparib was stronger in patients with DNA repair defects, as measured by the companion diagnostic test. Women with HRD tumors but no germline (inherited) BRCA mutation who received rucaparib lived for a median of 13.6 months without disease progression. Women with germline BRCA mutations treated with rucaparib had a median progression-free survival of 16.6 months.

Serious side effects were more common in the women receiving rucaparib, including anemia, nausea, and headache. These side effects are common in women treated with any of the PARP inhibitors, explained Dr. Kohn. Two patients in the rucaparib group died because of secondary cancers related to treatment, compared with none in the placebo group.

The ARIEL3 researchers are continuing to follow trial participants over time to see whether treatment with rucaparib improves how long women live overall (overall survival).

Future Paths for PARP Inhibition

As clinicians become more comfortable using companion diagnostics to measure HRD and other biomarkers to gauge the potential vulnerability of a tumor to PARP inhibition, "they could end up being important decision-making tools," said Dr. Coleman.

Future trials will likely look at administering PARP maintenance therapy sooner in ovarian cancer treatment, after initial therapy (called primary maintenance), Dr. Coleman explained.

Researchers are also interested in testing PARP inhibitors as an initial, or first-line, treatment in both BRCA-positive and BRCA-negative ovarian cancers, continued Dr. Coleman.

Research in PARP inhibitors has also been expanded to include combinations with immunotherapies, such as immune checkpoint inhibitors, and with targeted therapies, like cediranib, explained Dr. Kohn. "There's a huge [effort] looking at how to leverage the activity of PARP inhibitors in combination therapies. That's the next step," she said.

Many of these trials are based on new knowledge of DNA repair mechanisms that has been gleaned from studying why some tumors are resistant to PARP inhibition, which in turn has led to the development of new drugs targeting DNA repair, she continued.

"It's a really nice circle that's been a welcome development," concluded Dr. Kohn.

Other Cancer Currents posts about PARP Inhibitors

© 2018 The National Cancer Institute

MD Anderson, Spectrum Pharmaceuticals complete poziotinib licensing deal

MD Anderson Cancer Centre -- May 3, 2018

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    HOUSTON - The University of Texas MD Anderson Cancer Center and Spectrum Pharmaceuticals have signed a licensing agreement that covers discoveries by MD Anderson researchers about the company's drug poziotinib, a targeted therapy for lung cancer.

    A research team led by John Heymach, M.D., Ph.D., professor and chair of Thoracic/Head and Neck Medical Oncology, found that poziotinib's size and structure make it a good fit for non-small cell lung cancer with an alteration called an exon 20 insertion in either the epidermal growth factor receptor (EGFR) or the human epidermal growth factor receptor 2 (HER2).

    Patients with the exon 20 alteration have had no options for successful treatment. The drug is in phase II clinical trials for these patients at MD Anderson and in a multi-center trial sponsored by Spectrum.

    "John Heymach and his Lung Cancer Moon Shot team uncovered the potential of Spectrum's drug poziotinib to help a neglected group of lung cancer patients and then worked closely with the company to bring this targeted therapy to clinical trial rapidly," said Ferran Prat, Ph.D., J.D., MD Anderson senior vice president, research administration and industry relations.

    "We are pleased to continue our collaboration with Spectrum under this agreement, which highlights how MD Anderson allies with private sector partners to provide new options for cancer patients."

    Researchers recently published their scientific findings in the journal Nature Medicine, and early results of MD Anderson's phase II clinical trial were first reported at an international meeting last fall.

    "We have been aggressively pursuing the potential of exon 20 mutations and treatment with poziotinib since the inception of our relationship with MD Anderson, but we've both only begun to scratch the surface of the science and poziotinib's potential as a targeted treatment for various solid tumors," said Joe Turgeon, president and CEO of Spectrum. "Late-stage poziotinib clinical data targeting the exon 20 mutation are promising, and we are thrilled to enter this new agreement that strengthens and potentially extends our patent protection until 2037 as we continue this journey of discovery together."

    About 3 percent of patients with either EGFR or HER2 non-small cell lung cancer have the exon 20 insertion, amounting to about 7,000 people diagnosed annually in the United States. Other approved EGFR inhibitors achieved response rates ranging from 3 percent to 12 percent among exon 20 patients in clinical trials. Median progression-free survival for these patients has been two months.

    So far in the MD Anderson trial, 7 of 11 patients (64 percent) have responded to poziotinib, with tumor shrinkage of at least 30 percent. After 6.6 months, median progression-free survival had not been reached. More detailed data from the trial will be reported later this year.

    "A deep dive into exon 20"

    Heymach says his team decided "to do a deep dive into exon 20" as part of its drug repurposing pipeline project opened under MD Anderson's Moon Shots Program, a collaborative effort to accelerate the development of scientific discoveries into life-saving advances.

    Postdoctoral fellow Jacqulyne Robichaux, Ph.D., and colleagues tested targeted therapies against lung cancer cell lines with exon 20 insertions in EGFR or HER2 and found the cells were strongly resistant to those drugs.

    Structural modeling conducted with Shuxing Zhang, PHARMD, Ph.D., associate professor of Experimental Therapeutics, revealed unique aspects of the target pocket in exon 20 EGFR and HER2 lung cancer. Additional structural analysis of poziotinib, which had failed against other EGFR mutations, indicated that it would more efficiently hit those exon 20 targets.

    Cell line and mouse model experiments confirmed that hypothesis. The team contacted Spectrum Pharmaceuticals and collaborated to launch the first phase II trial at MD Anderson.

    Heymach, Robichaux and colleagues continue to study resistance mechanisms to poziotinib and are working with MD Anderson colleagues to look at exon 20 insertions in other types of cancer.

    © 2018 The University of Texas MD Anderson Cancer Center

Study Shows Experimental Screening Test Can Detect Endometrial and Ovarian Cancers

by NCI Staff

The National Cancer Institute -- May 2, 2018

companies img PapSEEK detects genetic alterations in DNA that ovarian and endometrial tumors have shed into the uterus, cervix, and blood (plasma).

Credit: Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University

Researchers have shown that an experimental screening test can detect some endometrial and ovarian cancers at their early, more treatable stages. The test, called PapSEEK, is a type of liquid biopsy that identifies cancer-related alterations in DNA obtained from fluids collected during a routine Pap test.

In the NCI-funded study, which used Pap test samples from women already diagnosed with cancer, PapSEEK correctly identified most women with endometrial cancer and one-third of women with ovarian cancer. The test's ability to accurately identify cancer (its sensitivity) improved when the researchers also tested DNA collected from blood and other tissues.

Sudhir Srivastava, Ph.D., M.P.H., of NCI's Division of Cancer Prevention, called the findings "a good star" for developing an effective screening test for early-stage endometrial and ovarian cancer. "This lays the foundation for future studies," added Dr. Srivastava, who was not involved in the study.

The retrospective study was published March 21 in Science Translational Medicine. Additional prospective studies are needed to determine whether PapSEEK can correctly identify women with cancer who have not yet been diagnosed, the investigators noted.

Screening for Ovarian and Endometrial Cancers

For many years, researchers have strived to develop a feasible and reliable way to detect early-stage endometrial and ovarian cancers in women who do not have any symptoms. To date, there is no clinically validated biomarker for either cancer type that can be detected noninvasively.

But in an earlier study, Nickolas Papadopoulos, Ph.D., of Johns Hopkins University School of Medicine, and his colleagues found that they could detect trace amounts of DNA from endometrial and ovarian cancers in Pap test samples. For a Pap test, an instrument called a Pap brush is used to scrape the surface of the cervix to collect a sample of cells and DNA. While most of this DNA comes from cervical cells, endometrial and ovarian tumors also shed DNA that can reach the cervix.

Building on these findings, the research team developed PapSEEK, a test that analyzes Pap test samples for certain DNA mutations that are commonly found in endometrial and ovarian cancers. The test also detects aneuploidy, a genetic alteration associated with cancer in which cells have an abnormal number of chromosomes.

When the investigators used PapSEEK to analyze Pap test samples from women with cancer, the test identified cancer-related alterations in 81% of women with endometrial cancer and 33% of women with ovarian cancer. Alterations were detected in more women with late-stage than early-stage endometrial cancer and about the same fraction of women with early- and late-stage ovarian cancer.

In addition, PapSEEK gave only 1.4% of women without cancer a false-positive test result, showing that "the specificity of PapSEEK was high," the researchers wrote.

Enhancing PapSEEK's Sensitivity

To increase the test's sensitivity, the investigators decided to test samples taken from a location that is closer to the site of endometrial and ovarian cancers. They analyzed fluid samples collected from the lining of the uterus using an instrument called a Tao brush, which is approved by the Food and Drug Administration as a tool to diagnose endometrial cancer.

The test found cancer-related alterations in 93% of Tao samples from women with endometrial cancer, including 98% of women with late-stage endometrial cancer. It also identified cancer-related alterations in 45% of Tao samples from women with ovarian cancer.

No cancer-related alterations were detected in any of the Tao samples collected from women without cancer-an "ideal" characteristic for a screening test, Dr. Srivastava noted.

Testing Tao samples may have provided greater sensitivity for detecting ovarian and endometrial cancer than testing Pap samples because these tumors are located closer to the uterus than the cervix, Dr. Papadopoulos noted. Indeed, the researchers found that Tao samples contained more endometrial and ovarian tumor DNA than Pap samples, he explained.

Tumors can also shed DNA and tumor cells into the bloodstream. When the researchers tested blood samples from women with ovarian cancer, the sensitivity of PapSEEK was 43%. Combining PapSEEK results from blood and Pap samples from the same woman, however, increased the test's sensitivity to 63%.

There are likely several reasons why the sensitivity of PapSEEK was lower, across the board, for ovarian cancer than for endometrial cancer, Dr. Papadopoulos said.

One limitation, Dr. Srivastava said, is that the genetic mutations included in the PapSEEK panel appear to be "more common in endometrial cancer than ovarian cancer." Indeed, the test identified mutations in 97% of endometrial tumor samples but only 80% of ovarian tumor samples, the researchers found.

Another potential issue is that not every tumor sheds DNA into certain body fluids. When the investigators measured the amount of tumor DNA in Pap and Tao samples, they found comparatively more DNA from endometrial tumors than from ovarian tumors, Dr. Papadopoulos explained. This could be due to the location (ovarian cancers are further away from the site where Pap and Tao brush sampling are performed) or the biology of ovarian tumors, he added.

Overall, Dr. Papadopoulos said, "I think a shift in thinking needs to happen. A screening test with less than 100% sensitivity does not make the test useless. The important thing is to try to catch cancer early to reduce the number of people who may unknowingly have cancer and are doing nothing about it until it is too late."

While Dr. Srivastava agreed that a screening test for ovarian cancer is much needed, a test with low sensitivity "means you miss out on catching cancer," he noted. And false-positive results "can bring undue burden-physical, psychological, and financial burdens from the additional testing that is triggered. That's something that needs to be taken into consideration," he added, though PapSEEK produced very few false-positive results.

Not Reinventing the Wheel

While more studies of the PapSEEK test are needed before it can be considered for patient care, it does have several theoretical advantages for potential clinical use, Dr. Papadopoulos explained. For example, it is inexpensive, noninvasive, and easily administered.

"Women already go for Pap smears. We're using the same material, so we're not introducing a new type of exam," he added. "We didn't want to invent a new device or approach for [sample] collection."

The PapSEEK test is potentially "very doable and amenable to clinical use," Dr. Srivastava noted. "It could be performed at the same time women undergo a Pap test for cervical cancer."

The investigators are continuing to explore whether combining PapSEEK results from different body fluids increases the test's sensitivity for ovarian cancer.

Dr. Papadopoulos and his colleagues have also developed another liquid biopsy test, called CancerSEEK, that scans blood samples for a combination of genetic mutations and proteins that occur in eight different types of cancer.

In a similar retrospective study, CancerSEEK had 98% sensitivity for ovarian cancer, with a false-positive rate of less than 1%. As with PapSEEK, additional prospective studies are needed to determine whether CancerSEEK can identify cancer in asymptomatic people.

© 2018 The National Cancer Institute

Melody Management

Cancer Research & APP Development

NExT: Advancing Promising Cancer Therapies from the Lab to Clinical Trials

by James Doroshow, M.D. & Barbara Mroczkowski, Ph.D.

The National Cancer Institute -- June 29, 2018

companies img The NExT pipeline has three different stages, and projects can be entered at any one of the stages.

Credit: National Cancer Institute

    James Doroshow, M.D., is director of NCI's Division of Cancer Treatment and Diagnosis, and Barbara Mroczkowski, Ph.D., is the director of the NCI Experimental Therapeutics (NExT) program.

At the intersection of the federal government and the private sector lies a unique program called the NCI Experimental Therapeutics (NExT) program.

Although NCI operates the program, it runs very much like a small pharmaceutical or biotechnology company, working with external investigators and top scientific experts to advance promising or novel therapies from the earliest stages of research to human clinical trials.

Earlier this week, in fact, we were encouraged to see signs of promise from one NExT-developed therapy, when researchers from Duke University reported results from the first human trial of their cancer-killing, or oncolytic, virus therapy in patients with the brain cancer glioblastoma.

The genetically-modified poliovirus therapy, called PVSRIPO, is a feat of remarkable engineering: an inactivated poliovirus that has been programmed to target cells harboring a protein called CD155, which is overexpressed in many different cancer types, including glioblastoma.

The results from the phase 1 trial-presented on June 26 at the International Conference on Brain Tumor Research and Therapy and published simultaneously in the New England Journal of Medicine-are preliminary, but they also hint at a potentially important advance.

The trial enrolled patients with advanced glioblastoma whose cancer had progressed after numerous earlier treatments. Although phase 1 trials are primarily meant to assess whether a therapy is safe enough to move into larger human studies, the trial's lead investigator, Matthias Gromeier, M.D., and his colleagues reported that the 2- and 3-year survival rates among those in the trial were substantially higher than what is historically seen in patients with this highly fatal cancer.

Delivering Technology and Expertise to Drug Development

NExT focuses primarily on therapies that have the potential to provide an important advance or meet a critical need but are unlikely to initially attract private sector investment because they are too high risk or may only be of potential benefit to a small patient population.

And the poliovirus therapy is a good example.

For more than a decade, NCI worked with the Duke team to transform a virus with a propensity for killing cancer cells into a clinical-grade therapy. That painstaking work improved the virus's potency in eradicating tumor cells while ensuring that it would not mutate into a disease-causing infectious agent. This effort involved extensive laboratory testing and manufacturing work by many investigators, including the development of a next-generation sequencing test to ensure the engineered virus was genetically stable from batch to batch.

The development and production of this oncolytic virus required difficult, complicated science that relies on technology and expertise that is not available at most institutions, even large academic centers. And it involved a type of therapy that, at the time PVSRIPO was accepted into the program, the private sector considered to be high risk and was unwilling to pursue. [One oncolytic virus is now approved to treat cancer, melanoma, and others are being tested in clinical trials.]

Excitingly, this therapy will soon be tested in trials involving other cancer types, including childhood brain cancers, breast cancer, and melanoma.

An Evolving Program

This oncolytic virus is just one example of NExT in action. There are others, and their rapid ascension through the NExT development pipeline reflects the evolution and maturation of this program.

For example, although NExT has always relied on cutting-edge science and the expertise of leading researchers and clinicians, over the past decade NExT has approached developing drugs much like biotechnology or pharmaceutical companies do.

That includes doing things like forming multidisciplinary teams to address the critical factors needed to move a therapy forward. The members of these teams include scientists from outside NCI with the specific expertise needed to advance drugs through the development process, from optimizing the chemical structure of a small-molecule drug to how best to test certain types of therapies in cell lines and preclinical animal models.

It also means embracing a sense of urgency by establishing aggressive timelines so that the agents in the NExT pipeline can advance through this preclinical process as expeditiously as possible.

For example, researchers at Vanderbilt University initially discovered a small-molecule drug that targets the protein MCL-1, one of the most commonly overexpressed proteins in human cancer. MCL-1 has also been linked in a number of studies to treatment resistance, making it a highly attractive target for a cancer therapy.

Stephen Fesik, Ph.D., and his colleagues at Vanderbilt initially applied to the NExT program in 2013 to help further develop their MCL-1 inhibitor. After being accepted, the compound then went through numerous studies, including complex analyses to understand and optimize its structure so that it more effectively binds to its target on cancer cells, thus reducing the risk of side effects.

Another compound that recently graduated from NExT is one that blocks the activity of mutant forms of the protein IDH1, which are thought to be important drivers in glioblastoma.

Initially accepted into the NExT program in 2011, this compound has been tested extensively in the lab to ensure that it potently blocks the activity of IDH1 in cancer cells, to validate its ability to shrink tumors with IDH1 mutations, and to identify any signs of potential side effects.

Like the MCL-1 inhibitor, this drug was recently licensed to a private-sector company, in this case Fortress Biotech, where it is also expected to continue its progression toward human clinical trials.

Validation of the NExT Approach

The rapid turnaround from an initial compound to the brink of human studies seen with both the MCL-1 and IDH1 inhibitors is on par with what is typically achieved in the private sector.

With at least one other agent in the NExT pipeline poised for licensure, we believe this is a validation of the program and its approach to advancing the development of promising new cancer therapies.

We encourage all investigators-in academia or the nonprofit or private sectors-with a promising lead on a potentially game-changing therapy to apply to the NExT program. We believe we have a proven model, one that is only getting better with time.

And whether you are a cancer researcher or somebody who has been touched by cancer, that's definitely good news.

© 2018 The National Cancer Institute

Altering Chemotherapy Improves Outcomes in Early-Stage Pancreatic Cancer

by NCI Staff

The National Cancer Institute -- June 28, 2018

companies img In stage IIA pancreatic cancer, the cancer has not spread and the tumor can be removed surgically.

Credit: National Cancer Institute

Results from two clinical trials are expected to improve the outlook for people diagnosed with early-stage pancreatic cancer that can be treated with surgery.

In the first trial, changing the type of chemotherapy given after surgery from a single drug to a multi-drug regimen greatly improved how long patients lived. Patients in the trial treated with the multi-drug regimen survived for an average of 4.5 years after treatment, substantially longer than expected.

Such a long duration of survival for patients with this aggressive cancer type "is something that I thought I would never see in my lifetime," said Colin Weekes, M.D., Ph.D., of Massachusetts General Hospital, who was not involved in the study.

In the other trial, giving chemotherapy and radiation before surgery (neoadjuvant therapy), in addition to chemotherapy after surgery (adjuvant therapy), increased the number of patients who could successfully have their whole tumor removed. People in the neoadjuvant therapy group also lived longer without the cancer coming back after surgery than those who received chemotherapy only after surgery.

The results from both trials were presented earlier this month at the American Society of Clinical Oncology annual meeting in Chicago.

"We now have data showing that if we do something pretty radically different than we did before, we're going to get better results," commented Allyson Ocean, M.D., a gastrointestinal oncologist at Weill Cornell Medicine and NewYork-Presbyterian, who was not involved in either trial.

Practice-Changing Results for Early-Stage Pancreatic Cancer

Since the 1990s, the chemotherapy drug gemcitabine (Gemzar) has been the backbone of treatment for people with pancreatic cancer that can be removed with surgery (resectable). Traditionally, gemcitabine has been given as adjuvant chemotherapy, after the patient has recovered from surgery, which for many patients is a grueling procedure known as the Whipple procedure. (More recently, gemcitabine is sometimes combined with the chemotherapy drug capecitabine (Xeloda).)

An alternative chemotherapy regimen called FOLFIRINOX, which consist of four different drugs, is the first treatment option for patients whose cancer has already spread to distant sites in the body, or metastasized, at the time of their diagnosis.

Although FOLFIRINOX is a more effective than gemcitabine in patients with metastatic pancreatic cancer, doctors have thought that it would have too many debilitating side effects as adjuvant therapy for patients who have recently undergone and are recovering from surgery, explained Udo Rudloff, M.D., Ph.D., of NCI's Center for Cancer Research, who was not involved in either trial.

Although the patients who received mFOLFIRINOX had more side effects than patients who received gemcitabine and were less likely to finish all of their chemotherapy, outcomes were better in the mFOLFIRINOX group. Compared with gemcitabine, mFOLFIRINOX almost doubled the median length of time patients lived without their disease recurring, reported Thierry Conroy, M.D., of the Institut de Cancerologie de Lorraine in France, who led the trial. After 3 years, 63.5% of patients who had received mFOLFIRINOX were still alive, compared with 48.6% of patients who received gemcitabine.

"I really believe these are practice-changing data," commented Dr. Ocean. She changed the planned treatment for one of her patients the day after the PRODIGE 24 results were presented, just hours before he was scheduled to start chemotherapy with gemcitabine and capecitabine.

Although most patients who undergo surgery for early-stage pancreatic cancer are not as healthy as the patients in the trial, Dr. Ocean thinks that doctors will still likely try to give mFOLFIRINOX, or a further modified version, to many of them and see whether they can tolerate it.

"And if we're not sure, the best thing is always to discuss it with the patient and see if they want to take a risk with the more intense regimen," she said. "Most of the time they will."

Advantages to Giving Chemotherapy Before Surgery?

Although adjuvant chemotherapy has been shown to extend survival of patients with early-stage pancreatic cancer, Dr. Rudloff noted that waiting until after surgery to give chemotherapy has potential problems and might lead to inferior outcomes. "When patients have surgery first, a proportion have complications and then aren't healthy enough to receive chemotherapy, or there is a significant delay in starting chemotherapy," he said.

Almost all patients with early-stage disease likely have tiny, undetectable deposits of pancreatic cancer cells, called micrometastases, in other organs at the time of diagnosis, added Dr. Rudloff. So, if patients aren't healthy enough to receive chemotherapy after surgery, they are at higher risk of their disease recurring earlier and having worse outcomes, he explained.

In addition, said Geertjan van Tienhoven, M.D., Ph.D., of the Academic Medical Center in Amsterdam, who presented results from the neoadjuvant chemotherapy study at ASCO, in some patients the tumor is too close to blood vessels to be safely removed completely (borderline resectable pancreatic cancer). Giving chemotherapy before surgery may shrink such tumors enough to make complete removal safe.

In that trial, called PREOPANC-1, investigators enrolled 246 patients, about half of whom had borderline resectable tumors. The participants were randomly assigned to one of two groups. The neoadjuvant group received radiation therapy and gemcitabine before surgery, and also received gemcitabine after surgery. The standard treatment group received gemcitabine after surgery only, and no radiation or chemotherapy before surgery. Both groups were given the same total dose of gemcitabine.

PREOPANC-1 is still ongoing, so the results are preliminary, Dr. Tienhoven explained. Nevertheless, more than twice as many patients in the neoadjuvant group than the adjuvant group had their whole tumor removed successfully. And patients in the neoadjuvant group lived for a median of 11.2 months without their disease progressing, compared with 7.9 months for patients in the standard chemotherapy group. Two years after treatment began, 42% of patients in the neoadjuvant group were still alive, compared with 30% in the standard chemotherapy group.

Many oncologists who treat pancreatic cancer have already been giving neoadjuvant treatment, hoping to allow more patients to undergo surgery, explained Dr. Ocean. "And now there's data showing that we should," she said.

Further Improving Pancreatic Cancer Treatment

Together, the two trials immediately raise additional questions, Dr. Rudloff said. They include whether mFOLFIRINOX should replace gemcitabine as neoadjuvant therapy and whether using newer types of radiation therapy, such as stereotactic body radiation therapy, in neoadjuvant treatment regimens could further improve outcomes.

While waiting for further trials, more oncologists will probably start to use mFOLFIRINOX both in the neoadjuvant and adjuvant settings, speculated Dr. Ocean. "The challenge will be to accurately predict which patients will be able to handle this more intensive regimen, especially after a major surgery such as a Whipple or pancreatic cancer resection," she said.

Moving forward, Dr. Rudloff added, more laboratory studies and clinical trials are needed to develop completely new therapies for pancreatic cancer.

"What we need in pancreatic cancer, without any question, are better drugs," he said. "And while these studies represent progress, it is incremental. There's so much room for improvement."

© 2018 The National Cancer Institute

Approval Expanded for Venetoclax in Chronic Lymphocytic Leukemia

by NCI Staff

The National Cancer Institute -- June 22, 2018

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Credit: iStock

The targeted therapy venetoclax (Venclexta) can now be used for a broader group of patients with chronic lymphocytic leukemia (CLL).

Venetoclax was initially approved by the Food and Drug Administration (FDA) in 2016 to treat people with CLL that has a specific genomic alteration, called deletion 17p. On June 8, the agency expanded the drug's approval to include people with CLL whose cancer has progressed after receiving at least one previous treatment, regardless of whether their cancer cells have this genetic alteration.

This new approval was based on the results of a large clinical trial called MURANO, which was funded by the companies that manufacture and distribute venetoclax, AbbVie and Roche.

In the trial, patients treated with venetoclax in combination with rituximab (Rituxan) lived longer without their cancer progressing than patients who were treated with rituximab and bendamustine (Treanda). The improvement in progression-free survival was seen regardless of whether patients' cancers had the 17p deletion.

Further details on the findings from the MURANO trial and how this expanded approval of venetoclax should affect the care of patients with CLL were reported earlier this year in Cancer Currents.

© 2018 The National Cancer Institute

Do Frequent Follow-Up Tests Benefit Colorectal Cancer Survivors?

by NCI Staff

The National Cancer Institute -- June 20, 2018

companies img A test to detect CEA in the blood can be used to tell if colorectal cancer may have returned.

Credit: iStock

Undergoing follow-up testing for cancer recurrence more than once a year may not benefit people who have been treated for colorectal cancer, results from two new studies show.

The goal of follow-up testing, or surveillance, of people who have been treated for cancer is to improve patient survival by detecting and treating a recurrence early. But results from both studies, published May 22 in JAMA, showed that more frequent tests did not change the rate of detection of recurrence or death due to cancer.

For people who are diagnosed with colorectal cancer that has not spread to distant locations in the body, surgery can cure most patients. But in some patients, the cancer will return, usually within 3 years after surgery.

To try to detect recurrences as early as possible, people who have finished colorectal cancer treatment regularly return to their doctors for imaging tests (like CT or MRI scans) and a blood test to detect CEA, a substance that can indicate if cancer is growing. However, current medical guidelines differ on the recommended surveillance tests and how often they should be performed.

The National Comprehensive Cancer Network, for example, recommends that people who are treated for stage II or III colon or rectal cancer have CEA testing every 3 to 6 months for 2 years and then every 6 months for 3 additional years, plus CT scans every 6 to 12 months for 5 years.

"The data [from these studies] should definitely force us to get back together as a group and think about whether we need to revise the guidelines," said Blase Polite, M.D., an oncologist at the University of Chicago Medical Center.

Based on the findings of these and other studies, "there is now a considerable body of evidence that imaging and CEA testing more often than every year does little to improve survival in a meaningful way," wrote Hanna Sanoff, M.D., of the University of North Carolina at Chapel Hill, in an editorial on the two studies.

What Is the Best Surveillance Strategy for Colorectal Cancer?

Both of the new studies aimed to determine whether increased surveillance improved outcomes of colorectal cancer, but they took different approaches.

In one study, more than 2,500 people from several European countries who had had surgery to treat colorectal cancer were randomly assigned to receive either high- or low-intensity surveillance testing. Within 3 years after surgery, the high-intensity group received a CT scan and CEA assay 5 times each, while the low-intensity group received both tests twice.

The study, called COLOFUL, was led by Peer Wille-Jorgensen, D.M.Sc., of the Danish Colorectal Cancer Group.

After 5 years, the rate of detected cancer recurrence was unchanged between the high-intensity group and the low-intensity group. In addition, there was no difference in deaths overall or deaths from colorectal cancer between the two groups, the researchers found.

The findings were similar when the investigators stratified participants by cancer stage.

The other study was a retrospective cohort study, funded partly by NCI, of more than 8,500 people who had been treated for colorectal cancer in the United States and who were registered in the National Cancer Database-a collection of clinical oncology data gathered from multiple hospitals. The researchers used the database and additional information regarding surveillance testing and recurrence to track the patients' care for a minimum of 5 years, beginning with their cancer surgery.

"We noticed that there was tremendous variation in the number of [follow-up] tests patients received" and that the facility where patients received their follow-up strongly influenced the number of tests, explained the lead investigator, George J. Chang, M.D., of the University of Texas MD Anderson Cancer Center.

When the researchers characterized each facility as one that performed high- or low-intensity surveillance, they found that patients who were treated at low-intensity surveillance facilities received an average of 1.6 imaging tests and 1.6 CEA tests in 3 years. At high-intensity surveillance facilities, patients received an average of 2.9 imaging tests and 4.3 CEA tests in 3 years. On average, patients who were initially treated for advanced stage colorectal cancer received more tests.

Cancer recurrence was not detected earlier in patients who were tested at high-intensity facilities, regardless of cancer stage, Dr. Chang and his colleagues found. Nor did they find a significant difference in rates of treatment for cancer recurrence between patients who were tested at high- and low-intensity facilities.

Overall survival was also unaffected by the intensity of surveillance. The 5-year overall survival rate was about 74% for participants tested at both high- and low-intensity facilities.

What the results from these two studies reveal, said Dr. Polite, is that tumor biology trumps surveillance intensity. A slow-growing colorectal cancer "probably isn't going to change all that much between year 2 and year 3. So, you're probably not missing that window of opportunity" by doing surveillance tests once a year, he said. And colorectal cancer that spreads quickly between yearly surveillance tests is not likely to respond to available treatments anyway, he explained.

But for people who have been treated for colorectal cancer and who have certain risk factors that increase the risk of recurrence, more intense surveillance might be appropriate, Dr. Polite added. "I think we will end up risk-adapting guidelines as we learn more," he said.

Important, But Imperfect, Studies

Although these new studies are important, they do have limitations, Dr. Sanoff pointed out. For example, she noted, the COLOFUL trial investigators modified the design of their study to increase enrollment and aid trial completion.

And because the trial was conducted in Europe, another question is "whether the findings apply to the US population, with our diet and exercise habits," said Dr. Polite.

Dr. Chang's study compared the outcomes of patients who got tested at a high- or low-intensity facility, rather than comparing the outcomes of patients who received high-intensity or low-intensity testing, Dr. Sanoff noted. "Multiple factors, such as the aggressiveness of surgical resection at an individual facility, might influence these outcomes other than surveillance frequency," she wrote.

The Bottom Line for Survivors and Their Physicians

Based on their findings, Dr. Chang and his colleagues agreed with the surveillance recommendations of the National Institute for Health and Care Excellence in the United Kingdom: In the first 3 years following initial surgery, people who have been treated for colorectal cancer should receive CEA testing every 6 months in addition to two CT scans.

Although some patients may prefer more frequent surveillance for peace of mind, the tests are not without harms, Dr. Chang pointed out. Follow-up tests can be a psychological and financial burden on patients. In addition, every test comes with the risk of false-positive results that can lead to unnecessary and invasive additional tests.

"The message for survivors is one of reassurance," Dr. Chang said. "They don't have to get a CT scan at every follow-up visit."

The emphasis during follow-up should be not only on recurrence detection, but on the entire survivorship experience, he added. This encompasses monitoring people who have undergone cancer treatment for toxicities from their treatment, counseling them about leading a healthy lifestyle, and providing them with appropriate resources for psychosocial support and management of financial toxicity when needed.

That aspect of follow-up shouldn't change, said Dr. Polite.

© 2018 The National Cancer Institute

Mendelsohn shares Tang Prize for leadership in developing targeted therapy

MD Anderson Cancer Center -- June 18, 2018

companies img John Mendelsohn, M.D.

HOUSTON -- Targeted cancer therapy pioneer John Mendelsohn, M.D., researcher and former president of The University of Texas MD Anderson Cancer Center, will share the 2018 Tang Prize in Biopharmaceutical Science for his leadership in developing antibodies to block cancer-promoting growth factor receptors on the surface of cancer cells.

In announcing the award on June 19 in Taiwan, the Tang Foundation noted the three awardees launched the field of targeted therapy - attacking tumors based on their genetic and molecular aberrations -- with their research to understand the role of tyrosine kinase proteins and to design ways to block their activity.

Their work led to "a thorough understanding of the fundamental principles of cell growth and cancer development," the Tang Foundation noted in its announcement, and the therapies they developed "fundamentally changed the practices of cancer clinics."

Mendelsohn, president of MD Anderson from 1996 to 2011, is a professor of Genomic Medicine and director of the Zayed Institute for Personalized Cancer Therapy at MD Anderson, as well as the L.E. & Virginia Simmons Senior Fellow in the Division of Health and Technology Policy at Rice University's Baker Institute.

The honor cites Mendelsohn's role in conceiving the approach of using antibodies to target the epidermal growth factor receptor (EGFR), which is overexpressed or mutated to a cancer-promoting form in a variety of cancers.

Then at the University of California at San Diego, working with colleague Gordon Sato, Ph.D., Mendelsohn's team conducted preclinical research and developed the anti-EGFR antibody cetuximab (Erbitux), which went on to approval by the U.S. Food and Drug Administration for the treatment of colon cancer and head and neck cancer. This first tyrosine kinase-targeting antibody was "a trail-blazer which has spurred many others to follow," the Tang announcement notes.

"It's an honor to be recognized by the Tang Foundation with colleagues who opened such an important chapter of cancer research," Mendelsohn said. "By highlighting the vital connection between basic research and progress in the clinic, the Tang Foundation encourages the progress we need in scientific, translational and clinical research to continue to improve cancer treatment."

The Tang prizes, announced in 2012 by Taiwanese entrepreneur Samuel Yin, have been awarded every two years since 2014.

Also honored in Biopharmaceutical Science with Mendelsohn this year are:

  • Tony Hunter, Ph.D., professor of Biology at the Salk Institute, who discovered tyrosine phosphorylation, found that the Src oncogene is a tyrosine kinase, and demonstrated the role of tyrosine phosphorylation in uncontrolled cancer growth.
  • Brian Druker, M.D., director of the Oregon Health Sciences University Knight Cancer Institute, who advocated for and led the successful clinical trial of imatinib (known commercially as Gleevec) for chronic myelogenous leukemia, the first successful small-molecule tyrosine kinase inhibitor.

Tang prizes are awarded in four categories: Biopharmaceutical Science, Sustainable Development, Sinology (the study of Chinese language, history, customs and politics) and Rule of Law. Winners receive a medal and diploma and share a cash award of approximately $1.33 million and a $330,000 research grant.

© 2018 The University of Texas MD Anderson Cancer Center

Biosimilars for Cancer Emerge as Patents on Widely Used Biological Drugs Expire

by NCI Staff

The National Cancer Institute -- June 18, 2018

companies img Biological products, including biosimilars, are large and generally complex molecules.

Credit: Food and Drug Administration

When the patent on the cancer drug trastuzumab (Herceptin) expires next year, patients who have been receiving this biological therapy will have another treatment option: a biosimilar drug-a drug that is very similar, but not identical, to trastuzumab.

Last fall, the Food and Drug Administration (FDA) approved the first trastuzumab biosimilar for the treatment of some breast and stomach cancers based on research showing that, in terms of safety and effectiveness, the drug was comparable to trastuzumab.

To be approved as a biosimilar, a drug must be highly similar to the original biological drug-in this case, trastuzumab. And in terms of safety, purity, and potency, there can be no clinically meaningful differences between the biosimilar and the original product, which FDA calls the reference product.

When the trastuzumab biosimilar, trastuzumab-dkst (Ogivri), becomes available in 2019, it could be part of a wave of new biosimilars for patients with cancer.

"To date, eleven biosimilars have been approved in the United States, but nearly 70 more are in the development pipeline," said Leah Christl, Ph.D., director of the Therapeutic Biologics and Biosimilars Staff (TBBS) in FDA's Office of New Drugs, noting that the patents on some widely used biological drugs will expire in the coming years.

"The main advantage of biosimilar products," Dr. Christl continued, "is that they can provide additional treatment options and create market competition, potentially lowering the costs of treatment and enabling greater access to biological therapies for more patients."

Addressing the High Costs of Cancer Drugs

Biological drugs, or biologics, are generally large, complex molecules or mixtures of molecules that are derived from living organisms, such as yeast, bacteria, or plant or animal cells.

Unlike generic drugs, which have the same active ingredients as their corresponding brand-name drugs, a biosimilar drug is not an exact copy of its reference product, in part because biological drugs are derived from living organisms, which are inherently complex.

For patients with cancer, biological products include some immunotherapies and targeted therapies.

In 2005, biological products made up 39.1% of the $9.5 billion in Medicare drug spending. By 2014, these agents accounted for 62% of the $18.5 billion spent by Medicare on prescription drugs.

In a recent report on the rising costs of cancer drugs, the President's Cancer Panel concluded that biosimilars may play a role in reducing these expenses.

"We have to address the problem of cancer drug costs, and biosimilars may help us," agreed Sara A. Hurvitz, M.D., of UCLA's Jonsson Comprehensive Cancer Center, who moderated a panel on biosimilars at the 2018 American Association for Cancer Research (AACR) annual meeting.

The high prices of biological drugs represent one of the main challenges facing community cancer programs, Dr. Hurvitz noted.

She cautioned, however, that the potential impact of biosimilars on health care costs in the United States is still unclear and will depend on many factors, including the prices of biosimilars. Whether patients and clinicians view biosimilars as acceptable alternatives to the corresponding reference products will also play a role, she noted.

The Concept of Biosimilarity

Congress paved the way for the approval of biosimilars in 2010 with the passage of the Biologics Price Competition and Innovation Act, which created an abbreviated regulatory process for biosimilars. Five of the eleven biosimilars approved by FDA since then are for patients with cancer.

The first biosimilar to be approved in the United States, in 2015, was filgrastim-sndz (Zarxio), a biosimilar to filgrastim (Neupogen), which is used to prevent infection during chemotherapy. FDA has since approved ten other biosimilar products, including two drugs for treating cancer.

In addition to trastuzumab-dkst, FDA has also approved a biosimilar to bevacizumab (Avastin) for the treatment of multiple types of cancer. Called bevacizumab-awwb (Mvasi), the biosimilar could reach the US market by 2020, after the patent on bevacizumab expires.

And in May, FDA approved the first epoetin alfa biosimilar for the treatment of anemia caused by chronic kidney disease, chemotherapy, or the use of zidovudine in patients with HIV infection.

Manufacturers do not need to independently demonstrate the safety and effectiveness of biosimilars in large clinical trials to meet the approval standards of biosimilarity. If the same level of evidence from such trials were required for the approval of biosimilars as for the reference products, there would be less potential for cost savings, Dr. Hurvitz said.

For companies developing biosimilars, the goal is to establish biosimilarity, Sue Lim, M.D., director of the Scientific Review Staff within TBBS, said at the AACR meeting. This means that a new biosimilar product is highly similar to, and has no clinically meaningful differences from, the reference product.

The first step in establishing biosimilarity, Dr. Lim explained, is to characterize the chemical structure and biological function of the proposed biosimilar in a comparative fashion to the reference product.

"The thinking is that if a biosimilar has a highly similar structure and function as the reference product, then it should behave like the reference product-that is, be as effective and safe as the reference product in the clinical setting," she added.

Throughout the process of establishing biosimilarity, manufacturers work with FDA to determine the amount and the type of data required at each step. During the process, manufacturers may use existing, publicly available scientific data about the safety and effectiveness of a reference product to compare with the biosimilars they are developing.

Subtle Differences among Biological Products

Despite the requirement to be highly similar, biosimilars and reference products are allowed to have minor differences in clinically inactive ingredients. Furthermore, because biological products are produced in living cells, there may be slight variations between batches of biological products, including biosimilars, even among batches produced at the same facility.

"You can synthesize small-molecule drugs and expect to get the same product each time," Simon Hotchin, executive director of Regulatory Affairs at Amgen, Inc., said at the AACR meeting. "But the manufacturing of biological products is a proprietary, highly complex, and multistep process."

Biological products have "inherent variability," agreed Dr. Hurvitz. But FDA's manufacturing and quality-control standards ensure that naturally occurring variations in biological products do not affect a product's safety or effectiveness, she noted. In addition, as with all biological products, FDA requires manufacturers to monitor the safety and side effects of new biosimilars in patients.

The Concept of Extrapolation

Although biosimilars do not need to be independently tested for efficacy and safety, conducting a trial can help establish biosimilarity. One of the largest such trials to date compared a proposed trastuzumab biosimilar with trastuzumab in more than 450 patients with HER2-positive metastatic breast cancer.

There were no notable differences in side effects between the two treatment groups in the trial, but the study authors cautioned that additional follow-up is needed to ensure that the therapies have equal safety and effectiveness over the long term.

Although the proposed trastuzumab biosimilar was not tested in patients with stomach cancer, it was approved for both breast and stomach cancers-the same diseases for which the reference drug is approved. This is an example of a concept FDA calls "extrapolation."

"Understanding extrapolation is really important, and there are misconceptions about this concept," said Dr. Lim. If a company can show that its product is indeed biosimilar to its reference product for the agency to approve it for one indication, then, based on extrapolation, there is the potential for the biosimilar product to be approved for one or more conditions of use for which the reference product is also licensed, she explained.

Extrapolation is a familiar concept among regulators, Dr. Hurvitz noted. "Clinicians are going to have to be trained in the concept of extrapolation if they are to embrace the approval of biosimilars for applications beyond the initial approved setting."

Setting a Higher Bar for Interchangeability

Clinicians will also need to be educated about the idea of interchangeability, Dr. Hurvitz continued. An interchangeable product is a biosimilar product that may be substituted for the reference product without involving the health care provider who prescribed the drug.

Additional evidence is required from manufacturers for a biosimilar product to receive designation as an interchangeable product. For instance, manufacturers need to show that a biosimilar product is expected to produce the same clinical result as the reference product in any given patient.

And for a product that is administered more than once to an individual, manufacturers must show that switching between the proposed interchangeable drug and the reference product does not pose safety risks or compromise effectiveness.

FDA's high standards for approval of interchangeable products are intended to assure patients and health care providers that they can have confidence in the safety and effectiveness of an interchangeable product, just as they would for an FDA-approved reference product, Dr. Hurvitz noted.

No biosimilar has yet been approved as an interchangeable product, she added.

Lessons from the European Experience with Biosimilars

A theme of the AACR panel discussion was the need to educate clinicians and patients about biosimilar products, including what they are and how they are approved.

FDA has developed educational materials on biosimilars for patients and prescribers, as well as for nurses who will administer biosimilars and pharmacists who will dispense them. The agency intends to provide health care professionals with the information they need to consider prescribing these drugs as they become available, FDA Commissioner Scott Gottlieb, M.D., has said.

Thirty biosimilars have been approved in Europe since 2006, and these agents have helped to "lower costs and increase patient access to biologics," the President's Cancer Panel noted in its report. The report highlighted a study on the use of biosimilars in Europe, which raised no concerns about the safety or effectiveness of these treatments.

"The fact that biosimilars have been used in Europe and in Japan should give us some assurance that the drugs are as safe and effective as the corresponding reference products," said Chadi Nabhan, M.D., M.B.A., the chief medical officer at Cardinal Health Specialty Solutions, who conducted a survey of oncologists about their perceptions and acceptance of biosimilars.

"It's important to explain to clinicians and to patients that the FDA uses rigorous methods to approve biosimilars," continued Dr. Nabhan. "Many oncologists don't know how biosimilars get approved, but education can help address this gap in knowledge."

In the survey, many oncologists responded that once a biosimilar has been approved, they would be as comfortable prescribing it as they would a reference treatment-regardless of the patient's stage of disease and the goal of therapy, Dr. Nabhan explained.

"A lack of familiarity with-and concerns about-the concept of extrapolation also emerged in the survey as a barrier to adoption of biosimilars," he added.

Many More Biosimilars in the Pipeline

The favorable perceptions of clinicians toward biosimilars "are a critical first step" toward the adoption of these medicines, Dr. Nabhan concluded. But with so few FDA-approved biosimilars for cancer, it's too soon to know what impact biosimilars will have in the United States, including whether they will ultimately lead to lower costs for cancer care, he added.

That could change.

"As patents and exclusivity protections for biologics continue to expire in the US, we can expect many more biosimilars to be submitted for approval, creating greater competition within the marketplace," said Dr. Christl.

More products on the market "will influence uptake the most," she noted.

"Biosimilars," Dr. Nabhan added, "are here to stay. As more biosimilars come on the market, we can begin to assess the potential impact on health care costs."

© 2018 The National Cancer Institute

Phase III study shows quizartinib prolongs overall survival for patients with deadly type of relapsed or refractory AML

MD Anderson Cancer Center -- June 16, 2018

companies img Jorge Cortes, M.D.

A study led by The University of Texas MD Anderson Cancer Center revealed that the investigational drug quizartinib prolonged overall survival for patients with a deadly form of acute myeloid leukemia (AML) linked to a genetic mutation called FMS-like internal tandem duplications (FLT3-ITD).

Findings from the Phase III trial were presented June 16 at the European Hematology Society's 23rd Congress in Stockholm by Jorge Cortes, M.D., deputy chair and professor of Leukemia and lead investigator of the study called QUANTUM-R.

"Currently, there are no approved targeted therapies for patients with relapsed FLT3-ITD-associated AML, which represent a significant unmet medical need," said Cortes. "Our findings demonstrated that patients on quizartinib alone had an estimated overall survival of 27 percent after 52 weeks of treatment compared to20 percent for patients on standard chemotherapies."

The study confirmed the efficacy and safety of quizartinib and the value of targeting FLT3-ITD with this novel agent. It is the first trial to demonstrate improved overall survival for FLT3-ITD-associated AML patients who were treatment-resistant or who relapsed after prior therapy. The study followed 367 patients for 103 weeks at which time the first analyses were conducted. Minimal side effects were observed.

Cortes led the multi-institutional effort to develop and test quizartinib, a small molecule receptor tyrosine kinase inhibitor (TKI) targeting ITD abnormalities within the FLT3 gene. FLT3, a receptor tyrosine kinase commonly expressed in AML, is mutated in approximately one-third of AML patients. Tyrosine kinases are enzymes often linked to cancer as they play a critical role in cellular processes including cell growth, division, differentiation and cell death.

Patients enrolled in QUANTUM-R were 18 years or older who had refractory AML or who had relapsed six months or less following complete remission after receiving standard AML therapies. The study allowed participation regardless of whether the patient had received stem cell transplantation. Patients were randomized to be administered once-daily treatments with quizartinib, or to receive one of several chemotherapy options typically used after standard treatments have failed. Chemotherapies allowed were low-dose cytarabine, the combination of mitoxantrone, etoposide, and cytarabine, or the combination of fludarabine, cytarabine and idarubicin.

The two study arms were similar in patient makeup with a median age of 55 years for patients receiving quizartinib, and 57 years for those receiving chemotherapy. Of the quizartinib group, 33 percent of patients were refractory and 67 percent had relapses after an initial complete remission of six months or less prior to the study. Thirty-four percent of patients in the chemotherapy group were refractory and 66 percent had relapsed after pre-study complete remission of six months or less.

"These pivotal data confirm that targeting FLT3-IT with this potent new therapy may be of significant clinical value," said Cortes. "These results represent the first positive Phase III trial to demonstrate improved overall survival in patients with AML-associated FLT3-ITD."

Other participating institutions in the study included City of Hope National Medical Center, Duarte, Calif.; Instituto Scientifico Romangolo per lo Studio e la Cura dei Tumori, Meldola, Italy; University of Pennsylvania, Philadelphia; the University of Kansas Health System, Kansas City; Nottingham University Hospital, Nottingham, U.K.; University of Heidelberg and German Cancer Research Center, Heidelberg, Germany; University Paris Diderof, Paris; Vancouver General Hospital, Vancouver, British Columbia; University of California Davis Comprehensive Cancer Center, Sacramento, Calif.; The University of Hong Kong; The University of Bristol, Bristol, U.K.; Hospital Universitari i Politecnic La Fe, Valencia, Spain; University Medical Center of Johannes Gutenberg University, Mainz, Germany; Universita Cattolica del Sacro Cuore, Rome; Daiichi Sankyo, Inc., Basking Ridge, N.J.; and Sidney Kimmel Cancer Center at Johns Hopkins, Baltimore. The study was funded by Daiichi Sankyo, Inc. Cortes serves as a consultant for the company.

© 2018 The University of Texas MD Anderson Cancer Center

Trial Produces Practice-Changing Findings for Some Children, Young Adults with Leukemia

by NCI Staff

The National Cancer Institute -- June 14, 2018

companies img

Credit: Cancer.Gov

Adding the drug nelarabine (Arranon) to standard chemotherapy improves survival for children and young adults newly diagnosed with T-cell acute lymphoblastic leukemia (T-ALL), according to new results from an NCI-sponsored Children's Oncology Group (COG) clinical trial.

The trial was the largest ever conducted for patients with newly diagnosed T-ALL and T-cell lymphoblastic lymphoma (T-LL).

Four years after starting treatment, among those patients with T-ALL who had a moderate or high risk of their cancer returning, 89% of those who received nelarabine in addition to standard chemotherapy had no signs or symptoms of leukemia, compared with 83% of those who received chemotherapy alone.

"These results are practice changing and identify a new standard treatment for children with T-ALL," said Malcolm Smith, M.D., Ph.D., of NCI's Division of Cancer Treatment and Diagnosis, which helps fund COG.

ALL is the most common cancer in children, and T-ALL represents about 10% to 15% of all childhood ALL diagnoses.

An improvement in 4-year disease-free survival is noteworthy because most relapses of T-cell cancers occur in the first 3 or 4 years after diagnosis, said lead author Kimberly Dunsmore, M.D., of Virginia Tech Carilion School of Medicine.

Dr. Dunsmore presented the new findings at a May 16 press briefing ahead of the 2018 American Society of Clinical Oncology annual meeting in Chicago.

Trial Designed to Answer Two Questions

The COG AALL0434 trial, begun in 2007, enrolled 1,895 patients ranging from 1 to 30 years old. Most patients in this phase 3 trial (94% of participants) had T-ALL; the rest had T-LL.

All patients in the trial received standard chemotherapy as well as radiation therapy to the head to prevent or treat cancer that may have spread (metastasize) to the brain or central nervous system.

The trial included four treatment groups, reflecting the fact that it included two separate randomizations to answer two different questions.

First, the trial compared two ways of giving the drug methotrexate (Trexall, Rheumatrex) as part of the interim maintenance phase of chemotherapy treatment. Study participants were randomly assigned to receive either high-dose methotrexate (which requires hospitalization and additional medication to reduce side effects) or escalating-dose methotrexate (which involves starting with a low dose and gradually increasing the dose over time and can be done on an outpatient basis).

Second, the study asked whether adding nelarabine to standard therapy is superior to standard therapy alone in those patients judged to have a moderate or high risk of cancer recurrence. So those patients were also randomly assigned to receive or not receive six 5-day courses of nelarabine, which specifically targets T cells.

As the COG investigators reported previously, the 4-year disease-free survival rate was higher among patients who received escalating doses of methotrexate than among patients who received a very high dose of methotrexate. These findings contrasted with results from previous, smaller trials.

Patients in the trial who received both nelarabine and escalating-dose methotrexate had the best outcomes. This group of patients had a 4-year disease-free survival rate of 91%, which "is spectacular for pediatric T-ALL," Dr. Smith said.

Patients with T-ALL who failed to go into remission after 29 days were treated with high-dose methotrexate and nelarabine. Those patients had a disease-free survival rate of 55% at 4 years. "To put that into historical perspective, patients in [a large number of] other studies had a disease-free survival rate of 19%," Dr. Dunsmore noted.

Although nelarabine can have serious side effects, particularly in the nervous system (neurotoxicity), adverse side effects in general were not markedly different between the four treatment groups in the trial. And neurotoxicity, including peripheral and sensory neuropathy, occurred in 6% to 9% of participants in all four treatment groups, Dr. Dunsmore said.

The Food and Drug Administration (FDA) granted accelerated approval to nelarabine in 2005 for the treatment of T-cell leukemia or lymphoma that has not gotten better with other treatments or has recurred after earlier chemotherapy.

That provisional approval was based on results of two earlier NCI-funded phase 2 clinical trials, one in children and one in adults, Dr. Smith said. The COG trial was designed in the hopes of providing evidence to support a full FDA approval for nelarabine in newly diagnosed patients, he explained.

A Dramatic Improvement in Outcomes Since the Early 1990s

As recently as the early 1990s, Dr. Smith noted, 4-year disease-free survival rates for children with T-ALL were only about 60%. To achieve 4-year disease-free survival of more than 90% "is really a remarkable advance," he said.

Furthermore, 90% of all patients in the trial, regardless of which treatment they received, were still alive after 4 years.

"These are the best outcomes reported to date in a COG trial for children with this cancer, and they are equivalent to or better than outcomes that have been reported by [other clinical trial] groups throughout the world," Dr. Dunsmore said.

Until recently, the best 4- to 5-year disease-free survival rates for childhood T-ALL hovered around 80%.

Although the patients in the COG trial received lower doses of radiation than were used in the past, most oncologists are moving away from using any radiation to treat ALL, when possible, to avoid the risk of late effects, Dr. Smith said. These effects can include cognitive problems, learning disabilities, and hormonal problems, as well as new cancers that develop in the irradiated area.

"Some clinicians are already using nelarabine similarly to the way it was used in this trial and omitting the radiation," Dr. Smith said. But, he added, "we'll need more research before we can ensure that a nelarabine treatment regimen without cranial irradiation is an appropriate standard of care."

The COG researchers plan to follow patients in the trial for several more years, "as we do for all COG studies, so we can make sure patients are maintaining the results that we've seen and to try to understand what future complications may arise," Dr. Dunsmore said.

© 2018 The National Cancer Institute

Researchers find combination can enhance ipilimumab immunotherapy

Anti-CTLA-4 treatment triggers immune-suppressing EZH2 on T cells; clinical trial open

MD Anderson Cancer Center -- June 14, 2018

companies img Padmanee Sharma, M.D., Ph.D.

HOUSTON -- Using a targeted therapy to block a protein that suppresses T cell activity could improve cancer treatment with immune checkpoint inhibitors, researchers at The University of Texas MD Anderson Cancer Center report today in the Journal of Clinical Investigation.

The team showed that EZH2 is elevated in immune T cells in patients after treatment with ipilimumab, a drug that unleashes an immune response by blocking the activity of CTLA-4 on T cells, white blood cells that serve as the targeted warriors of the adaptive immune system.

"Immune checkpoint therapy has led to significant clinical responses in some patients but in order to provide benefit to even more patients, we will need rationally designed combination therapies," said senior author Padmanee Sharma, M.D., Ph.D., professor of Genitourinary Medical Oncology and Immunology.

"Our studies show that anti-CTLA-4 therapy can lead to increased EZH2 expression in T cells, which can act to diminish T cell responses," Sharma said.

Preclinical research in mouse models showed that combination therapy using a drug that inhibits EZH2 and ipilimumab improved T cell responses, tumor rejection and extended survival. MD Anderson researchers have translated these findings into the clinic, with a phase I clinical trial of the combination open this spring.

First clue in ipilimumab-treated patients

companies img Sangeeta Goswami, M.D., Ph.D.

The team's research began with an observation in Sharma's lab with experiments conducted by first author Sangeeta Goswami, M.D., Ph.D., who was studying patient samples from a clinical trial of ipilimumab. Sharma's team, working through MD Anderson's Immunotherapy platform, examined samples from bladder cancer, prostate cancer and melanoma patients taken before and after treatment to analyze changes in immune activity.

Goswami found EZH2 levels in patients' T cells elevated after treatment with ipilimumab and that increase was correlated in prostate cancer patients with cancer progression as measured by prostate specific antigen levels.

EZH2 is known to work epigenetically, repressing genes by regulating a histone protein to stabilize expression of a transcription factor in regulatory T cells that act to suppress immune response.

To better understand the consequences of EZH2 elevation, Goswami, Sharma and colleagues conducted a series of lab experiments.

They were the first to show that EZH2 inhibition enhances the function of effector T cells (CD8+ and CD4+ T cells). Goswami ran a series of tests on four different inhibitors and showed for the first time that CPI-1205 had the greatest effect suppressing T cell differentiation into regulatory T cells.

Follow-up experiments showed that EZH2 inhibition forced regulatory T cells to lose their suppressive capacity, changing their phenotype to effector-like T cells. Additionally, mice genetically altered to lack EZH2 on their regulatory T cells had significant tumor regression compared to control mice after inoculation with a bladder cancer cell line. They also had elevated levels of CD8-positive T cells in and around their tumors

Connection with anti-CTLA-4

T cells are activated by CD28, a co-stimulatory molecule that fires up the cells once their T cell receptor has connected with an antigen target. CD28 also turns on CTLA-4, an immune checkpoint. The team hypothesized that blocking CTLA-4 with ipilimumab results in exaggerated CD28 signaling that increases EZH2 in T cells.

By examining T cells collected before and after treatment with ipilimumab for bladder, melanoma and prostate cancer patients, the team found increased EZH2 expression in effector T cells and regulatory T cells after treatment. Among prostate cancer patients, elevated EZH2 in those T cells was correlated with PSA-measured tumor progression.

Combination thwarts tumor growth

Treatment with the ipilimumab and CPI-1205 combination caused major reductions in tumor growth, significantly increased survival, reduced the percentage of regulatory T cells and increased tumor-penetrating effector cells compared to treatment with either drug alone in two types of mice, one that develops bladder cancer and one with melanoma.

Treating mice that have EZH2 knocked out with ipilimumab resulted in complete tumor rejection by the immune system.

No immune-related toxicities were observed in mice treated with the combination.

The phase I clinical trial at MD Anderson is a safety and dosing trial that treats patients with advanced tumors with either combination of CPI-1205 and ipilimumab or CPI-1205 and pembrolizumab, which blocks PD1, a different immune checkpoint.

Co-authors with Sharma and Goswami are Jan Zhang, Swetha Anandhan, Liangwen Xiong, Ph.D., Ana Aparicio, M.D., and Sumit Subudhi, M.D., Ph.D., of Genitourinary Medical Oncology; Irina Apostolou, Ph.D., Jill Skepner, and Patrick Trojer, Ph.D., of Constellation Pharmaceuticals; Xuejun Zhang, M.D., and Hao Zhao, Ph.D., of MD Anderson's Immunotherapy Platform; and Jim Allison, Ph.D., of Immunology. Anandhan is a graduate student in the MD Anderson/UTHealth Graduate School of Biomedical Sciences.

Sharma serves on the scientific advisory board of Constellation Pharmaceuticals, which makes CPI-1205. She has consulted for Bristol-Myers Squibb, which makes ipilimumab, known commercially as Yervoy

Funding for this research was provided by the Parker Institute for Cancer Immunotherapy and a grant from the National Cancer Institute of the National Institutes of Health (RO1CA163793).

© 2018 The University of Texas MD Anderson Cancer Center

MD Anderson, Houston Methodist scientists detect new ovarian cancer target

Preclinical research shows malignant cells' tie to supportive fibroblasts can be hit with Calcitriol

MD Anderson Cancer Center -- June 13, 2018

companies img Credit: PharmamarStock

HOUSTON -- Researchers at Houston Methodist Research Institute and The University of Texas MD Anderson Cancer Center have found a prescription drug, Calcitriol, approved by the Food and Drug Administration for the treatment of calcium deficiency and kidney diseases, may increase the likelihood of surviving ovarian cancer.

Their preclinical research, reported in the Journal of the National Cancer Institute, integrated computational modeling and biology experiments in cell lines and mouse models to pinpoint a molecular pathway between malignant cells and supportive cells, called fibroblasts, associated with poor prognosis for patients with high-grade serous ovarian cancer, the most common and difficult form of the disease.

A review of potential drugs by Houston Methodist researchers indicated that a synthetic and active form of a vitamin D analog called Calcitriol might break up molecular communication between cancer cells and fibroblasts, a finding confirmed in mouse models by MD Anderson researchers.

This study opens a new potential avenue for treating ovarian cancer. Since Calcitriol is an FDA-approved drug, no additional research is needed before the drug can advance to human clinical trials for ovarian cancer. The researchers are working to address regulatory procedures, planning and funding required to open a clinical trial.

"Targeting cancer cells might not be the only solution to treating cancer. Other cells in the tumor and surrounding microenvironment, such as fibroblasts, immune cells, fat cells and other supportive cells make up the very complex ecosystem of tumors that we need to understand," said Samuel Mok, Ph.D., professor of Gynecologic Oncology and Reproductive Medicine and co-senior author of the study.

Using a computer modeling technique pioneered by co-senior author Stephen Wong, Ph.D., the Houston Methodist team processed and analyzed genomic big data to identify crosstalk targets and screen FDA-approved drugs. Their approach allowed them to look at the complexity of the interactions among tumor cells and different types of supporting cells to see a full map of their intricacies.

"In this era of big data, we can systematically identify pathways and therapies, as we're using an unbiased approach to look at all possibilities," said Wong, chair of systems medicine and bioengineering and John S. Dunn Sr. Presidential Distinguished Chair in Biomedical Engineering at Houston Methodist. "Our computational modeling can tell you which pathway is important for a particular disease. It allows for the heterogeneous tumor data to be fed in to the model to precisely identify these pathways, giving us a comprehensive view and allowing us to see specifically which malfunctioning cells to target."

Fibroblasts make and maintain connective tissue that provides a scaffolding for organs. To better understand their role, Mok, co-lead author Tsz-Lun Yeung, Ph.D., and colleagues carved out fibroblasts from tumor samples to study separately, using a precise process called laser microdissection.

They studied gene expression by these cancer-associated fibroblasts (CAFs) and found the fibroblasts had two distinct expression, or signatures that they named CAF-C and CAF-N.

"A survival analysis of these two CAF types in 46 ovarian cancer patients showed that patients with CAF-C fibroblasts had a poor prognosis, with median overall survival of 16 months compared to 33 months for the other type," Mok said.

Smad signaling between cancer cell, fibroblasts

The next step was to sort out what, specifically, makes the CAF-C group promote aggressive disease. Using a multi-cellular crosstalk modeling tool developed by Wong, called CCCExplorer (Cell-Cell Communication Explorer), co-lead author Jianting Sheng, Ph.D., and colleagues of the Houston Methodist team input gene-expression profiles from micro-dissected fibroblasts and neighboring ovarian cancer cells provided by Mok to compute, predict and prioritize crosstalk pathways and cell-to-cell interactions in the tumor microenvironment.

"We identified a signaling pathway, called Smad, as the culprit of poor ovarian cancer outcomes," Wong said. "Reprogramming these cells by targeting their communication networks presents an opportunity for the development of new cancer treatment strategies. If we focus on targeting these supportive cells in the tumor microenvironment instead of the tumor, itself, it could lead to less toxic, more effective treatments."

Experiments by Mok and colleagues confirmed the primacy of Smad signaling. Gene expression analysis again clustered patients into two groups; those with high expression of Smad-regulated genes had median overall survival of 15 months compared to 26 months for those with low expression.

Wong and colleagues at Houston Methodist applied another computational module in their CCCExplorer tool to predict known drugs that have passed phase I safety trials that might target Smad signaling. Calcitriol was selected for further studies in part because previous research shows it can inhibit the binding of Smad proteins to their target genes.

MD Anderson cell line experiments showed Calcitriol blocks Smad signaling. Treating ovarian-tumor bearing mice with Calcitriol reduced cancer cell proliferation and tumor volume while lengthening median overall survival from 36 to 48 weeks.

"We know that cells in the tumor microenvironment actually support the cancer and may contribute to its aggressiveness. This study opens up a new potential avenue for developing ovarian cancer treatments," said co-author Karen Lu, M.D., chair of Gynecologic Oncology and Reproductive Medicine at MD Anderson and J. Taylor Wharton, M.D., Distinguished Chair in Gynecologic Oncology.

"These researchers have developed a unique and powerful concept to decode crosstalk and interactions among different cell components in the complex tumor microenvironment," said Jenny C. Chang, M.D., director of Houston Methodist Cancer Center and Emily Herrmann Chair in Cancer Research. "Instead of testing one hypothesis at a time, the modeling tool now allows the cancer researchers and drug designers to comprehensively evaluate major intercellular crosstalk pathways simultaneously to find novel targets for ovarian and other cancers."

Co-authors with Mok, Wong, Yeung, Sheng and Lu are: Cecilia Leung, Ph.D., and Samuel Hoof Gynecologic Oncology and Reproductive Medicine at MD Anderson; Fuhai Li, Ph.D., of The Ohio State University College of Medicine, Columbus, Ohio; Jaeyon Kim, Ph.D., Melvin & Bren Simon Cancer Center, University of Indiana, Indianapolis; and Martin Matzuk, M.D., Ph.D., Baylor College of Medicine, Houston.

The study was funded by grants from the National Cancer Institute of the National Institutes of Health (R01CA133057, R01CA142832, RC4CA156551, U01188388, U54CA151668, U54CA149196, and UH2 TR000943) MD Anderson's Ovarian Cancer Specialized Program of Research Excellence (SPORE) (P50CA083639), MD Anderson's Uterine SPORE grant (P50CA098258) and by MD Anderson's Cancer Center Support Grant (P30CA016672 ) from the National Institutes of Health; by the U.S. Department of Health and Human Services; the Ovarian Cancer Research Program, U.S. Department of Defense; the Gilder Foundation; the Cancer Prevention and Research Institute of Texas (CPRIT) and a CPRIT Core Facility Support Award: funding from Mr. Carl L. Norton, the Anna and John J. Sie Foundation, The Mary K. Chapman Foundation, the Ovarian Cancer Research Fund, the Ting Tsung and Wei Fong Chao Center for Bioinformatics Research and Imaging for Neurosciences (BRAIN), Cancer Fighters of Houston, Inc., and the John S. Dunn Foundation.

© 2018 The University of Texas MD Anderson Cancer Center

OncoArray Links Dozens of DNA Variants to Risk for Common Cancers

by NCI Staff

The National Cancer Institute -- June 12, 2018

companies img The OncoArray Network uses a customized high-throughput DNA processing array to identify genetic differences, or variants, linked to increased cancer risk.

Credit: National Cancer Institute

Over the last decade, genome-wide association studies (GWAS) have begun to identify common inherited genetic differences, or variants, that influence disease risk. Now, researchers with the NCI-supported GAME-ON initiative and OncoArray Network are on their way to completing the latest round of cutting-edge studies of inherited risk factors.

These researchers have recently published studies identifying dozens of new genetic variants associated with the risk for developing cancer.

A recent study published in Nature Genetics, for example, found 10 new variants associated with lung cancer, and studies published in Nature and Nature Genetics found 72 new variants associated with breast cancer.

In the case of breast cancer, 10 of the risk variants are associated specifically with the risk of developing estrogen receptor-negative disease, which tends to have a poor prognosis and for which few genetic influences were previously known.

The latest results to come out of the OncoArray Network, published June 11 in Nature Genetics, identified 63 additional genetic variants associated with risk for prostate cancer.

The GAME-ON, or Genetic Associations and Mechanisms in Oncology, initiative was funded by NCI beginning in 2010 to provide a comprehensive look at genetic variants that influence the risk for five common types of cancer and then investigate the underlying biology of how those variants contribute to risk.

The OncoArray Network was formed by scientists from the GAME-ON initiative and other disease-based consortia to develop a new, more useful custom genotyping array. This new array was used to test for DNA variants across hundreds of thousands of people and several different cancer types.

The types of common variants identified each have a small effect and "are not necessary or sufficient" on their own to cause cancer, said Stephen Chanock, M.D., director of NCI's Ma href="https://dceg.cancer.gov/". They "contribute to the complexity of cancer," Dr. Chanock said.

Ultimately, the aim of GAME-ON was to help researchers better understand the biological causes of the cancers being studied and how multiple risk factors, each with a small effect, stack up to make some people more likely to develop cancer.

With this information in hand, researchers may, for example, be able to identify specific groups of people who might benefit most from earlier screening for a given cancer or who might safely put off screening for a few years, said Stefanie Nelson, Ph.D., a program director in NCI's Division of Cancer Control and Population Sciences, who administers GAME-ON grants.

Screening for cancer is "not easy," she said. "If we can help clinicians shift their focus to those most at risk, that would be really helpful."

Strength in Numbers

A spur for GAME-ON was to try to develop promising leads obtained from the first wave of GWAS, which are used to identify DNA variants that are associated with risk of a disease. Starting just over a decade ago, Dr. Chanock and other researchers began to use GWAS to link DNA variants located throughout the genome to cancer risk.

GWAS studies reveal markers-signposts that highlight a region of the genome as potentially important for disease risk. The next step is to painstakingly map and explore those regions, trying to pinpoint the actual DNA variations that may trigger cells to evade normal checks on growth and become cancer.

Before GWAS came along, geneticists typically tried to work out how genetics influences cancer risk by looking for altered genes in families with an unusually high rate of cancer. In contrast, GWAS research derives its strength from numbers-testing DNA from huge numbers of unrelated people both with and without cancer.

The GAME-ON initiative was launched to provide a comprehensive analysis of genetic variants that influence the risk for five common types of cancer.

GAME-ON and its spin-off project, the OncoArray Network, brought together genetic and detailed clinical information from hundreds of thousands of patients to try to locate the changes in DNA that contribute to the development of cancer-a process that occurs over years-and analyze the interplay between genetics and factors such as weight, height, tobacco use, alcohol consumption, vitamin D levels, and hormone use.

GAME-ON and OncoArray collaborators hail from around the world and from many disciplines-including epidemiology, statistics, genetics, and molecular biology. They conduct research at more than 350 institutions in 60 countries and have published more than 400 scientific articles, including some of the largest genetic association studies of cancer.

Economies of Scale

Working with network researchers, the company Illumina produced a customized DNA microarray for the OncoArray project. The array includes more than half a million variants across the genome.

Some variants were chosen because researchers already had reason to believe they might be linked to cancer, while others were distributed evenly throughout the genome to allow for the discovery of new regions associated with cancer risk. Researchers in the network were able to use the array for only $40 a sample.

OncoArray was a huge project taking years and a great deal of coordination, said Christopher Amos, Ph.D., a biomedical data scientist at the Baylor College of Medicine and Dartmouth College.

"The cost was exceptionally low. That was part of the impetus," Dr. Amos said.

By forming such a large collaboration, the OncoArray Network was able to develop a high-density microarray manufactured for a price that allowed for large-scale study. The initial plan for the network was to test 410,000 people for over 500,000 markers, but the number of people tested with the array has surpassed that goal.

Studies reporting OncoArray findings began to be published last summer and will continue to be published over the next few years.

The chip is a "phenomenal resource that can be used to study all kinds of cancers," Dr. Amos said. Genetic epidemiologists and any researchers "who want to investigate the biology of cancer risk" could use the array, Dr. Nelson said. Researchers could also use the chip to see how much cancers in different tissues overlap genetically.

Dr. Amos points out that the OncoArray Network drove technology development in an additional way; the project's large number of samples prompted Illumina to create a new microarray format that can test twice as many DNA samples at a time compared with the previous format-24 instead of 12.

Dozens of research groups contributed DNA to be genotyped using the OncoArray chip, which was crucial to detect rarer variants. For lung cancer alone, researchers from 30 different projects contributed patient DNA, Dr. Amos noted. The DNA was tested at eight genotyping centers, and the data from the genotyping centers were pooled and analyzed at three central sites-the University of Southern California, Dartmouth, and Cambridge University.

In accordance with a tradition of open sharing of data among genomic researchers, all network participants have agreed to deposit research results into NIH's Database of Genotypes and Phenotypes to allow for public access to the data.

Next Steps

The GAME-ON and OncoArray studies have been "sort of a treasure hunt," Dr. Nelson said. They have linked dozens of variants for the first time to the risk for developing cancer, shining a spotlight on regions of the human genome that had never before been linked to cancer risk.

The new risk variants found by the GAME-ON and OncoArray Network scientists are located throughout the genome. The variants are not clustered together, and few of them are within genes. Instead, almost all of them are within sites of the genome that appear to be important for controlling the activity of genes, Dr. Chanock said.

Variants found through GWAS together can account for a little less than half of the familial risk for breast cancer, Dr. Chanock said. When rare mutations are added to the mix, it may now be possible to explain as much as two-thirds of a woman's familial risk for breast cancer.

Much remains to be understood about the newly identified variants that have been linked to risk for different cancer types, Dr. Chanock cautioned, noting that researchers can explain the function of only about 5% of the regions.

While biologists try to understand how specific variants influence cancer risk, epidemiologists are using the results from GAME-ON and the OncoArray studies to develop models that predict cancer risk in individuals and are starting to test those predictions in large group studies.

The outlook seems particularly promising for estimating the risk for prostate and breast cancer. Trials are evaluating whether genetic profiles can help improve screening for these cancers.

A study in the United Kingdom, for example, is evaluating the use of genetic risk profiles to decide who should be screened for prostate cancer and to interpret screening results. As part of another large study, researchers are assessing whether genetic profiling can help improve breast cancer screening, Dr. Amos noted.

Dr. Chanock calls these kinds of studies an effort at "precision prevention." The goal, he said, is less overtreatment and more successful intervention, possibly when the disease is still precancerous.

"This GWAS age is very exciting," said Dr. Chanock. But, echoing Winston Churchill, he said, "The most we can say is that it's the end of the beginning, not the beginning of the end. We have a long way to go."

© 2018 The National Cancer Institute

Maximizing the Prospects for Progress Against Cancer

by Norman E. Sharpless, M.D.

The National Cancer Institute -- June 11, 2018

companies img NCI Director Dr. Norman Sharpless speaking during the opening session of the American Society of Clinical Oncology's 2018 annual meeting.

Credit: ASCO/Scott Morgan 2018

Since the beginning of my training as an oncologist in 1996, I have often attended the American Society of Clinical Oncology (ASCO) annual meeting. This year's meeting, however, was the first where I had the honor of attending and speaking in my role as NCI director.

In my remarks at the meeting's opening session, I explained to the audience that I initially joined ASCO when I was a young oncologist-in-training. And that I did so out of abject fear-fear that I did not yet have the experience and expertise to provide the best care possible to the patients I was seeing. Joining ASCO was a way to change that. My patients needed a really good oncologist, and joining an organization like ASCO would help me become one.

The ASCO annual meeting is one of the most important events each year for clinical oncologists from around the world. Researchers and clinicians at every level will tell you that they always leave the meeting more informed, inspired, and connected than when they arrived.

It was gratifying to see so many NCI investigators and NCI-funded investigators reporting on their work at this year's meeting. And the breadth of that work-lab studies identifying biologic factors that can fuel treatment resistance, late-phase trials of new therapies, innovative supportive-care studies, to cite just a few examples-is staggering.

A number of study results presented at this year's meeting deservedly received a lot of attention and praise. Although there are too many to discuss them all, here's a sample of some results that I found to be particularly intriguing and that will change practice or have tremendous potential to do so:

  • The 10,000-patient, NCI-funded TAILORx trial found that approximately 70% of women with the most common form of early-stage breast cancer do not need cytotoxic chemotherapy given after surgery to remove their tumors. By allowing clinicians to safely and confidently de-escalate therapy, these findings will allow thousands of women each year to be spared the physical and financial toll that can often come along with chemotherapy.
  • An industry-funded phase 3 trial showed a nearly 40% improvement in median overall survival for some patients with advanced non-small cell lung cancer using a combination of the immune checkpoint inhibitor pembrolizumab (Keytruda) and classical cytotoxic chemotherapy.
  • In a phase I clinical trial, an investigational targeted inhibitor of the RET kinase, Loxo-292, produced tumor response rates of nearly 80% in patients with advanced cancers (especially lung and thyroid cancer) whose tumors had alterations in the RET gene.
  • In great results from a trial led by investigators from NCI's Center for Cancer Research, the MEK inhibitor selumetinib showed impressive efficacy in some children with neurofibromatosis type 1 (NF1). At the meeting, the NCI investigators reported that the drug substantially shrank tumors in many children with NF1 who had developed large tumors called plexiform neurofibromas that can cause significant health problems. Parents of several children on this trial have told me how this drug has been life changing for their children.
  • From a phase 3 trial performed in Europe, researchers showed that, in patients with pancreatic cancer that could be removed by surgery, a four-drug chemotherapy combination (mFOLFIRINOX) led to dramatic improvements in how long patients lived compared with those who were treated with standard therapy. Although this is an important finding that should change the standard of care, it's important to note that most people diagnosed with pancreatic cancer already have inoperable or metastatic disease at the time of their diagnosis. NCI is funding efforts to develop ways to identify pancreatic cancer in its earliest stages so that more patients can be treated surgically.
  • Initial results from three more treatment arms of patients in the NCI-MATCH trial were also presented at the meeting. The findings confirm that this innovative trial can identify "signals" that targeted therapies may have promise in specific patients or cancers and these drugs should be further studied in these specific groups.

Of course, there were many other important research findings presented at the meeting. But the examples I've cited demonstrate an important point about the state of cancer research and care right now.

I would argue that almost any of the results listed above would have 'stolen the show' at ASCO a decade ago. But now progress is coming so rapidly in cancer therapy that great results like these are beginning to seem commonplace. It feels like we've almost become inured to the progress we're making.

And our national statistics bear out this progress. As was just reported in the most recent Annual Report to the Nation, over the past 15 years, there has been a steady decline in overall cancer death rates in men, women, and children in the United States in all major racial and ethnic groups.

This long and sustained trend, which all indicators suggest will continue, includes major reductions in some cancer-related racial/ethnic disparities, as well as improvements in death rates for some of the most intractable cancers.

Given such progress, it is vital to point out that these successes have been very hard won-the result of decades of elegant and detailed basic science that have allowed us to have a more precise understanding of cancer biology. And as I said during my address to ASCO, we still don't have cancer totally figured out, so now is not the time to reduce our efforts in the basic investigation of cancer biology which are beginning to pay off so handsomely.

It is also important to acknowledge that despite these areas of hope and good news, there are many formidable challenges that remain for patients with cancer.

Although overall cancer death rates have declined, death rates for certain types of cancer-including brain, liver, and uterine cancer-have increased. Too many children diagnosed with cancer are still dying or having to endure lifelong toxicities as a result of their treatment. And we're just starting to come to grips with an increasingly common side effect of being diagnosed with cancer: financial toxicity.

To better address those challenges, I recently announced my four key focus areas as NCI director: a continued commitment to basic science, developing and preparing the cancer workforce, strengthening our data infrastructure, and enhancing the value of clinical trials. Following this approach will allow us, as a research community, to maximize our chances for achieving rapid and meaningful progress in cancer research and care.

And I'm confident that NCI can and should be the catalyst to make all of this happen.

As I told the ASCO audience in closing my talk, one of the biggest challenges we face as oncologists-or anybody involved in caring for patients or working to improve how we prevent and treat cancer-is managing expectations.

Of course, we don't want to overpromise and give people, especially patients, false hope. But too many from my generation are afraid to be optimistic, too sheepish to ever use the word "cure." But that's what we want to do, cure our patients. We are, in fact, curing patients right now, more than ever, including those with metastatic cancer.

There is undoubtedly reason for carefully using that word, because we are dealing with an immensely complex disease that we still do not fully understand.

But I contend there are times to talk about curing cancer with patients and the public, because thanks to decades of progress in cancer science, now we have hope, we have options, and, sometimes, we even have cures.

© 2018 The National Cancer Institute

MD Anderson Therapeutics Discovery team identifies and advances a drug that targets metabolic vulnerability and impairs cancer cell growth and survival

Pre-clinical results for IACS-10759 drug leads to Phase I clinical trials in AML and solid tumors; two papers published in Nature Medicine

MD Anderson Cancer Center -- June 11, 2018

companies img

Joseph Marszalek, Ph.D.

HOUSTON - A drug discovered and advanced by The University of Texas MD Anderson Cancer Center's Institute for Applied Cancer Science (IACS) and the Center for Co-Clinical Trials (CCCT) inhibits a vital metabolic process required for cancer cells' growth and survival.

IACS-10759 is the first small molecule drug to be developed from concept to clinical trial by MD Anderson's Therapeutics Discovery team, which includes IACS and the CCCT. Therapeutics Discovery is a unique group of clinicians, researchers and drug development experts working collaboratively to create new treatment options, including small molecules, biologics, and cell-based therapies.

New data related to IACS-10759 were published in two papers in the June 11 online issue of Nature Medicine. The first paper reports the preclinical work led by Joseph Marszalek, Ph.D., head of Translational Biology for CCCT, and Emilia Di Francesco, Ph.D., associate director of Medicinal Chemistry at IACS, which resulted in the discovery of IACS-10759 and its advancement into Phase I clinical trials for acute myeloid leukemia (AML) and solid tumors. A second paper, authored by Andrew Futreal, Ph.D., chair, and Yonathan Lissanu Deribe, Ph.D., instructor, both of Genomic Medicine, describes the potential of IACS-10759 for treatment of lung cancers harboring a specific epigenetic alteration.

The pathway to discovery of IACS-10759

Metabolic reprogramming is an emerging hallmark of tumor biology where cancer cells evolve to rely on two key metabolic processes, glycolysis and oxidative phosphorylation (OXPHOS), to support their growth and survival. Extensive efforts have focused on therapeutic targeting of glycolysis, while OXPHOS has remained largely unexplored, partly due to an incomplete understanding of tumor contexts where OXPHOS is essential.

"Through a comprehensive translational effort enabled by collaboration across MD Anderson, we have identified multiple cancers that are highly dependent on OXPHOS," said Marszalek.

This effort inspired the discovery and development of IACS-10759, a potent and selective inhibitor of OXPHOS. Its advancement to clinical trials was made possible by a multidisciplinary team of more than 25 scientists across Therapeutics Discovery.

"Through this collaborative, 18-month process, we identified and rapidly advanced IACS-10759 as the molecule for clinical development," said Di Francesco. "We believe IACS-10759 will provide a promising new therapy for cancer patients."

The pre-clinical research conducted by IACS and CCCT led to an ongoing first-in-human Phase I clinical trial, launched in October 2016, evaluating IACS-10759 in AML, led by Marina Konopleva, M.D., Ph.D., professor, and Naval Daver, M.D., associate professor, both of Leukemia. A second Phase I trial in solid tumor indications, started in November 2017, is led by Timothy Yap, M.D., Ph.D., associate professor of Investigational Cancer Therapeutics.

IACS-10759's potential for clinical study of mutant lung cancers

IACS-10759 was evaluated in pre-clinical studies for treating lung cancers harboring mutations in the SMARCA4 gene, which render tumors sensitive to the drug due to an increased dependence on OXPHOS for survival.

companies img

Yonathan Lissanu Deribe, Ph.D.

SMARCA4 is a component of a chromatin modeling complex called SWI/SNF, which plays a vital role in gene expression. The study team's analyses showed SMARCA4 mutant cells have enhanced oxygen consumption and increased respiratory capacity, making them susceptible to treatment with an OXPHOS inhibitor like IACS-10759.

"Our findings provide the mechanistic basis for further development of OXPHOS inhibitors as therapeutics against cancers with SWI/SNF-mutant tumors," said Lissanu Deribe. "Through multidisciplinary studies of new agents like IACS-10759, we aim to accelerate the availability of enhanced therapies for our patients."

Marszalek and Di Francesco Team Members and Funding Sources:

MD Anderson study team members included: Jennifer Molina, Ph.D.; Yuting Sun, Ph.D.; Marina Protopopova, Ph.D.; Sonal Gera; Madhavi Bandi, Ph.D.; Christopher Bristow, Ph.D.; Edward Chang, Ph.D.; Angela Deem, Ph.D.; Ningping Feng, Ph.D.; Guang Gao; Jason Gay; Virginia Giuliani, Ph.D.; Jing Han, Ph.D.; Tin Khor, Ph.D.; Timothy Lofton; Mikhila Mahendra; Robert Mullinax; Michael Peoples; Thomas Shi; Melinda Smith;; Carlo Toniatti, M.D., Ph.D.; Giulio Draetta, M.D., Ph.D.; and Timothy Heffernan, Ph.D., all of CCCT; Timothy McAfoos, Ph.D.; Jennifer Bardenhagen; Christopher Carroll, Ph.D.; Jason Cross, Ph.D.; Barbara Czako, Ph.D.; Mary Geck Do, Ph.D.; Jennifer Greer; Sha Huang; Yongying Jiang, Ph.D.; Zhijun Kang; Gang Liu, Ph.D.; Pietro Morlacchi, Ph.D.; Alessia Petrocchi; Jay Theroff; Quanyun Xu, Ph.D.; and Philip Jones, Ph.D., all of IACS; Naval Daver, M.D.; Lina Han, M.D., Ph.D.; Helen Ma; Polina Matre, Ph.D.; Yoko Tabe, M.D., Ph.D.; Qi Zhang, Ph.D.; and Marina Konopleva, M.D., Ph.D., all of Leukemia; Gheath Al-Atrash, D.O., Ph.D.; and Stefan Ciurea, M.D.; of Stem Cell Transplantation and Cellular Therapy; Caroline Carrillo; Verlene Henry; John Frederick de Groot, M.D.; and Jian-Wen Dong, all of Neuro-Oncology; Sergej Konoplev, M.D., Ph.D., of Hematopathology; Jeffrey Ackroyd; Yu-Hsi Lin; and Florian Muller, Ph.D.of Cancer Imaging Systems; Jaime Rodriguez-Canale, M.D., of Translational Molecular Pathology; and Ronald DePinho, M.D. of Cancer Biology. Other participating institutions included The University of Texas at Austin; Cambridge University, U.K.; Agilent Technologies, Inc., Lexington, Mass.; Beth Israel Medical Center and Harvard Medical School, Boston; and the Juntendo University School of Medicine, Tokyo.

The studies were funded by MD Anderson's Center for Co-Clinical Trials, Institute for Applied Cancer Science, the Glioblastoma Moon Shot, and the Myelodysplastic Syndromes and Acute Myeloid Leukemia Moon Shot, all part of the MD Anderson's Moon Shots Program, a collaborative effort to accelerate the development of scientific discoveries into clinical advances that save patients' lives.

The studies were also supported by the Cancer Prevention and Research Institute of Texas (RP140218, RP140612); the American Cancer Society (RSG1514501CDD); the American Association for Cancer Research (13-90-25); the National Institutes of Health (P50CA12700107); the Sheikh Ahmed Bin Zayad Al Nahyan Center for Pancreatic Cancer; the Leukemia and Lymphoma Societies Therapeutic Accelerator Program; the Medical Research Council (U105663141).

Futreal and Lissanu Deribe Team Members and Funding Sources

MD Anderson study team members included Christopher Terranova, Ph.D.; Fatima Khan; Juan Martinez-Ledesma, Ph.D.; Chia-Chin Wu,Ph.D.; Claudia Reyes; Qian Peng; Akira Inoue, M.D., Ph.D.; and Kunal Rai, Ph.D., all of Genomic Medicine; Yuting Sun, Ph.D.; Jason Gay; Guang Gao, Ph.D.; Robert Mullinax; Tin Khor, Ph.D.; Ningping Feng, Ph.D.; Frederick Robinson; and Joseph Marszalek, Ph.D., all of IACS; Yu-Hsi Lin; and Florian Muller, Ph.D., of Cancer Systems Imaging; Veena Kochat, Ph.D., of Surgical Oncology; Chang-Gong Liu, Ph.D., of Experimental Therapeutics; Cesar Moran, M.D., of Pathology; Jing Wang, of Bioinformatics and Computational Biology; Bingliang Fang, Ph.D.; and Vali Papadimitrakopoulou, M.D., of t Thoracic, Head and Neck Medical Oncology; and Ignacio Wistuba, M.D., of Translational Molecular Pathology.

The studies were funded by the Cancer Prevention and Research Institute of Texas (R120501 and RP140612); the American Cancer Society (RSG1514501CDD); and the Welch Foundation (G-0040). The team's findings were based, in part, by data supplied through The Cancer Genome Atlas at the National Institutes of Health.

© 2018 The University of Texas MD Anderson Cancer Center

PARP inhibitor improves overall response rates in small cell lung cancer patients

Novel biomarker identified those with improved progression-free and overall survival, MD Anderson study finds

MD Anderson Cancer Center -- June 11, 2018

companies img Lauren Averett Byers, M.D.

HOUSTON - In a randomized, Phase II trial led by researchers at The University of Texas MD Anderson Cancer Center, adding the PARP inhibitor veliparib to a standard chemotherapy agent improved overall response rates (ORR) in patients with small cell lung cancer (SCLC). Researchers also identified a select group of patients - those whose tumors expressed SLFN11- who also saw a progression-free survival (PFS) and overall survival (OS) benefit, suggesting a promising biomarker for the PARP-inhibitor sensitivity in SCLC.

The study was published in Journal of Clinical Oncology. Ongoing follow-up studies are underway to confirm the results, which could result in the first new therapeutic option for this rare and aggressive lung cancer in more than three decades, said Lauren Averett Byers, M.D., associate professor of Thoracic/Head and Neck Medical Oncology.

According to the American Cancer Society, more than 234,000 people will be diagnosed with lung cancer and 154,050 will die from the disease in 2018, making it the leading cause of cancer death. SCLC primarily is associated with smoking and accounts for about 10 to 15 percent of all lung cancers. While recent advances in immunotherapy and targeted agents have begun to offer hope for those with non-small cell lung cancer (NSCLC), patients with SCLC have not experienced the same degree of clinical advances benefit.

"Currently, the survival for most small cell lung cancer patients is less than a year - it's the sixth leading cause of cancer death in the U.S., independent of non-small cell lung cancer," said Byers, the study's corresponding author. "We currently have no approved targeted therapies, no biomarkers. Patients desperately need new treatment options. However, I think we are on the cusp of changing the outlook for our patients."

PARP as a therapeutic target in SCLC was discovered by Byers during her fellowship at MD Anderson while working in the lab of John Heymach, M.D., Ph.D., professor and chair, Thoracic/Head and Neck Medical Oncology, also and author on this study. In 2012, Byers and Heymach published a milestone paper reporting the target, which generated great clinical interest. This clinical trial is the first randomized study published as a result of that first study.

PARP inhibitors block a DNA repair pathway; the class of inhibitors currently are approved for the treatment of BRCA-mutated metastatic breast and ovarian cancers.

"As important as discovering PARP's target, our study has found a biomarker determining which small cell lung cancer patients will benefit from the therapy," said Byers. "Currently, there are no biomarkers for the management of this disease. To be able to select patients for the appropriate treatment would significantly change the care we are able to offer."

For the Phase II study, Byers and her colleagues enrolled 104 patients with relapsed SCLC from seven centers across the country. Between 2012 and 2015, patients were randomized to receive either veliparib or placebo twice daily, with a standard chemotherapy regimen temozolomide (TMZ) - all oral agents.

Byers noted that many trial participants had advanced disease with brain metastasis and/or had failed standard chemotherapy.

PFS at four months was the primary endpoint, with ORR, OS, and safety and tolerability of veliparib with TMZ as secondary endpoints. Response was determined by imaging at weeks four and eight, followed by every eight weeks thereafter.

Toxicities associated with the PARP therapy include blood count deficiencies, but treatment generally was well tolerated, said Byers.

At four months, researchers found that, in an unselected population, the study did not reach a statistically significant difference in PFS between the TMZ/veliparib cohort, 36 percent, and TMZ/placebo cohort, 27 percent. In the two groups, the median OS also was similar at 8.2 months and 7 months respectively.

However, the ORR, defined as percentage of patients with tumor shrinkage, almost was three times higher in the TMZ/veliparib cohort compared to the TMZ/placebo cohort, 39 percent vs. 14 percent, a statistically significant difference.

As part of this trial, researchers also investigated candidate biomarkers that might predict response to PARP inhibitors in SCLC. These included expression of PARP1 and the protein called SLFN11, which previously had shown to confer sensitivity to PARP inhibitors in the laboratory by Byers and other groups.

In those patients whose tumors expressed the elevated levels of SLFN11, treatment with TMZ/veliparib resulted in significantly prolonged PFS, 5.7 vs. 3.6 months, and OS, 12.2 vs. 7.5 months. This is the first study to investigate SLFN11 as a predictive biomarker in the clinical setting.

"My hope is that the PARP inhibitors one day will serve as the first targeted therapy to benefit small cell lung cancer patients," said Byers. "Now, with the discovery of the biomarker, we have a way to determine which patients potentially could garner the most benefit."

Based on these results, studies are ongoing to explore PARP inhibitors in the frontline treatment setting. Byers also is testing veliparib at a higher dose in combination with TMZ in a randomized trial, also in the frontline setting. Byers also has a grant from the National Institutes of Health to study whether PARP inhibitors, combined with immunotherapies, improve responses in SCLC.

The preclinical research for this study was supported by the Lung Cancer Moon Shot, part of MD Anderson's Moon Shots Program, a collaborative effort to accelerate the development of scientific discoveries into clinical advances that save patients' lives. The research also was supported by: the Cancer Therapy Evaluation Program at the National Cancer Institute (NCI; U10 CA180858); National Institutes of Health (NIH)/NCI Grants, CCSG P30-CA008748 and NIH/NCI CCSG P30-CA016672; NIH/NCI award No. 1-R01-CA207295; and The LUNGevity Foundation.

In addition to Byers and Heymach, other MD Anderson authors on the national study include: Robert Cardnell, Ph.D., Eric Sulman, M.D., Ph.D., Ignacio Wistuba, M.D., Patricia de Groot, M.D., Junya Fujimoto, Ph.D., Jing Wang, Ph.D., Lixia Diao, and Lihong Long. Additional authors include: M. Catherine Pietanza, M.D., Lee M. Krug, M.D., Mark G. Kris, M.D., Charles M. Rudin, M.D., Ph.D., Kaitlin M. Woo, Yevgeniya Bensman, Martin Fleisher, Ph.D. and Brenda Hurtado all of Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College; Saiama N. Waqar, MBBS, Washington University School of Medicine; Afshin Dowlati, M.D., Case Western Reserve University and University Hospital, Seidman Cancer Center; Christine L. Hann, M.D., Ph.D., Johns Hopkins University; Alberto Chiappori, M.D., H. Lee Moffitt Cancer Center; Taofeek K. Owonikoko, M.D., Ph.D., Emory University and Alice Chen of the National Cancer Institute.

Regarding relevant disclosures, Byers has served as a consultant and received research funding from Abbvie.

© 2018 The University of Texas MD Anderson Cancer Center

Selumetinib Continues to Show Promise in Children with NF1

by NCI Staff

The National Cancer Institute -- June 8, 2018

companies img Travis Carpenter, who received the drug selumetinib to treat NF1, with Zilly, a therapy dog at The Children's Inn at NIH. Credit: National Cancer Institute

An investigational drug called selumetinib can shrink tumors in children and young adults with a genetic syndrome called neurofibromatosis type 1 (NF1) and may improve symptoms such as pain and reduced mobility that result from tumors called plexiform neurofibromas, which develop in many people with NF1, according to preliminary results from a clinical trial.

The phase 2 trial, which involves 50 patients aged 2 to 18 with NF1 and plexiform neurofibromas, confirms the results of a smaller trial that in 2016 demonstrated for the first time that the drug could shrink large tumors.

Up to half of all patients with NF1 develop plexiform neurofibromas, which form in nerve cells. Although most of these tumors are not cancerous, they typically grow on or just under the skin, causing pain and other problems such as difficulty breathing or walking and disfigurement.

"The new results are exciting because they confirm what we learned in the phase 1 study, where, for the first time in this disease, we saw large tumors shrink," said Andrea M. Gross, M.D., of NCI's Center for Cancer Research, who presented the findings June 2 at the American Society of Clinical Oncology annual meeting in Chicago.

In a message on Twitter, NCI Director Ned Sharpless, M.D., also called the results "exciting." He summarized the findings on Twitter: "Tumors shrink, kids feel better, drug seems safe."

Confirming that Selumetinib Can Shrink Neurofibromas

Selumetinib, which is taken as a pill, blocks a protein called MEK that is part of the RAS signaling pathway in cells. This pathway is improperly activated in patients with NF1 as well as in patients with certain types of cancer, leading to the growth of tumors.

In the trial, 36 of the 50 patients (72%) had a partial response to selumetinib, meaning that tumor volume shrank by at least 20%. This result was essentially the same as in the smaller phase 1 study published 2 years ago, in which 17 of 24 patients (71%) had a partial response.

In the current trial, the median change in plexiform neurofibromas volume from baseline was -27% (the range was from -50.6% to 2.2%), the researchers reported. The median age of patients in the trial was approximately 10 years old.

Plexiform neurofibromas grow most quickly in young children with NF1 and then slow down during adolescence, according to Brigitte Widemann, M.D., chief of NCI's Pediatric Oncology Branch and a leader of the study, whose team also developed a method of measuring the volume of tumors.

Before treatment, the most common NF1-related health problems in the patients were disfigurement (44 patients), motor dysfunction (33 patients), and pain (28 patients).

Some plexiform neurofibromas grow to be as large as a several-liter bottle and up to 20% of body weight. Surgery to remove even small tumors is often not feasible, because many tumors are intertwined with healthy nerves and tissue. In addition, tumors that have been partially removed by surgery tend to grow back, especially in young children.

The side effects of selumetinib are generally manageable, noted Dr. Gross. Nausea, vomiting, diarrhea, and rashes were among the most frequent side effects in the trial, but these side effects were still relatively uncommon and improved when drug was paused. For 12 patients, the dose of selumetinib had to be reduced because of side effects, and four of these individuals eventually stopped treatment.

Assessing Health Problems Related to Neurofibromas

In addition to causing some tumors to shrink, selumetinib appeared to help improve health problems associated with tumors. After a year of treatment, most patients in the trial (or their parents) reported improved pain scores, strength, and range of motion, Dr. Gross noted.

"In this trial, we're trying to show if selumetinib produces a clinical benefit-that is, that the patients are feeling better and are more active than they've ever been with the disease," she explained.

To this end, the researchers used multiple tests to measure changes in a patient's health and ability to function during treatment. Patients return to the NIH campus for evaluations on a regular basis, allowing the researchers to monitor a range of health measures.

"This is a unique and resource-intensive study in terms of the level of detail in the functional and patient reported assessments of patients," said Dr. Gross. In addition to the clinical testing, patients provide anecdotal information that gives the researchers a richer view of how the treatment has changed their everyday lives.

"One patient explained that his clothes fit better after being on the medicine, and another said that he was able to wrestle his sister again," Dr. Gross recalled. "Parents and the neurofibromatosis type 1 community are excited about this trial because patients for the first time see benefits from the treatment of large plexiform neurofibromas."

After Dr. Gross shared the results in Chicago, the mother of a study participant wrote on Twitter that her son's "tumor is no longer threatening the airway, and we can see down his throat again. Not to mention the psychosocial impact of kids not asking about his neck anymore."

The mother of another participant in the trial tweeted that her son's tumor was shrinking and that he was feeling better with less pain and more energy. The biggest side effect, she added, was "blond hair."

Exploring Unanswered Questions

In February, the Food and Drug Administration (FDA) granted "orphan drug" status to selumetinib for the treatment of patients with NF1. This designation allows drug developers-in this case, AstraZeneca and Merck-to receive incentives such as tax credits and exclusive marketing rights for a period of years.

During the phase 2 trial, some tumors stopped responding to selumetinib and began to regrow, particularly after the dose of the drug was reduced in patients experiencing side effects. It appears that a certain dose of selumetinib is needed for shrinkage of plexiform neurofibromas. More research is needed to understand why some tumors may show growth despite an adequate dose of selumetinib.

Some clues may emerge from an NCI-sponsored clinical trial testing selumetinib in adults with NF1, Dr. Gross said. The adult participants in that study are providing serial tissue samples, which could help the researchers gain insights into mechanisms of response and possible resistance mechanisms.

Dr. Widemann, Dr. Gross, and their colleagues will continue to follow the younger patients in the phase 2 pediatric study and the adult patients as well.

"We're incredibly grateful to the patients and their families who come and do all of our intensive evaluations," said Dr. Gross. "We think that we're making a clinical difference for many patients and are pleased to be documenting these changes in a prospective study."

© 2018 The National Cancer Institute

Toxin-Based Drug Moxetumomab Pasudotox May Be New Option for Rare Leukemia

by NCI Staff

The National Cancer Institute -- June 5, 2018
companies img A peripheral blood smear showing several hairy leukemia cells. Credit: Case Rep Pathol July 2014. doi: 10.1155/2014/497027. CC BY 3.0.

People diagnosed with hairy cell leukemia (HCL), an uncommon form of leukemia, may soon have an effective new treatment option, according to findings from an international phase 3 clinical trial. In the trial, three-quarters of people with HCL that had come back or progressed after earlier treatment responded to treatment with the toxin-based drug moxetumomab pasudotox (Moxe).

The disease disappeared completely during treatment in 33 of the 80 patients (41%), and more than 70% of these patients remained cancer free after 6 months of follow-up. The trial results were presented June 2 at the American Society of Clinical Oncology (ASCO) annual meeting in Chicago.

"This drug offers an option for patients with relapsed or refractory hairy cell leukemia that avoids additional chemotherapy and also has the potential to provide better long-term outcomes," said Robert Kreitman, M.D., of NCI's Center for Cancer Research (CCR), who led the trial.

Bringing a Toxin to Its Target

Moxe is a type of drug called an immunotoxin. It consists of a fragment of a toxin naturally made by the bacterium Pseudomonas aeruginosa, which is genetically fused to a carrier molecule. This carrier molecule, a portion of a monoclonal antibody, recognizes a protein called CD22, which is found in abundance on HCL cells. When the antibody locates and binds to a cell bearing CD22, the toxin is taken inside the cell and kills it.

Moxe was initially developed in CCR's Laboratory of Molecular Biology, by a team led by Ira Pastan, M.D., and that included David FitzGerald, Ph.D., also of CCR. The drug was later licensed for commercial development to MedImmune, a subsidiary of AstraZeneca.

Based on these results, the Food and Drug Administration (FDA) allowed the researchers to go straight from the phase 1 trial to the international phase 3 trial, which was sponsored by MedImmune.

Eliminating the Repository of Resistance

Because there are no drugs approved by FDA for the treatment of relapsed or refractory HCL, the phase 3 trial was a single-arm study, in which all participants received Moxe.

The trial included 80 participants from 14 countries, who had received an average of three previous treatments for their HCL. During the trial, participants could receive up to six cycles of the drug over a 6-month period.

Repeated cycles of treatment with Moxe can eliminate minimal residual disease, explained Dr. Kreitman. Minimal residual disease refers to tiny deposits of cancer cells that can hide deep within the bone marrow and avoid being killed by standard chemotherapies.

"Minimal residual disease is what we think causes HCL to relapse and is the reason this disease keeps coming back over and over again," he said. "We feel that the long-term results for HCL patients will be better if we can get rid of the minimal residual disease."

Treatment was stopped early, however, in trial participants who had a complete remission without evidence of minimal residual disease before receiving the full 6 cycles.

After almost 17 months of follow-up, 80% of trial participants had a hematologic remission-that is, normal blood cells returned to acceptable levels. More than 40% of patients experienced a complete response with Moxe treatment, the researchers reported, most of whom had no evidence of minimal residual disease.

Side effects from the drug were mostly mild. They included nausea, swelling in the hands and feet, headache, and fever. Importantly, Dr. Kreitman said, the researchers did not see any cumulative toxicity in patients. Cumulative toxicity is when side effects get worse the longer a treatment goes on.

"That's important because we want to get rid of minimal residual disease, and that can happen if patients are given enough treatment cycles," he explained.

Unlike chemotherapy drugs used to treat HCL, Moxe did not cause any permanent damage to the stem cells in the bone marrow, which produce red and white blood cells.

Next Directions for Moxe

Because HCL cells express a very large amount of CD22 on their surface, in theory, all patients could experience a complete remission with Moxe, explained Dr. Kreitman. However, multiple factors can affect whether an individual patient benefits from the drug.

For example, people who have been exposed to P. aeruginosa before being diagnosed with HCL would have developed antibodies to it and the toxins it can produce. These antibodies could recognize Moxe and inactivate it before it reaches enough HCL cells, Dr. Kreitman said.

This would not be the only reason for treatment resistance, though. During the trial, the researchers tested participants for antibodies to Moxe, and many patients with antibodies still had a good response to the drug, particularly if antibody levels were low, Dr. Kreitman said. He and others in Dr. Pastan's laboratory are trying to better understand why some patients with HCL don't respond to the drug.

Others are testing the drug in other types of leukemia. Moxe was recently tested in a clinical trial that enrolled children with B-cell acute lymphoblastic leukemia. Although resistance to the drug developed quickly, studies are looking at ways to combine Moxe with other drugs to overcome this resistance.

Using Moxe earlier in the treatment of HCL could also potentially be beneficial, said Dr. Pastan.

"The dream now is to not use drugs that are toxic to patients' bone marrow, like cladribine, which is currently used as a first-line therapy for hairy cell leukemia," he said.

© 2018 The National Cancer Institute

NCI-MATCH precision medicine clinical trial releases new findings, strengthens path forward for targeted cancer therapies

by NCI Staff

The National Cancer Institute -- June 4, 2018

companies img

Credit: National Cancer Institute

The National Cancer Institute's Molecular Analysis for Therapy Choice (NCI-MATCH) trial, the largest precision medicine trial of its kind, has achieved a milestone with the release of results from several treatment arms, or sub-studies, of the trial. The new results offer findings of interest for future cancer research that could ultimately play a role in bringing targeted treatments to patients with certain gene abnormalities, regardless of their cancer type.

Findings from three arms were released at this year's American Society of Clinical Oncology (ASCO) annual meeting in Chicago, adding to findings from one arm released in November 2017. The study was co-developed by NCI, part of the National Institutes of Health, and the ECOG-ACRIN Cancer Research Group, part of the NCI-sponsored National Clinical Trials Network (NCTN). ECOG-ACRIN and NCI are co-leading the trial.

"The outcomes data being released today from this groundbreaking precision medicine trial are an exciting step for NCI-MATCH," said Lyndsay Harris, M.D., of NCI's Cancer Diagnosis Program and NCI study chair. "These findings represent a large collection of data in populations of patients who may not have been studied in conventional clinical trials, and they will have important implications for future precision medicine trials."NCI-MATCH, a phase 2 clinical trial, seeks to determine whether targeted therapies for people whose tumors have certain gene mutations will be effective regardless of their cancer type. Researchers use a DNA sequencing test to identify gene mutations in patients' tumors. The test looks for mutations in 143 genes associated with cancer that can be targeted by one of the drugs being studied in the trial. The trial launched in August 2015 and has nearly 40 treatment arms, each of which aims to enroll at least 35 patients whose tumors have a specific genetic change. As the first findings are released at ASCO, many other arms are still enrolling patients and several additional arms are in development for possible opening later in 2018.

"NCI-MATCH represents the first attempt to systematically leverage next-generation sequencing to explore so many therapies in parallel," said ECOG-ACRIN study chair Keith T. Flaherty, M.D., a medical oncologist at Massachusetts General Hospital Cancer Center in Boston. "By focusing our investigational effort on new biomarker-guided therapies in understudied cancer types, we have accelerated the opportunity to find signals of efficacy."

The study is a signal-finding trial, meaning that treatments that show promise can advance to larger, more definitive studies outside of the trial. NCI-MATCH is for adults who have solid tumors, lymphoma, or myeloma that have progressed on standard treatment or rare cancers for which there is no standard treatment. A goal of the study was for about 25 percent of patients in the trial to have rare cancers. Surprisingly, 62.5 percent of the first 6,000 patients enrolled in NCI-MATCH had tumors other than the four most common cancers (breast, colorectal, non-small cell lung, and prostate), providing more opportunities for less common and rare tumors than expected based on initial estimates.

The first arm for which results were released (Arm Z1D), in November 2017 at the Society for Immunotherapy of Cancer annual meeting, showed that the drug nivolumab has promising activity in mismatch repair-deficient non-colorectal cancers.

Highlights from the findings from the three arms announced at ASCO include:

  • Arm I studied the drug taselisib in 65 patients with mutations in the PIK3CA gene. There were no objective responses to the drug, meaning the tumors did not shrink substantially. However, 24 percent of the patients had progression-free survival-or prolonged stable disease-of greater than six months. This prolonged stable disease was seen even in patients with aggressive cancer types, including lung cancer and cholangiocarcinoma (bile duct) cancer. The observation of prolonged disease control in these cancer types suggests the drug warrants further research.
  • In Arm Q, the drug ado-trastuzumab emtansine (T-DM1) was studied in patients with HER2-overexpressing tumors, excluding breast and gastric/gastroesophageal junction cancers. Partial responses (at least 30 percent shrinkage of the tumor) were seen in three of the 37 patients, each of whom had a rare cancer: mucoepidermoid carcinoma of the parotid gland, squamous cell cancer of the parotid gland, and extramammary Paget disease of the scrotum. In addition, 46 percent of the patients had stable disease, including patients with ovarian, uterine, and colorectal cancers. The researchers concluded that the findings warrant further study, particularly in certain rare cancers.
  • Arm W tested the drug AZD4547 in 50 patients with mutations in the FGFR pathway. Ten percent of patients had a partial response. Among four patients who had a partial response, whose tumors all had different sites of origin, two had point mutations in the FGFR2/3 gene and the other two had FGFR3 gene fusions, in which part of the FGFR gene is joined to part of another gene. This suggests that these mutations may be particularly sensitive to the drug, warranting further studies in tumors harboring these fusions.

Many of the patients in these three arms had been treated with more than three lines of therapy before entering the trial (Arm I: 37 percent, Arm Q: 33 percent, Arm W: 50 percent), so the results are particularly encouraging. It suggests that future studies in populations with earlier-stage disease could potentially see more responses.

Results of additional treatment arms that have completed accrual will be released on a rolling basis as their data mature. The trial is ongoing and enrolling patients at more than 1,100 cancer centers and community hospitals in every state, the District of Columbia, and Puerto Rico. All trial sites are either members of the research groups in the NCTN that focus on adult cancers-the Alliance for Clinical Trials in Oncology, ECOG-ACRIN Cancer Research Group, NRG Oncology, and SWOG-or are members of the NCI Community Oncology Research Program (NCORP).

Genentech, a member of the Roche group, provided the study drugs for Arms I and Q, and AstraZeneca provided the drug for Arm W.

About the ECOG-ACRIN Cancer Research Group (ECOG-ACRIN): ECOG-ACRIN is a membership-based scientific organization that designs and conducts cancer research involving adults who have or are at risk of developing cancer. Research personnel in nearly 1,200 member institutions are involved in Group science, which is organized into three programs: Cancer Control and Outcomes, Therapeutic Studies, and Biomarker Sciences. The Group's primary funding is from the National Cancer Institute (NCI). Visit www.ecog-acrin.org, follow on Twitter @eaonc, or call 215-789-3631.

About the National Cancer Institute (NCI): NCI leads the National Cancer Program and NIH's efforts to dramatically reduce the prevalence of cancer and improve the lives of cancer patients and their families, through research into prevention and cancer biology, the development of new interventions, and the training and mentoring of new researchers. For more information about cancer, please visit the NCI website at cancer.gov or call NCI's Contact Center (formerly known as the Cancer Information Service) at 1-800-4-CANCER (1-800-422-6237).

About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit nih.gov.

© 2018 The National Cancer Institute

New approach to immunotherapy leads to complete response in breast cancer patient unresponsive to other treatments

by NCI Staff

The National Cancer Institute -- June 4, 2018

companies img Left: MRI scans of a woman with breast cancer before TIL therapy show a lesion invading the chest wall (top) and metastatic lesions in the liver (bottom).

Right: Scans 14 months after treatment show all lesions have disappeared.

Credit: National Cancer Institute

A novel approach to immunotherapy developed by researchers at the National Cancer Institute (NCI) has led to the complete regression of breast cancer in a patient who was unresponsive to all other treatments. This patient received the treatment in a clinical trial led by Steven A. Rosenberg, M.D., Ph.D., chief of the Surgery Branch at NCI's Center for Cancer Research (CCR), and the findings were published June 4, 2018 in Nature Medicine. NCI is part of the National Institutes of Health.

"We've developed a high-throughput method to identify mutations present in a cancer that are recognized by the immune system," Dr. Rosenberg said. "This research is experimental right now. But because this new approach to immunotherapy is dependent on mutations, not on cancer type, it is in a sense a blueprint we can use for the treatment of many types of cancer."

The new immunotherapy approach is a modified form of adoptive cell transfer (ACT). ACT has been effective in treating melanoma, which has high levels of somatic, or acquired, mutations. However, it has been less effective with some common epithelial cancers, or cancers that start in the lining of organs, that have lower levels of mutations, such as stomach, esophageal, ovarian, and breast cancers.

In an ongoing phase 2 clinical trial, the investigators are developing a form of ACT that uses tumor-infiltrating lymphocytes (TILs) that specifically target tumor cell mutations to see if they can shrink tumors in patients with these common epithelial cancers. As with other forms of ACT, the selected TILs are grown to large numbers in the laboratory and are then infused back into the patient (who has in the meantime undergone treatment to deplete remaining lymphocytes) to create a stronger immune response against the tumor.

A patient with metastatic breast cancer came to the trial after receiving multiple treatments, including several chemotherapy and hormonal treatments, that had not stopped her cancer from progressing. To treat her, the researchers sequenced DNA and RNA from one of her tumors, as well as normal tissue to see which mutations were unique to her cancer, and identified 62 different mutations in her tumor cells.

The researchers then tested different TILs from the patient to find those that recognized one or more of these mutated proteins. TILs recognized four of the mutant proteins, and the TILs then were expanded and infused back into the patient. She was also given the checkpoint inhibitor pembrolizumab to prevent the possible inactivation of the infused T cells by factors in the tumor microenvironment. After the treatment, all of this patient's cancer disappeared and has not returned more than 22 months later.

"This is an illustrative case report that highlights, once again, the power of immunotherapy," said Tom Misteli, Ph.D., director of CCR at NCI. "If confirmed in a larger study, it promises to further extend the reach of this T-cell therapy to a broader spectrum of cancers."

Investigators have seen similar results using mutation-targeted TIL treatment for patients in the same trial with other epithelial cancers, including liver cancer and colorectal cancer. Dr. Rosenberg explained that results like this in patients with solid epithelial tumors are important because ACT has not been as successful with these kinds of cancers as with other types that have more mutations.

He said the "big picture" here is this kind of treatment is not cancer-type specific. "All cancers have mutations, and that's what we're attacking with this immunotherapy," he said. "It is ironic that the very mutations that cause the cancer may prove to be the best targets to treat the cancer."

The research team includes Nikolaos Zacharakis, Ph.D.; Steven A. Feldman, Ph.D.; and Stephanie L. Goff, M.D.

For more on the clinical trial, see: https://clinicaltrials.gov/ct2/show/NCT01174121

About the Center for Cancer Research (CCR): CCR comprises nearly 250 teams conducting basic, translational, and clinical research in the NCI intramural program-an environment supporting innovative science aimed at improving human health. CCR's clinical program is housed at the NIH Clinical Center-the world's largest hospital dedicated to clinical research. For more information about CCR and its programs, visit ccr.cancer.gov.

About the National Cancer Institute (NCI): NCI leads the National Cancer Program and NIH's efforts to dramatically reduce the prevalence of cancer and improve the lives of cancer patients and their families, through research into prevention and cancer biology, the development of new interventions, and the training and mentoring of new researchers. For more information about cancer, please visit the NCI website at cancer.gov or call NCI's Contact Center (formerly known as the Cancer Information Service) at 1-800-4-CANCER (1-800-422-6237).

About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit nih.gov.

© 2018 The National Cancer Institute

Checkpoint inhibitor shrinks advanced squamous cell skin cancer

MD Anderson-led clinical trial shows nearly 50 percent of patients respond to cemiplimab

MD Anderson Cancer Center -- June 4, 2018

companies img Michael Migden, M.D.

HOUSTON - Clinical trials show that an immune checkpoint inhibitor shrinks the tumors of nearly half of patients with an incurable, advanced form of a common skin cancer, an international team led by a researcher at The University of Texas MD Anderson Cancer Center reports in the New England Journal of Medicine.

"These results mark a potential paradigm shift in the treatment of patients with advanced cutaneous squamous cell carcinoma, who to date have had very limited results with chemotherapy and targeted therapies," said lead author Michael Migden, M.D., associate professor of Dermatology and of Head and Neck Surgery.

Migden is principal investigator of the international, multicenter phase II registrational clinical trial of cemiplimab, an immune checkpoint inhibitor that works by blocking PD1, a surface receptor on T cells that shuts down immune response to cancer.

Cutaneous squamous cell carcinoma is the second most common skin cancer, with an estimated 1 million new cases diagnosed annually. More than 95 percent of patients are cured by surgery and radiation at the disease's early stages. But for the fraction who progress, there are no systemic therapies approved as a standard of care, the researchers note.

At a median follow-up of 7.9 months, 28 of 59 patients with metastatic disease (47.5 percent) had an objective response to cemiplimab, defined as at least 30 percent tumor shrinkage observed via imaging. Four were complete responses, 24 had partial responses, and 82 percent of responders remain on the drug.

"Patients continue to do well, so median progression-free survival and overall survival have not been reached yet," said Migden, a Mohs surgeon and dermatologic oncologist at MD Anderson. The durable disease control rate of responders plus those with stable disease for at least 105 days was 61 percent.

Migden notes that response rates to chemotherapy regimens or targeted therapy against the epidermal growth factor receptor (EGFR) now used against advanced cutaneous squamous cell carcinoma range from 15-25 percent, with many debilitating side effects.

In the phase I trial of patients with metastatic or locally advanced but inoperable disease, 13 of 26 (50 percent) had a partial response. At 11 months median follow-up, seven patients remained in response.

Two patients (7.7 percent) had to discontinue treatment due to adverse events. Median age was 73.

The U.S. Food and Drug Administration has granted an application for breakthrough therapy status for the drug, providing a faster potential route for FDA approval. Regeneron Pharmaceuticals, Inc., and Sanofi are co-developing cemiplimab.

Cutaneous squamous cell carcinoma develops from genetic damage caused by exposure to UV light. These tumors have a high mutation burden, providing a target-rich environment for immune system attack and this cancer also is strongly associated with immune suppression. Those factors made it a strong candidate for PD1 inhibition, which unleashes the immune system to attack cancer.

The clinical trials are funded by Regeneron and Sanofi.

Co-authors with Migden are co-first author Danny Rischin, M.D., and Alesha Thai, M.D., of Peter MacCallum Cancer Centre, University of Melbourne, Melbourne, Australia; Chrysalyne Schmults, M.D., of Brigham and Women's Hospital, Harvard Medical School, Boston; Alexander Guminski, M.D., Ph.D., of Royal North Shore Hospital, St. Leonards, Australia; Axel Hauschild, M.D., Schleswig-Holstein University Hospital, Kiel, Germany; Karl Lewis, M.D., University of Colorado Denver, School of Medicine; Christine Chung, M.D., and Nikhil Khushalani, M.D., of H. Lee Moffitt Cancer Center and Research Institute, Tampa; Leonel Hernandez-Aya, M.D., Washington University School of Medicine, St. Louis; Annette Lim, M.D., Ph.D., of Sir Charles Gairdner Hospital, Perth, Australia; Anne Lynn Chang, M.D., Stanford University School of Medicine, Redwood City, CA; Guilherme Rabinowits, M.D., of Dana-Farber Cancer Institute, Boston; Lara Dunn, M.D., of Memorial Sloan Kettering Cancer Center, New York; Brett Hughes, M.D., Royal Brisbane & Women's Hospital and University of Queensland, Brisbane, Australia; Badri Modi, M.D., of City of Hope, Duarte, CA; Dirk Schadendorf, M.D., of University Hospital Essen, Essen and German Cancer Consortium, Germany; Bo Gao, Ph.D., Siyu Li, Ph.D., Jingjin Li, Ph.D., Jocelyn Booth, and Elizabeth Stankevich, Frank Seebach, M.D., Melissa Mathias, M.D., Kosalai Mohan, Ph.D., George D. Yancopoulos, M.D., Ph.D., Israel Lowy, M.D., Ph.D., and Matthew G. Fury, M.D., Ph.D., of Regeneron Pharmaceuticals; Hani M. Babiker, M.D., of University of Arizona Cancer Center, Tucson; Irene Brana, M.D., Ph.D., of Vall D'Hebron University Hospital, Barcelona, Spain; Marta Gil-Martin, M.D., of Institut Catala D'Oncologia, L'Hospitalet de Llobregat, Barcelona; Jade Homsi, M.D., and Jiaxin Niu, M.D., Ph.D., of Banner MD Anderson Cancer Center, Gilbert, AZ; Melissa Johnson, M.D., of Sarah Cannon Research Institute, Nashville, TN; Victor Moreno, M.D., Ph.D., START Madrid-FJD, Hospital Fundacion Jimenez Diaz, Madrid, Spain; Taofeek Owonikoko, M.D., Ph.D., Winship Cancer Institute, Emory University, Atlanta; and Kyriakos P. Papadopoulos, M.D., South Texas Accelerated Research Therapeutics, San Antonio, TX.

© 2018 The University of Texas MD Anderson Cancer Center

TAILORx trial finds most women with early breast cancer do not benefit from chemotherapy

by NCI Staff

The National Cancer Institute -- June 3, 2018

companies img Credit: iStock

New findings from the groundbreaking Trial Assigning Individualized Options for Treatment (Rx), or TAILORx trial, show no benefit from chemotherapy for 70 percent of women with the most common type of breast cancer. The study found that for women with hormone receptor (HR)-positive, HER2-negative, axillary lymph node--negative breast cancer, treatment with chemotherapy and hormone therapy after surgery is not more beneficial than treatment with hormone therapy alone. The new data, released at the American Society of Clinical Oncology (ASCO) annual meeting in Chicago, will help inform treatment decisions for many women with early-stage breast cancer.

The trial was supported by the National Cancer Institute (NCI), part of the National Institutes of Health, and designed and led by the ECOG-ACRIN Cancer Research Group. Findings from the study will be published in The New England Journal of Medicine.

"The new results from TAILORx give clinicians high-quality data to inform personalized treatment recommendations for women," said lead author Joseph A. Sparano, M.D., associate director for clinical research at the Albert Einstein Cancer Center and Montefiore Health System in New York City and vice chair of the ECOG-ACRIN Cancer Research Group. "These data confirm that using a 21-gene expression test to assess the risk of cancer recurrence can spare women unnecessary treatment if the test indicates that chemotherapy is not likely to provide benefit."

TAILORx, a phase 3 clinical trial, opened in 2006 and was designed to provide an evidence-based answer to the question of whether hormone therapy alone is not inferior to hormone therapy plus chemotherapy. The trial used a molecular test (Oncotype DX Breast Recurrence Score) that assesses the expression of 21 genes associated with breast cancer recurrence to assign women with early-stage, HR-positive, HER2-negative, axillary lymph node--negative breast cancer to the most appropriate and effective post-operative treatment. The trial enrolled 10,273 women with this type of breast cancer at 1,182 sites in the United States, Australia, Canada, Ireland, New Zealand, and Peru.

When patients enrolled in the trial, their tumors were analyzed using the 21-gene expression test and assigned a risk score (on a scale of 0--100) for cancer recurrence. Based on evidence from earlier trials, women in the trial who had a score in the low-risk range (0--10) received hormone therapy only, and those who had a score in the high-risk range (26 and above) were treated with hormone therapy and chemotherapy.

Women in the trial who had a score in the intermediate range (11--25) were randomly assigned to receive hormone therapy alone or hormone therapy with adjuvant chemotherapy. The goal was to assess whether women who received hormone therapy alone had outcomes that were as good as those among women who received chemotherapy in addition to hormone therapy.

"Until now, we've been able to recommend treatment for women with these cancers at high and low risk of recurrence, but women at intermediate risk have been uncertain about the appropriate strategy to take," said Jeffrey Abrams, M.D., associate director of NCI's Cancer Therapy Evaluation Program. "These findings, showing no benefit from receiving chemotherapy plus hormone therapy for most patients in this intermediate-risk group, will go a long way to support oncologists and patients in decisions about the best course of treatment."

The researchers found that the primary endpoint of the trial, invasive disease-free survival-the proportion of women who had not died or developed a recurrence or a second primary cancer-was very similar in both groups. Five years after treatment, the rate of invasive disease-free survival was 92.8 percent for those who had hormone therapy alone and 93.1 percent for those who also had chemotherapy. At nine years, the rate was 83.3 percent for those with hormone therapy alone and 84.3 percent for the group that had both therapies. None of these differences were considered statistically significant.

The rates of overall survival were also very similar in the two groups. At five years, the overall survival rate was 98.0 percent for those who received hormone therapy alone and 98.1 percent for those who received both therapies, and at nine years the respective overall survival rates were 93.9 percent and 93.8 percent.

The researchers also found that women with a score of 0-10 had very low recurrence rates with hormone therapy alone at nine years (3 percen). This confirms similar findings from earlier studies. In addition, they found that women with a score of 26-100 had a distant recurrence rate of 13 percent despite receiving both chemotherapy and hormone therapy. This finding indicates the need to develop more effective therapies for women at high risk of recurrence.

According to the authors, the new findings suggest that chemotherapy may be avoided in about 70 percent of women with HR-positive, HER2-negative, node-negative breast cancer:

  • older than 50 and with a recurrence score of 11-25 (45 percent)
  • any age with a recurrence score of 0-10 (16 percent)
  • 50 years old or younger with a recurrence score of 11-15 (8 percent)

The findings suggest that chemotherapy may be considered for the remaining 30 percent of women with HR-positive, HER2-negative, node-negative breast cancer:

  • any age with a recurrence score of 26-100 (17 percent)
  • 50 years old or younger with a recurrence score of 16-25 (14 percent)

The new results demonstrate that chemotherapy is not beneficial for most women in the intermediate-risk group. This data adds to findings from a TAILORx analysis published in 2015 that provided prospective evidence that the gene expression test could identify women with a low risk of recurrence who could be spared chemotherapy.

There is one caveat to the new findings. When the researchers analyzed premenopausal women and those younger than 50 years old at the higher end of the intermediate-risk range (16-25) separately, the results showed there may be a small benefit from chemotherapy, and thus these women should consider chemotherapy with their doctor. However, it is unclear if this benefit is due to the effect of chemotherapy or to endocrine suppression caused by chemotherapy-induced menopause.

"Before TAILORx, there was uncertainty about the best treatment for women with a mid-range score of 11-25 on the Oncotype DX Breast Recurrence Score test. The trial was designed to address this question and provides a very definitive answer," said Dr. Sparano. "Any woman with early-stage breast cancer age 75 or younger should have the 21-gene expression test and discuss the results with her doctor to guide her decision to the right therapy."

TAILORx was one of the first large-scale trials to examine a methodology for personalizing cancer treatment. When the trial was activated, the best available genomic profiling data in women with early-stage breast cancer were retrospective.

The study was supported in part by the Breast Cancer Research Foundation, Komen Foundation, and the Breast Cancer Research Stamp. The stamp funding provided more than $5 million to the trial. Since 1998, when the charity stamp was authorized by Congress and first issued by the United States Postal Service, more than $86 million has been raised for breast cancer research. The net proceeds from sales of the stamp are transferred to NIH and the Medical Research Program of the Department of Defense to fund breast cancer research.

The genomic assay used in the trial was the Oncotype DX Breast Recurrence Score test from Genomic Health, Inc., Redwood City, California.

About the ECOG-ACRIN Cancer Research Group (ECOG-ACRIN): ECOG-ACRIN is a membership-based scientific organization that designs and conducts cancer research involving adults who have or are at risk of developing cancer. Research personnel in nearly 1,200 member institutions are involved in Group science, which is organized into three programs: Cancer Control and Outcomes, Therapeutic Studies, and Biomarker Sciences. The Group's primary funding is from the National Cancer Institute (NCI). Visit www.ecog-acrin.org, follow on Twitter @eaonc, or call 215-789-3631.

About the National Cancer Institute (NCI): NCI leads the National Cancer Program and NIH's efforts to dramatically reduce the prevalence of cancer and improve the lives of cancer patients and their families, through research into prevention and cancer biology, the development of new interventions, and the training and mentoring of new researchers. For more information about cancer, please visit the NCI website at cancer.gov or call NCI's Contact Center (formerly known as the Cancer Information Service) at 1-800-4-CANCER (1-800-422-6237).

About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit nih.gov.

© 2018 The National Cancer Institute

Erdafitinib shows promise in urothelial cancer patients with specific mutations

MD Anderson-led Phase II trial suggests FGFR inhibitor may benefit patients when immunotherapy fails

MD Anderson Cancer Center -- June 3, 2018

companies img Arlene Siefker-Radtke M.D

CHICAGO - In an international Phase II trial led by researchers at The University of Texas MD Anderson Cancer Center, treatment with the oral FGFR inhibitor erdafitinib (ERDA) was well-tolerated and achieved a robust response for patients with metastatic urothelial, or urinary tract, cancers harboring mutations in the FGFR3 gene.

The targeted therapy also appeared effective in a subset of patients for whom immunotherapy had previously failed, suggesting ERDA may provide benefit for patients without further treatment options. The results, presented today at the 2018 American Society of Clinical Oncology Annual Meeting by principal investigator Arlene Siefker-Radtke, M.D., professor of Genitourinary Medical Oncology, also were granted the "Best of ASCO" designation.

"Given the limited treatment options for urothelial cancer, we still have a long way to go to benefit our patients. Having a therapy with a response rate around 40 percent, with the convenience of being an oral medication, certainly fits an unmet need," said Siefker-Radtke.

Urothelial cancers, which account for the vast majority of bladder cancers, arise in the urothelial cells that line the inside of the bladder, ureter and urethra. According to the American Cancer Society, more than 81,000 cases of bladder cancer are expected to be diagnosed in the U.S. this year, with more than 17,000 deaths from the disease.

For several decades, standard of care for urothelial cancers has been chemotherapy with a cisplatin-based regimen, but five new checkpoint blockade inhibitors have been approved in recent years, explained Siefker-Radtke. However, the overall response (OR) rate, defined as percentage of patients with tumor shrinkage, is just 15 to 20 percent with these immunotherapies, she said.

Erdafitinib is an oral medication that blocks activity of all FGFR proteins, including FGFR3. Genetic alterations in FGFR3 can be found in approximately 15 to 20 percent of patients with metastatic bladder cancer and are thought to drive development of the disease. Further, tumors with FGFR3 mutations do not appear to display signs of immune activation, and there is growing evidence suggesting these tumors may not respond as well to immunotherapy, explained Siefker-Radtke.

For the international, open-label, Phase II trial, 99 patients were enrolled and treated with a median of five cycles of the optimized ERDA regimen, consisting of 8 mg daily for 28 days, with escalation to 9 mg allowed in the absence of significant adverse events. All patients had metastatic or surgically unresectable urothelial cancer with a verified mutation in FGFR3 or fusion in FGFR2 or FGFR3. Previous treatment with chemotherapy and/or immune checkpoint inhibitors was allowed.

Treatment-related adverse events were manageable, with just 10 percent of patients discontinuing treatment due to symptoms. There were no treatment-related deaths and no Grade 4 events. The most common adverse events were Grade 1 and 2, including hyperphosphatemia (high blood phosphate levels) (72 patients, Grade =3 in 2 patients), stomatitis (inflammation of the mouth and lips) (54 patients, Grade = 3 in 9 patients), and diarrhea (37 patients, Grade = 3 in 4 patients).

"ERDA treatment has been very tolerable. There have been few dose reductions, and most patients have been able to continue on treatment," said Siefker-Radtke. "Even with evidence of high phosphate levels or other toxicities, usually a period of just holding the drug was enough to reduce symptoms."

Treatment with ERDA met the primary objective with a 40 percent OR rate, including complete response, or tumor disappearance, in three percent of patients and partial response, or tumor shrinkage, in 37 percent. An additional 39 percent of patients had stable disease without progression. Preliminary data from the trial indicate a median overall survival of 13.8 months.

Among 22 patients who previously had been treated with checkpoint blockade inhibitors, ERDA treatment yielded an OR in 59 percent of patients.

"We will need confirmation in future studies, but there may be more benefit from an FGFR-targeted therapy in patients with an FGFR alteration as compared to immunotherapy," said Siefker-Radtke. "It's an exciting time, as we are heading into the field of personalized therapy for urothelial cancer."

A Phase III trial currently is underway to evaluate the efficacy of ERDA relative to chemotherapy or the checkpoint blockade inhibitor pembrolizumab in patients with metastatic urothelial cancer and FGFR3 mutations. Based on the Phase II study, the U.S. Food and Drug Administration granted a breakthrough therapy designation to ERDA earlier this year, which will expedite development and review of the drug for metastatic urothelial cancer.

The study was funded by Janssen Research & Development, LLC. Siefker-Radtke serves on the scientific advisory committee for Janssen.

Collaborators on the international study include: Andrea Necchi, M.D., Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy; Se Hoon Park, M.D., Ph.D., Samsung Medical Center, Seoul, South Korea; Jesus Garcia-Donas, M.D., Clara Campal Comprehensive Cancer Center, Madrid, Spain; Robert Huddart, M.B, Ph.D., Institute of Cancer Research, London, UK; Earle Burgess, M.D., Levine Cancer Institute, Carolinas HealthCare System, Charlotte, NC; Mark Fleming, M.D., Virginia Oncology Associates, US Oncology Research, Norfolk, VA; Arash Rezazadeh, M.D., Norton Healthcare, Louisville, KY; Begona Mellado, M.D., Ph.D., Institut d'Investigacions Biomediques August Pi i Sunyer, Barcelona, Spain; Sergey Varlamov, M.D., Ph.D., Altai Regional Cancer Center, Barnaul, Russia; Monika Joshi, M.D., Penn State Cancer Institute, Hershey, PA; Ignacio Duran, M.D., Ph.D., Hospital Universitario Marques de Valdecilla, Santander, Cantabria, Spain; Scott Tagawa, M.D., Weill Cornell Medical College, New York, NY; Anne O'Hagan, Anjali Avadhani, M.D., and Bob Zhong, Ph.D., Janssen Research & Development, Spring House, PA; Peter De Porre, M.D., Janssen Research & Development, Beerse, Belgium; and Yohann Loriot, M.D., Ph.D., Institut Gustave Roussy, Villejuif Cedex, France .

© 2018 The University of Texas MD Anderson Cancer Center

Easing Concerns about Giving Research Study Participants Their Genetic Test Results

by NCI Staff

The National Cancer Institute -- June 1, 2018

companies img Credit: iStock

People who participate in a research study that includes a genetic test usually don't get those test results back. In part, that is because of concerns that doing so might create burdens for study participants that outweigh any potential benefits.

But a new study shows that many study participants reported feeling more knowledgeable and less anxious about genetic testing after receiving their results when they had talked about them with a genetic counselor.

These findings suggest that study participants who are interested in receiving their results have positive experiences, said lead investigator Angela Bradbury, M.D., an oncologist with the University of Pennsylvania Health System. "We aren't seeing all of the hypothetical harms and concerns in this study," she added.

However, about half of the study participants did not respond to the offer to receive their genetic research results, which required a consultation with a genetic counselor.

"We probably need to explore some alternative models for delivering genetic counseling" to try to increase the response rate, said Adam Buchanan, M.S., M.P.H., L.G.C., of Geisinger Genomic Medicine Institute in Danville, PA, who was not involved in the study.

Published April 16 in JCO Precision Oncology, the NCI-funded study begins to answer some of the major questions about returning genetic research results to participants of cancer studies, said Charlisse Caga-anan, J.D., a program director in NCI's Division of Cancer Control and Population Sciences.

Do Study Participants Want Genetic Results?

Although studies have shown that, in general, people hypothetically are interested in receiving genetic research results, there have been relatively few studies that have investigated how to return results and what their impact is, Caga-anan explained.

"That's the gap we were trying to fill," said Dr. Bradbury.

She and her colleagues contacted 402 women with a history of breast cancer but no harmful mutations in the BRCA1 or BRCA2 genes who had participated in a separate research study. That study involved a genetic test for mutations in multiple genes that may influence the risk of developing breast and other cancers. Having a mutation in one or more of these genes (a positive result) could change how a patient's cancer treatment is managed or how often they get screened for other cancers. A positive result could also impact medical care for the person's family members.

For the new study, Dr. Bradbury and her colleagues offered the women the opportunity to learn their individual test results after meeting with a genetic counselor. The researchers explained that the invitation to participate in the new study was not an indication of a positive test result.

Nearly half of the women did not respond to the researchers' letters; these women were more likely to be older and nonwhite. Some women declined to participate outright, while others discussed participation with the researchers via phone but did not enroll. Overall, 107 women-more likely to be younger, married, and white-indicated that they were interested in receiving their genetic research results and enrolled in the study.

In some ways, it was a surprise that so many women did not respond, said Dr. Bradbury. There is a presumption that everyone who participates in a genetic research study wants to receive their personal genetic results, she explained, but these findings raise questions about that assumption.

The researchers want to understand why some women declined or did not respond. "Whether they understood what was being offered and whether they want to engage with genetic information remains unknown," Dr. Bradbury said.

An Approach to Returning Genetic Research Results

Prior to receiving their results, each participant spoke with a genetic counselor about the risks and benefits of genetic testing. The counselors explained that genetic tests used in a research study may differ from genetic tests given in a clinical setting. For example, physicians and researchers use different types of tests and they may interpret the results differently. In addition, clinical genetic tests have to meet certain standards whereas tests used in research studies do not.

After these discussions, participants reported feeling less anxiety and uncertainty about receiving their results. The women then decided if they wanted to move forward with receiving their research results. Nearly 90% of the participants made an "informed decision"-a decision that was in line with their personal knowledge and perceptions about genetic testing.

Genetic counselors then conveyed the genetic research results to the women who wanted them, either by phone or in person. Only 13 of the 83 women who wanted their results had harmful mutations that are associated with an elevated cancer risk. Another 16 women had mutations, or variants, of uncertain significance (VUS), meaning it is unclear if the mutation is associated with an elevated cancer risk.

The genetic counselors advised women who had known harmful mutations or certain VUS to confirm their research results via clinical genetic testing. For the 64% of women who proceeded with confirmatory clinical testing, genetic counselors assisted them with the testing. Though research funds were available to cover costs of the confirmatory clinical testing, the participants' health insurance covered the costs in full for all but one of the women.

Confirmatory clinical testing verified nearly all of the mutations found by the research test. In some cases, the research investigators and the clinical lab staff had different interpretations of the results.

Outcomes of Returning Results

After receiving their results, participants reported feeling more knowledgeable about genetic testing and less anxious, depressed, uncertain, and distressed about cancer.

"They don't have the anxiety and depression that researchers, clinicians, and ethicists were concerned about-at least when they underwent genetic counseling," said Caga-anan. These results are consistent with other studies of returning genetic research results, said Buchanan.

But the perceived utility-how useful participants thought the information was-was lower after they received their results.

"Maybe people initially think that genetic results tell you more than they actually do," Caga-anan said. "That is one of the concerns with giving genetic information to people; they might overinterpret it."

Overall, the psychological effects were largely the same for all participants regardless of the genetic research result (no mutations, harmful, or VUS) they received. However, women who learned they have a VUS reported feeling an increase in cancer-specific distress.

"There's been a lot of concern about variants of unknown significance and the confusion and stress they may cause for patients," Dr. Bradbury noted. But because the participants also reported feeling less anxiety and depression, she said, "the data are mostly reassuring."

For a few women, the clinical test results changed their medical care. For example, one woman found out that she has Lynch syndrome, a genetic disorder that increases the risk of developing colorectal and other cancers. Consequently, her doctor recommended that she should up the frequency of colorectal cancer screening. For some of the women, their test results implied that their relatives might also carry mutations that increase their risk for developing cancer.

Study Limitations

One limitation of the study is that it only focused on the experiences of women who were interested in receiving their results. These women may feel less stress and anxiety about cancer to begin with, Dr. Bradbury pointed out. She also noted that a relatively small number of women in this study had harmful or VUS mutations.

And because of their cancer history, the women in this study know that they have increased breast cancer risk. "In that setting, the usefulness [of genetic testing] is better settled than in the setting of population screening," Buchanan explained. Whether it is helpful to provide genetic research results to people without cancer is still unknown, he added.

Dr. Bradbury also acknowledged that offering thorough discussions with genetic counselors may have affected their findings. "There may be a greater risk of psychological harms if a different approach is taken," she said.

"It is very resource-intensive to offer genetic counseling to everyone and [offer to] pay for clinical confirmatory testing when insurance doesn't cover it," Caga-anan noted. Not all research groups have the resources to do the same, she added.

To limit the resources needed to responsibly return results, Dr. Bradbury and her colleagues are exploring the use of a web-based tool to help research study participants decide if they want to receive their genetic research results. The investigators are testing the online tool, which is available in English and Spanish, in ongoing studies.

In addition, "there are a variety of models to help patients who are interested in genetic testing get access to it," Buchanan said. These models, which are still being investigated, potentially could be useful for returning genetic research results.

How researchers can return genetic research results to study participants in a responsible way is a major unanswered question, Caga-anan explained. The approach taken by Dr. Bradbury and her colleagues relied heavily on genetic counselors and is an approach that is typically adopted when genetic test results are returned in the clinical setting, said Buchanan.

© 2018 The National Cancer Institute

Melody Management

Cancer Research & APP Development

Aggressive Prostate Cancer Subtype More Common Than Expected

by NCI Staff

The National Cancer Institute -- July 31, 2018

companies img t-SCNC is diagnosed by its appearance under the microscope. Compared with adenocarcinoma (left), t-SCNC cells (right) are smaller and more crowded together.

Credit: Rahul Aggarwal, M.D., of the University of California, San Francisco

Nearly one-fifth of men with metastatic prostate cancer whose tumors were resistant to hormone therapy subsequently developed an aggressive prostate cancer subtype, a new study has shown. Men with this subtype, called treatment-emergent small-cell neuroendocrine prostate cancer (t-SCNC), appear to have shorter survival than men with other subtypes.

The researchers also found genetic differences between t-SCNC and the adenocarcinoma subtype, which accounts for most prostate cancers at diagnosis. Taking advantage of these unique features may improve the diagnosis and treatment of t-SCNC, said lead investigator Rahul Aggarwal, M.D., of the University of California, San Francisco.

The study was published July 9 in the Journal of Clinical Oncology.

"The fact that nearly 20% [of men in the study] had this subtype is a surprise," said William Dahut, M.D., head of the Prostate Cancer Clinical Research Section of NCI's Center for Cancer Research. "That's a greater percentage than we thought."

This finding could lead to clinical trials specifically for men with this subtype of prostate cancer, Dr. Dahut added.

Emergence of the Neuroendocrine Subtype

Potent hormone therapies like abiraterone (Zytiga) and enzalutamide (Xtandi) can be effective treatments for men with castrate-resistant prostate cancer. However, almost all men eventually develop drug resistance to these agents.

In some cases, the drug-resistant cancer may look and behave differently than the original cancer, so much so that it is considered a different subtype of the disease. For example, some men who were originally diagnosed with adenocarcinoma prostate cancer develop t-SCNC after treatment with abiraterone or enzalutamide.

Under the microscope, t-SCNC looks quite different from adenocarcinoma: the cells are smaller and more crowded together. And compared to adenocarcinoma prostate tumors, tumors of the t-SCNC subtype are thought to have less hormone signaling and lower prostate-specific antigen.

In addition, t-SCNC shares some features with a small-cell neuroendocrine subtype of prostate cancer that appears in less than 1% of men with newly diagnosed prostate cancer.

To understand how frequently t-SCNC develops after hormone treatment, Dr. Aggarwal and his colleagues analyzed metastatic tumor samples from 202 men with castrate-resistant prostate cancer who had received treatment at multiple institutions. The samples were obtained from metastatic tumors in the bone, lymph nodes, liver, or other soft tissues.

Metastatic tumor samples from 160 participants could be evaluated, of which 27 (17%) contained the t-SCNC subtype. Of these, 20 samples consisted exclusively of the neuroendocrine subtype, while the remaining 7 contained both adenocarcinoma and neuroendocrine subtypes.

The anatomical site where the metastatic tumor sample had been taken (bone, lymph node, liver, or soft tissue) did not appear to affect the frequency of the neuroendocrine subtype, the researchers found.

In current practice, only patients who have specific clinical features, such as liver metastases, are recommended to have a tumor biopsy to test for t-SCNC. But, based on the team's findings, "we should be thinking about testing more broadly," Dr. Aggarwal noted. A diagnosis of t-SCNC could lead to a change in treatment strategy, he added.

The investigators prospectively followed the participants to gather data on overall survival, starting from the date that the participant developed metastatic castrate-resistant disease. Men whose metastatic tumors were of the adenocarcinoma subtype lived longer (median of 44.5 months) than men whose tumors were of the t-SCNC subtype (36.6 months) or included both subtypes (36.8 months).

Genetic Features of Neuroendocrine Tumors

The researchers also examined patterns of gene expression in the t-SCNC tumors and compared them with those of adenocarcinoma tumors. This analysis identified a group of 61 genes that were expressed differentially between the two subtypes. The investigators also identified the topmost upregulated master regulators-proteins that control hundreds or thousands of other genes that are critical for cancer growth and survival-in the t-SCNC tumors.

Based on these findings, the researchers developed a unique pattern of gene expression-called a signature-for t-SCNC tumors that correctly distinguished t-SCNC tumors from adenocarcinoma prostate tumors in separate sets of tumor samples.

The validated signature has several potential clinical uses, said Dr. Aggarwal, such as to identify genes or pathways that potentially can be targeted by drugs. And if effective drugs become available, the signature could also be used to help diagnose t-SCNC prostate tumors in cases where a traditional tumor biopsy is not possible or would be unreliable, he added.

The researchers also found that t-SCNC and adenocarcinoma tumors differed in the types of genetic mutations they harbored. Consistent with a previous study, t-SCNC tumors were more likely to have mutations that lessen the activity of two genes that control cell division, TP53 and RB1. And while many of the adenocarcinoma tumors had activity-dampening mutations in, or fewer copies of, genes that help repair DNA, almost none of the t-SCNC tumors did.

Taken together, these findings suggest that t-SCNC tumors may have unique molecular characteristics that can potentially be targeted by drugs, Dr. Aggarwal explained.

Ongoing Work to Learn More

Dr. Aggarwal and his colleagues are investigating how the t-SCNC subtype develops in men with metastatic castrate-resistant prostate cancer.

"We think it arises from [the original] adenocarcinoma," Dr. Aggarwal said. "The cancer cells transform into this subtype of prostate cancer through genetic reprogramming."

Some aspects of this reprogramming event are understood, such as specific factors that control the transition. However, he added, "more studies still need to be done to understand how and when it happens."

Potent hormone therapies such as abiraterone and enzalutamide may push prostate cancer toward this transformation, said Dr. Dahut. That may be why this subtype is more prevalent in men who have received treatment than in men with newly diagnosed prostate cancer, noted Dr. Aggarwal.

The research team's ultimate goal is to find therapies for t-SCNC. Master regulator proteins are opportune drug targets, Dr. Aggarwal explained, because they control many pathways that contribute to cancer growth and survival.

Several of the master regulators that they identified in t-SCNC tumors can be targeted directly or indirectly by drugs that are in development, and the team hopes to be able to test these in clinical trials of men with this subtype of prostate cancer.

Dr. Dahut also speculated that a better understanding of the genetic reprogramming event that creates t-SCNC could potentially lead to the discovery of drugs that prevent the development of this hard-to-treat subtype.

© 2018 The National Cancer Institute

Developing Biomarkers for Immunotherapy: A Conversation with Drs. Magdalena Thurin and Helen Chen

by NCI Staff

The National Cancer Institute -- July 27, 2018

companies img NCI is funding an initiative to identify biomarkers that can predict which patients are most likely to respond to immunotherapy treatments. Credit: National Cancer Institute

    NCI is supporting a new network of research centers and a data center created to develop biomarkers for immunotherapy. The network consists of four Cancer Immune Monitoring and Analysis Centers (CIMACs) and a data storage center, the Cancer Immunologic Data Commons (CIDC).

    In this interview, Magdalena Thurin, Ph.D., of the Cancer Diagnosis Program and Helen Chen, M.D., of the Cancer Therapy Evaluation Program, both in NCI's Division of Cancer Treatment and Diagnosis, discuss the network and its goals.

What is the goal of the research network?

Dr. Thurin: The long-term goal is to identify molecular signatures or biomarkers that, in the future, doctors can use to identify patients with cancer who are likely to respond to immunotherapy.

Dr. Chen: Biomarkers identified as a result of this project could also be used to help investigate mechanisms of resistance to immunotherapy, which may guide the development of combination therapies that may overcome this resistance. In addition, biomarkers could be identified that help to monitor patients' responses to treatment.

How will the new network of laboratory centers and the data center achieve this goal?

Dr. Thurin: The four centers, or CIMACs, will use state-of-the-art technologies to perform a range of molecular and cell-based testing on biospecimens-such as blood and tumor samples-from patients enrolled in early-phase immunotherapy clinical trials-phase 1 and phase 2-that are funded by NCI. These test results and clinical information about patients will be stored in the CIDC, which researchers can then use in follow-up studies to identify potential biomarkers.

The four CIMACs will use standardized assays for analyzing biospecimens collected from these immunotherapy clinical trials. That will ensure that there is a uniformity in their work and the results they produce, and it will give us more statistical power and provide greater confidence in any potential biomarkers that are identified.

Can you explain how the CIMACs are set up?

Dr. Chen: Each of the four CIMACs-Dana-Farber Cancer Institute, Stanford University, MD Anderson Cancer Center, and Icahn School of Medicine at Mount Sinai-has a multidisciplinary team with expertise in immunology, clinical investigation, pathology, bioassays, and bioinformatics.

These teams will work closely with the clinical investigators who are leading the early-stage immunotherapy trials to design their biomarker studies, apply different assays for identifying potential biomarkers, and analyze the results.

Why are biomarkers of response to immunotherapy needed?

Dr. Chen: Currently, a minority of patients with cancer benefit from immunotherapies. But we don't know why only some patients respond to immunotherapy, and we cannot reliably predict which patients will benefit from the therapy. Validated biomarkers could help guide treatment decisions for patients and doctors who are considering immunotherapy.

Dr. Thurin: In addition, to improve the effectiveness of immunotherapies, we need to develop a better understanding of how the immune system interacts with tumors, which can help us develop tools for selecting the appropriate patients for a specific immunotherapy or combination therapy.

Do any biomarkers exist that can help guide treatment decisions about immunotherapy?

Dr. Chen: In recent years, several potential biomarkers have emerged, such as levels of a protein called PD-L1 expressed on tumor cells and immune cells in the tumor microenvironment. Another biomarker is tumor mutational burden, which is an assessment of the number of genetic mutations in a tumor. But we still need biomarkers that are more precise.

What is the CIDC's role?

Dr. Thurin: The CIDC is hosted at Dana-Farber Cancer Institute and has multiple functions. But its primary role is to collect the biomarker data generated at the four CIMACs and to provide a platform for integrating patients' clinical data-such as age, prior treatments, response to treatment, side effects-with data on the biospecimens. Having all of this information in the CIDC will help other researchers explore the data for biomarkers.

The CIDC will also provide some of the informatics tools for the analyses of the data. In the future, the CIDC is expected to serve the cancer research community in a manner similar to NCI's Genomic Data Commons.

© 2018 The National Cancer Institute

FDA Alters Approved Use of Two Checkpoint Inhibitors for Bladder Cancer

by NCI Staff

The National Cancer Institute -- July 26, 2018

companies img Several drugs that target immune checkpoint proteins like PD-1 and PD-L1 are approved to treat bladder cancer. Credit: Adapted from Onco Targets Ther April 2017. doi: 10.2147/OTT.S133385 CC BY 3.0.

The Food and Drug Administration (FDA) has changed the approved uses of two immunotherapy drugs to treat people with the most common form of bladder cancer, urothelial carcinoma.

Last year, the drugs-pembrolizumab (Keytruda) and atezolizumab (Tecentriq)-received approval for the treatment of patients with previously untreated urothelial carcinoma that has spread beyond the bladder. The 2017 approvals covered the use of the drugs for patients who, because of other health-related factors, cannot receive the chemotherapy drug cisplatin, which is a standard treatment for patients with advanced bladder cancer.

Approximately half of people diagnosed with bladder cancer that has spread can't receive cisplatin, explained Andrea B. Apolo, M.D., of the Genitourinary Malignancies Branch (GMB) in NCI's Center for Cancer Research.

Last year's approvals were based on results from two small, early-phase clinical trials. On June 20, however, the agency announced that data from two larger, ongoing clinical trials showed that patients with metastatic bladder cancer treated with either pembrolizumab or atezolizumab died sooner than those treated with a standard chemotherapy regimen.

The worse survival was seen specifically in people whose tumor cells had very low levels of the protein PD-L1.

As a result of the new findings, FDA announced that it was changing the prescribing label for both drugs. Under the change, pembrolizumab and atezolizumab should be used as an initial, or first-line, treatment in only those people with metastatic bladder cancer who can't receive cisplatin-based chemotherapy and whose tumors have high levels of PD-L1. The assessment of PD-L1 levels must be made using an FDA-cleared test.

Under the labeling change, Dr. Apolo noted, patients who can't be treated with any platinum-containing therapy can still receive either immunotherapy drug, regardless of their PD-L1 levels.

Following Up on Accelerated Approvals

Pembrolizumab and atezolizumab are both immune checkpoint inhibitors, and both are approved by FDA to treat patients with metastatic bladder cancer that has continued to progress on standard treatments such as combinations of chemotherapy drugs.

The expanded approvals of both drugs as first-line treatments in 2017 were accelerated approvals, based on the findings from smaller clinical trials showing that some patients' tumors shrank following treatment. Because they were not randomized trials that compared the drugs against standard treatments, however, the trials could not show whether patients who received the immunotherapy drugs lived longer.

Under an accelerated approval, a drug's manufacturer has to conduct a larger trial to confirm that the drug does indeed have a meaningful benefit for patients, such as improving survival or quality of life.

It was the early analyses of data from two of these confirmatory trials-KEYNOTE-361 (pembrolizumab) and IMvigor 130 (atezolizumab)-which showed that patients with low PD-L1 levels who received the checkpoint inhibitor alone "had decreased survival compared to patients who received cisplatin- or carboplatin-based chemotherapy," the agency reported.

PD-L1 levels have been widely studied as a biomarker for response to treatment with checkpoint inhibitors. PD-L1 on tumor cells is involved in dialing down the immune response, and both pembrolizumab and atezolizumab disrupt that process. Several checkpoint inhibitor approvals have been limited to people whose tumors have elevated PD-L1 levels.

However, using PD-L1 levels to select treatment for these patients "puts oncologist in the difficult position of finding a laboratory that will do the correct assay for that specific therapy," said Dr. Apolo. "The assays used with atezolizumab and pembrolizumab each look at different cells, the cut-off for a 'positive' result is still being fine-tuned for each assay, and some patients may not have tissue available for testing," she explained.

Also, for patients who are ineligible to receive cisplatin, selecting treatment based on the PD-L1 levels of their tumors "may eliminate a viable, effective treatment option for some patients," said Dr. Apolo. "Based on the reported studies that led to these approvals, approximately 20%-30% of cisplatin-ineligible bladder cancer patients with low PD-L1 levels had durable responses to atezolizumab or pembrolizumab."

According to FDA, patients with low PD-L1 levels are no longer being enrolled in the KEYNOTE-361 or IMvigor 130 trials.

Evolving Role of Immunotherapy in Bladder Cancer

It's not surprising that the patients who received chemotherapy responded well to treatment, said Dr. Apolo, who heads the GMB's Bladder Cancer Section. "Chemotherapy is very active in patients with urothelial carcinoma," she explained.

In fact, Dr. Apolo continued, evidence from previous bladder cancer trials has shown that the rates at which patients' tumors shrink after treatment with first-line chemotherapy regimens that include cisplatin or carboplatin are higher than the rate for cisplatin-ineligible patients treated with a first-line checkpoint inhibitor.

However, patients whose tumors do respond to checkpoint inhibitors tend to maintain those responses for long periods, she said. So the premise in these trials was that these extended responses "would translate into a survival benefit."

Data on whether survival will be improved for patients with high PD-L1 levels treated with only a checkpoint inhibitor are still not available. In addition, KEYNOTE-361 and IMvigor 130 also have a treatment group that is receiving the immunotherapy drug in combination with chemotherapy, but efficacy data are not yet available for those groups either.

Dr. Apolo stressed that, in patients whose cancer has progressed after chemotherapy treatment, "immunotherapy with checkpoint inhibitors [alone] is still the standard of care."

© 2018 The National Cancer Institute

Mouse Study Links Immune Cells to Diarrhea Caused by Chemotherapy

by NCI Staff

The National Cancer Institute -- July 18, 2018

companies img Research in mice suggests that targeting a receptor (green) on immune cells called macrophages (red) holds potential for treating chemotherapy-induced diarrhea. Credit: Center for the Study of Itch

Immune cells called macrophages may help regulate the contractions of muscles lining the walls of the intestines, according to a new study in mice.

The findings may shed light onto how some chemotherapy agents cause diarrhea and could be the basis for developing new anti-diarrheal treatments for patients with cancer who experience chemotherapy-induced diarrhea, researchers at the Washington University School of Medicine in St. Louis reported in Immunity on July 17.

Diarrhea is a frequent side effect of certain chemotherapy agents. Severe diarrhea may cause some individuals receiving chemotherapy to reduce the dose or to stop treatment altogether.

The Washington University researchers found that macrophages were part of a previously unknown signaling pathway that participates in controlling the activity of smooth muscle cells in the gastrointestinal (GI) tract.

This signaling pathway is necessary for normal smooth muscle contractions, or motility, in mice, the researchers concluded. It was through this pathway that the chemotherapy drug irinotecan (Camptosar) caused diarrhea in mice, they noted.

"This is an excellent, novel, and provocative study," said Simon J. Gibbons, Ph.D., of the Mayo Clinic College of Medicine and Science, who investigates the GI system but was not involved in the study. "There are many potential applications for human health," including new treatments for chemotherapy-induced GI side effects such as abdominal pain and diarrhea.

Focusing on a Macrophage Linked to Chronic Itching

It has recently become clear that macrophages affect neurons in the GI tract that send signals to smooth muscle cells in the gut, causing them to contract and relax when appropriate, Dr. Gibbons noted. There are approximately as many neurons in the gut as there are in the brain.

Although the smooth muscle layers of the gut are also home to a large population of macrophages, "the role of these cells in maintaining GI motility has not been clear," said Hongzhen Hu, Ph.D., of Washington University, who co-led the study with Brian S. Kim, M.D.

To learn more about the role of macrophages in gut motility, the researchers focused on macrophages that have a channel protein on their cell surfaces called the transient receptor potential vanilloid 4 (TRPV4).

The family of TRP channel proteins enables individual cells to detect changes in their local environments, such as heat and the movement of food through the intestine. In previous work led by Drs. Hu and Kim at the Center for the Study of Itch at Washington University, TRPV4 had been linked to chronic itching.

In the current study, the TRPV4 protein triggered the release of molecules called prostaglandins. These molecules in turn interact with the smooth muscle cells in the intestines to maintain normal GI motility.

"We learned that macrophages are acting like neurons in the gut," Dr. Kim explained. "The immune cells are triggering the contraction of the smooth muscles in the gut independently of nerve cells."

An Expanding View of Macrophages

The new findings add to a growing body of knowledge about the biological roles of macrophages. "Macrophages do much more than help the immune system," Dr. Gibbons said. "It is increasingly evident that macrophages are central to the normal physiological functioning of many tissues, including the gut and the brain."

Using genetic tools and pharmacological agents, the Washington University researchers found that macrophages expressing the TRPV4 channel appeared to be necessary for the normal functioning of the GI tract in the mice. When the channel was altered or blocked, GI motility slowed.

"We all think that the immune system is there to fight off infections, but it turns out that the immune system is also important in the gut for other reasons," said Dr. Kim.

Reversing Chemotherapy-Induced Diarrhea

Next, the researchers found that giving the mice the chemotherapy agent irinotecan altered the expression of TRPV4 protein and affected the GI functions in the animals. But by blocking the activity of TRPV4 in the mice, the researchers reduced symptoms such as diarrhea.

"The idea that immune cells are regulating a mechanical process in the intestines is exciting, because it opens new avenues to develop treatments not just for chemotherapy-induced diarrhea but for other bowel disorders as well, including irritable bowel syndrome," Dr. Kim said.

The movement of contents in the GI tract is a very complex process that depends on a variety of different types of cells, Dr. Gibbons cautioned, noting that more research is needed to better understand the newly identified signaling pathway in mice and in humans.

Nonetheless, Dr. Gibbons continued, "companies have developed small molecules targeting TRPV4 and these could be exploited to modulate GI motility."

© 2018 The National Cancer Institute

NIH and Prostate Cancer Foundation launch large study on aggressive prostate cancer in African-American men

by NCI Staff

The National Cancer Institute -- July 17, 2018

companies img Credit: iStock

The largest coordinated research effort to study biological and non-biological factors associated with aggressive prostate cancer in African-American men has begun. The $26.5 million study is called RESPOND, or Research on Prostate Cancer in Men of African Ancestry: Defining the Roles of Genetics, Tumor Markers, and Social Stress. It will investigate environmental and genetic factors related to aggressiveness of prostate cancer in African-American men to better understand why they disproportionally experience aggressive disease-that is, disease that grows and spreads quickly-compared with men of other racial and ethnic groups.

RESPOND is supported by the National Cancer Institute (NCI) and the National Institute on Minority Health and Health Disparities (NIMHD), both parts of the National Institutes of Health, as well as by the Prostate Cancer Foundation (PCF). The NCI funding will be provided from the 21st Century Cures Cancer Moonshot Initiative.

"Understanding why African-American men are more likely to be diagnosed with aggressive prostate cancer than men of other racial and ethnic groups is a critical, unanswered question in cancer disparities research," said NCI Director Ned Sharpless, M.D. "This large, collaborative study can help the cancer research community better understand and address these disparities."

African-American men have about a 15 percent chance of developing prostate cancer in their lifetimes, compared to about a 10 percent chance for white men, and African-American men are more likely to be diagnosed with aggressive disease. In addition, the risk of dying from prostate cancer for African-American men is about 4 percent compared to about 2 percent for white men. With the RESPOND study, researchers aim to learn more about why these disparities exist.

"This study, which is combining state-of-the-art molecular approaches with social and environmental science, will help unravel the complex interactions of biological, behavioral, and environmental factors that contribute to excess prostate cancer burden and poorer outcomes in African-American men, allowing development of tailored approaches for prevention, diagnosis, and treatment in this population," said NIMHD Director Eliseo Perez-Stable, M.D.

The investigators aim to enroll 10,000 African-American men with prostate cancer into the RESPOND study. The participants will be identified primarily via NCI's Surveillance, Epidemiology, and End Results (SEER) Program and the Centers for Disease Control and Prevention's National Program of Cancer Registries. In addition, this study builds on years of research collaboration involving investigators who are part of the African Ancestry Prostate Cancer (AAPC) consortium. These investigators will contribute additional information and samples from 10,000 African-American men with prostate cancer. In accordance with NIH data sharing policies, and with appropriate informed consent, the de-identified data and samples collected as part of this research will be made available as a resource to the scientific community, aiding future research.

Investigators in the study will examine possible associations between aggressive disease and exposures to neighborhood/environmental stressors such as discrimination, early-life adversity, and segregation. They will also study DNA and tumor samples to identify gene variants associated with aggressive prostate cancer. Once researchers have identified genetic changes associated with aggressive prostate cancer, they will investigate how the social environment interacts with those genetic changes.

"Previous research on prostate cancer disparities has investigated social and genetic factors separately, but we know these components interact with each other to contribute to disparities," said Damali Martin, Ph.D., program director for the study in NCI's Epidemiology and Genomics Research Program. "The ability to integrate genetic and environmental factors, including individual, neighborhood, and societal factors, into one large study will enable us to have a better understanding of how all of these factors contribute to the aggressiveness of prostate cancer."

RESPOND, a cooperative agreement, will be led by Christopher Haiman, Sc.D., of the University of Southern California (USC) in Los Angeles, in collaboration with John Carpten, Ph.D., Ann Hamilton, Ph.D., and David Conti, Ph.D., also of USC; Scarlett Gomez, Ph.D., of the University of California, San Francisco; Tamara Lotan, M.D., of Johns Hopkins University in Baltimore; and Franklin Huang, M.D., Ph.D., of Dana-Farber Cancer Institute in Boston.

NCI's Division of Cancer Epidemiology and Genetics will perform genotyping, and the Center for Inherited Disease Research at Johns Hopkins University will conduct DNA sequencing for the genetic component of the study. NCI's Division of Cancer Control and Population Sciences is administering the study grant.

"No group in the world is hit harder by prostate cancer than men of African descent, and, to date, little is known about the biological reasons for these disparities, or the full impact of environmental factors," said Jonathan W. Simons, M.D., PCF's president and CEO. "We celebrate our partnership and applaud NIH for spearheading this study, which we believe will help pave the way for groundbreaking discoveries that will improve health equity for African-American men and their families."

About the National Cancer Institute (NCI): NCI leads the National Cancer Program and NIH's efforts to dramatically reduce the prevalence of cancer and improve the lives of cancer patients and their families, through research into prevention and cancer biology, the development of new interventions, and the training and mentoring of new researchers. For more information about cancer, please visit the NCI website at cancer.gov or call NCI's Contact Center (formerly known as the Cancer Information Service) at 1-800-4-CANCER (1-800-422-6237).

About the National Institute on Minority Health and Health Disparities (NIMHD): NIMHD leads scientific research to improve minority health and eliminate health disparities by conducting and supporting research; planning, reviewing, coordinating, and evaluating all minority health and health disparities research at NIH; promoting and supporting the training of a diverse research workforce; translating and disseminating research information; and fostering collaborations and partnerships. For more information, visit nimhd.nih.gov.

About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit nih.gov.

About the Prostate Cancer Foundation (PCF): PCF is the world's leading philanthropic organization funding and accelerating prostate cancer research. Founded in 1993, PCF has raised more than $720 million and provided funding to more than 2,000 research programs at nearly 200 cancer centers and universities. The PCF global research enterprise now extends to 19 countries. PCF advocates for greater awareness of prostate cancer and more efficient investment of governmental research funds for transformational cancer research. Its efforts have helped produce a 20-fold increase in government funding for prostate cancer. For more information, visit www.pcf.org.

© 2018 The National Cancer Institute

The Opioid Epidemic and Cancer Pain Management: A Conversation with Dr. Judith Paice

by NCI Staff

The National Cancer Institute -- July 16, 2018

companies img The opioid epidemic is affecting people with cancer who rely on opioids to help manage their pain. Credit: iStock

    Pain is a common symptom in cancer patients. It can be caused by cancer, its treatments, or a combination of factors. Although some pain lasts a relatively short time and will resolve on its own, cancer or its treatments can also lead to long-lasting, chronic pain. Opioid medications are an important component of managing some types of unrelieved cancer pain.

    In this interview, Judith Paice, Ph.D., R.N., director of the Cancer Pain Program at Northwestern University's Feinberg School of Medicine, discusses the impacts of the opioid epidemic and how providers can address concerns about opioid misuse when managing cancer pain.

First of all, what types of medications or other approaches are used to manage pain in cancer patients and survivors?

Any of the prescription opioid medications can be used for people with cancer. Non-opioid agents, including medications like acetaminophen (Tylenol) and ibuprofen (Motrin or Advil), are also used. For nerve pain, we may use antiseizure medications like gabapentin (Neurontin or Gralise) or antidepressant-type medications like duloxetine (Cymbalta).

Oncology care providers rely heavily on opioids, but we never rely only on opioids. We're always using multiple therapies that work in different ways. That includes other pharmacologic (drug) therapy, and, as much as possible, non-pharmacologic approaches such as physical therapy, occupational therapy, orthotics, cognitive behavioral therapy, and massage and other integrative therapies.

companies img Judith Paice, Ph.D., R.N., director of the Cancer Pain Program, Northwestern University Feinberg School of Medicine

How has the opioid epidemic affected cancer patients, cancer survivors, and their family members?

It has enhanced fear-fear of addiction in particular-such that some patients are very reluctant to take opioid medications for pain. Sometimes, it's not the patient but the family member who is concerned [about addiction]. As a result, family members may withhold medicine from a loved one who is in pain, or they may question that person's need for opioid medications, even when that person is at the end of life.

Another major effect is reduced access to opioid pain medications. Recently released results of a study by the American Cancer Society Cancer Action Network and the Patient Quality of Life Coalition show that one-third or more of cancer patients and survivors are having difficulty getting access to their prescribed opioid medications and that the proportion of people experiencing such difficulties has increased markedly since 2016. From a policy perspective, one of the major challenges we're facing right now is the need to ensure that patients with cancer get the medications they need, and without significant delays.

How has concern about opioid misuse affected health care providers?

Many primary care doctors no longer prescribe opioids. Oncologists are still prescribing these medications, but in many cases they're somewhat anxious about doing so. That has led some patients to have trouble even obtaining a prescription for pain medication.

There's a great fear of legal action against people who prescribe opioids, and an awareness that prescribing practices are being monitored much more closely than in the past. In addition, insurance companies have made it much harder to obtain these medications, and as a result, more and more prescribers have been reluctant to introduce opioids into their patients' care regimens.

Have there been any positive developments for cancer pain management as a result of the increased focus on the opioid epidemic?

To some extent, providers in the oncology community have looked more closely at our opioid prescribing practices ... and are beginning to question the risk-benefit ratio of opioids more than we did in the past. As a community, oncology providers are beginning to look at long-term side effects of these medications, and whether their use is appropriate for the person who is not receiving active treatment, does not have active disease, and is going to live another 5, 10, or 20 years.

Are patient fears of opioid addiction a valid concern?

Anybody can have a disease of addiction. The prevalence of these diseases is unknown-it depends on how addiction is defined-but is likely around 10% or more in the general population. Furthermore, some of the risk factors for cancer are also risk factors for addiction, such as cigarette smoking and alcohol overuse.

Many people have assumed that people with cancer are not at risk for addiction, when in fact they may have the same risk as, or possibly even a greater risk than, the general population. Some people say, "Who cares if a cancer patient [with advanced disease] becomes an addict?" But many cancer patients do care, especially if they've had a problem with substance misuse in the past and have overcome that. These people may prefer to die with their sobriety intact.

What are the recommended best practices for using opioid medications to treat cancer?

Oncology care providers need to determine if opioids are the right drug for a particular type of cancer-related pain. According to a recent clinical practice guideline for chronic pain management in cancer survivors, published by the American Society of Clinical Oncology, careful assessment of the pain and its effect on function, and of the possible risks associated with use of an opioid, are the first step. When opioids are considered, providers should assess every patient for risk factors for addiction. Providers should also employ strategies to reduce the risk of misuse for all patients who are taking opioids. These strategies may include urine testing, checking state prescription drug monitoring programs to evaluate a person's history of filling prescriptions for controlled substances, doing pill counts, and using patient-provider agreements or contracts. Each provider must determine what makes the best sense in their practice.

We need to employ these techniques for all patients because implicit bias can occur if we just take precautions for those patients we think are at risk for addiction. Addiction crosses all gender lines, all racial lines, all economic lines, and affects people of all ages.

With patients who are thought to be at high risk of developing a substance use disorder, providers may even decide not to use an opioid. Or we may need to prescribe smaller amounts of medication at a time.

How can providers achieve a balance between the need for adequate pain control and concerns about possible misuse of opioids?

The use of these very clear assessments and universal precautions allows prescribers to identify the potential for problems early on. Another important factor is that, unlike 10 or 20 years ago, the goal no longer is to eliminate pain completely, which is unrealistic. Instead, the goal is to reduce pain enough that patients can fully function to the best of their capabilities.

We providers have to educate our patients to help them understand that the role of opioids and other pain medications is to allow them to move and function better.

For some people, that may mean being able to walk around the block. For some, controlling the pain will allow them to return to work. And for those patients who are more fragile, the goal of pain medications may be to make them sufficiently comfortable to be able to hold their grandkids, or to sit comfortably on a hard chair in a church or restaurant.

© 2018 The National Cancer Institute

Sodium Thiosulfate Prevents Cisplatin-Induced Hearing Loss in Some Children

by NCI Staff

The National Cancer Institute -- July 13, 2018

companies img An inner ear "organoid" showing hair cells (red) and hair cell bundles (yellow). Credit: Karl R. Koehler, Ph.D., Indiana University School of Medicine. CC BY 2.0.

The drug sodium thiosulfate can protect the hearing of children with cancer undergoing treatment with the chemotherapy drug cisplatin, results from a new study show.

The clinical trial involved children with liver cancer that had not spread (localized cancer), for whom cisplatin is the standard chemotherapy. Although cisplatin is very effective, it also causes hearing loss in many children.

The participants in the trial, which was conducted primarily in Europe, were randomly assigned to receive sodium thiosulfate 6 hours after each cisplatin treatment or to receive only cisplatin. The children in the sodium thiosulfate group were half as likely to experience permanent hearing loss than children who received cisplatin alone, the researchers reported.

Importantly, sodium thiosulfate did not appear to make cisplatin less effective: there was no difference in how many children in each treatment group were alive 3 years after completing treatment. The trial findings were published June 21 in the New England Journal of Medicine.

These results mirror those from a similar trial conducted in the United States, published last year, which tested sodium thiosulfate's ability to prevent cisplatin-induced hearing loss in children with diverse types of cancer.

"It's encouraging to see two studies show that you can reduce the risk of hearing loss in these kids without reducing the effectiveness of the chemotherapy," commented Lisa Cunningham, Ph.D., of the National Institute on Deafness and Other Communication Disorders, who was not involved in either trial.

Hearing Loss Impacts Development

Today, more than 80% of children diagnosed with cancer are alive at least 5 years after diagnosis, and many are considered to be cured.

Researchers are now turning greater attention to reducing the long-term side effects that children experience with many widely used cancer treatments. These can include heart or lung problems, cognitive difficulties, infertility, and hearing loss.

"Over the last decade or so, we've really developed a much deeper understanding of how [some of] these drugs damage the inner ear," commented Dr. Cunningham. Earlier this year, for example, her lab published results showing that cisplatin is retained for a long time in the inner ear, which may explain why its use can lead to hearing loss.

Hearing loss can have significant long-term consequences for children treated for cancer, said Edward Neuwelt, M.D., of Oregon Health & Science University, who helped lead both recent trials. "Around 60% to 80% of kids who get cisplatin have significant hearing loss," Dr. Neuwelt explained. The impact of that hearing loss can be profound, he continued, including greatly increasing the risk of failing a grade in school.

The consequences can be even more serious for very young children, added Dr. Cunningham. "Hearing loss actually impairs their ability to develop normal speech and language skills, which ... can lead to severe developmental problems for a child," she explained.

Confirming that Sodium Thiosulfate Doesn't Compromise Survival

Sodium thiosulfate is a type of drug called an antioxidant. It is thought to bind to harmful molecules called reactive oxygen species that are produced in cells that have taken up cisplatin. This binding may prevent free radicals from damaging the hair cells in the inner ear that play a critical role in hearing.

It's also possible that sodium thiosulfate is working by binding to cisplatin itself, preventing any residual cisplatin from killing cells in the ear, Dr. Cunningham said.

The results from the trial published last year, which was led by the NCI-supported Children's Oncology Group, enrolled children with a variety of cancer types who all received cisplatin as part of their initial treatment. The 104 participants were randomly assigned to receive chemotherapy alone or chemotherapy followed by sodium thiosulfate 6 hours after each dose of cisplatin.

The timing of the sodium thiosulfate infusions, Dr. Neuwelt explained, was based on several decades of laboratory and clinical work to establish how long cisplatin is active in the body. After 6 hours, cisplatin is no longer actively killing cancer cells, he continued, so giving sodium thiosulfate at that time should not interfere with cisplatin's anticancer effects.

Hearing loss occurred in 31 (56%) of the children who received chemotherapy alone, compared with 14 (29%) who also received sodium thiosulfate. Sodium thiosulfate did not appear to cause any side effects.

Overall, no differences in overall survival were seen between the groups. However, in an analysis that was not planned before the trial started, the researchers did see a reduction in overall survival for children who received sodium thiosulfate and who had cancer that had spread beyond the site of origin (disseminated disease).

Although such analyses are largely used to identify issues that should be explored with further research, some people became concerned about the safety of sodium thiosulfate in children with later-stage cancer, explained Dr. Neuwelt.

In the European trial, which was funded in part by NCI, the researchers enrolled only children with one type of cancer-a type of liver cancer called hepatoblastoma-and only those with localized disease. Cisplatin was the only chemotherapy drug received by participants in the trial. Of the 101 participants, hearing loss occurred in 29 (63%) of the children who received cisplatin alone, compared with 18 (33%) of those who also got sodium thiosulfate.

Three years after treatment, 98% of the children who received cisplatin and sodium thiosulfate and 92% who received cisplatin alone were alive. One child experienced a side effect (a buildup of acid in the blood) that required discontinuation of sodium thiosulfate during the trial. The researchers reported that other side effects possibly caused by sodium thiosulfate were mild, and included nausea, vomiting, and a reduction in blood cell numbers.

"These data are compelling, and the conclusions of this trial should trigger a major change in practice," commented Eric Bouffet, M.D., of the Hospital for Sick Children at the University of Toronto.

Remaining Questions about Sodium Thiosulfate

Some questions remain about protecting hearing in children undergoing cisplatin-based chemotherapy, added Dr. Bouffet. "Some children still present with hearing complications despite the use of sodium thiosulfate. The results of ongoing studies to better understand which patients may be at risk of hearing loss are needed," he said.

Additional trials are also needed to answer lingering concerns about the drug's use in children with disease that has spread, continued Dr. Bouffet.

Dr. Neuwelt is hoping to develop a clinical trial testing whether adding sodium thiosulfate as part of the treatment regimen can improve survival in children diagnosed with medulloblastoma. Often, parents of children with the disease opt to have them not complete their course of cisplatin because of hearing loss.

"We're going to see if we can decrease the number of kids who need a dose reduction [of cisplatin], and see if that will improve survival," he explained.

"There's enthusiasm right now in basic science and in the pharmaceutical industry for developing new therapies that will reduce hearing loss, both in children and in adults," said Dr. Cunningham. "There are a number of drugs at various stages of development in the pipeline right now that are being developed specifically for this purpose."

For now, "sodium thiosulfate is cheap and can be incorporated [easily] into chemotherapy protocols that contain cisplatin," Dr. Bouffet said. "The positive results from [the European] trial call for additional studies of sodium thiosulfate in other cancer types, including in adults."

© 2018 The National Cancer Institute

Study shows biomarker panel boosts lung cancer risk assessment for smokers

Blood test can extend reach of CT screening beyond those with heavy smoking history

MD Anderson Cancer Center -- July 12, 2018

companies img Sam Hanash, M.D., Ph.D.

HOUSTON -- A four-protein biomarker blood test improves lung cancer risk assessment over existing guidelines that rely solely upon smoking history, capturing risk for people who have ever smoked, not only for heavy smokers, an international research team reports in JAMA Oncology.

"This simple blood test demonstrates the potential of biomarker-based risk assessment to improve eligibility criteria for lung cancer screening with low-dose computed tomography," said study co-senior author Sam Hanash, M.D., Ph.D., professor of Clinical Cancer Prevention at The University of Texas MD Anderson Cancer Center.

The biomarker panel achieved superior sensitivity - identification of smokers who later developed lung cancer - without increasing false-positives compared to guidelines for screening approved by the U.S. Preventive Service Task Force (USPSTF) for heavy smokers based on age and smoking history.

USPSTF guidelines call for CT screening only of adults between ages 55 and 80 with a 30 pack-year smoking history who either smoke or have quit within the past 15 years.

"The biomarker panel more accurately identifies at-risk smokers who should proceed to screening, even if they're not at the highest risk based on smoking history alone," Hanash said. "A positive blood test means an ever-smoker is as much, if not more so, at risk of having lung cancer as a heavy smoker with a low biomarker score."

The paper reports a validation study of the biomarker model in 63 ever-smoking patients who developed lung cancer within a year of initial blood sample collection compared to 90 matched controls in two large European population-based cohorts.

Researchers compared a model based on smoking history to an integrated model that included the biomarker score based on the four markers plus smoking history.

At the same level of false-positive rate (specificity) set by the USPSTF guidelines, the integrated test with biomarkers identified 63 percent of future lung cancer cases (40 of 63), compared to 42 percent (20 of 62) based on smoking history alone.

The improved detection rate, Hanash said, reflects the biomarker panel's ability to identify at-risk people among the larger population of ever-smokers. In the validation study, smoking history did not improve prediction of future lung cancer cases beyond that provided by the biomarkers alone.

Hanash's group worked with European researchers affiliated with the International Agency for Research on Cancer (IARC), part of the World Health Organization. Co-senior authors were Mattias Johansson, Ph.D., of IARC and Paul Brennan, Ph.D., head of the Section on Genetics at IARC.

MD Anderson's Lung Cancer Moon Shot, part of the institution's Moon Shots Program, provided initial support of Hanash's research, mainly through funding from the Lyda Hill Foundation.

Prediagnosis blood samples were crucial

Hanash says the key to selecting the biomarkers was the availability of blood samples taken from people before they had developed the disease. This contrasts to most previous studies comparing biomarkers in early stage lung cancer patients to healthy controls. Such studies do not reflect how biomarkers can help to predict future cancers.

To develop the biomarker blood test, Hanash's group led the analysis of blood samples taken from 108 ever-smokers who went on to be diagnosed with lung cancer within a year of sampling, compared to 216 smoking-matched controls. All were participants in the Carotene and Retinol Efficacy Trial (CARET), a lung cancer prevention trial conducted in North America in the 1990s.

"We compared smokers with lung cancer to smokers who didn't have lung cancer, and we showed there are biomarker differences between those groups, so it wasn't only smoking status giving us differences," Hanash said. "Then we compared cancer cases to the general population and found similar differences."

The resulting panel includes four proteins found in the blood:

  • The precursor form of surfactant protein B (Pro-SFTPB)
  • Cancer antigen 125 (CA125)
  • Cytokeratin-19 fragment (CYFRA 21-1)
  • Carcinoembryonic antigen (CEA)

The validation study was conducted among patients from the European Prospective Investigation into Cancer and Nutrition and the Northern Sweden Health and Disease Study.

The researchers note that their findings need to be validated in larger studies to further validate and fine-tune the biomarker-based prediction model. Hanash said that will depend upon guidance from the U.S. Food and Drug Administration (FDA), and consultations with the FDA have begun.

Lung cancer causes an estimated 20-25 percent of all deaths from cancer -- 1.69 million annually worldwide and 155,000 in the United States. Early detection improves prospects of survival, but most countries do not screen for the disease and it's estimated that fewer than half of all U.S. cases are among people who are eligible under USPSTF guidelines.

Co-authors with Hanash, Johansson and Brennan include co-first authors Nan Sun, Ph.D., of Clinical Cancer Prevention and Leonidas Bantis, Ph.D., of Biostatistics, both from MD Anderson; Florence Guida, Ph.D., of IARC; and David Muller, Ph.D., of Imperial College of London School of Public Health. Zideng Feng, Ph.D., of MD Anderson Biostatistics also played a leading role.

Other MD Anderson co-authors are Ayumu Taguchi, M.D., Ph.D., of Translational Molecular Pathology; Dilsher Dhillon, Deepali Kundnani, and Nikul Patel of Clinical Cancer Prevention; and Qingxiang Yan, Ph.D., of Biostatistics. For a complete list of co-authors see JAMA Oncology web site.

Hanash holds the Evelyn and Sol Rubenstein Distinguished Chair for the Cancer Prevention Department.

In addition to the Lung Cancer Moon Shot, this study was supported by the Fondation ARC pour la recherche sur le cancer and INCa; grants from the U.S. National Cancer Institute of the National Institutes of Health, including an Early Detection Research Network grant (1U19CA203654, UO1194733), Canary Foundation, and The Jerry and Maury Rubenstein Foundation.

© 2018 The University of Texas MD Anderson Cancer Center

Cancer Prevention Message Is Key for HPV Vaccination Discussions with Parents

by NCI Staff

The National Cancer Institute -- July 10, 2018

companies img In a new study, researchers asked parents to select the best and worst reasons a doctor might give to support HPV vaccination for their kids.

Credit: National Cancer Institute

Health care providers should emphasize cancer prevention when discussing human papillomavirus (HPV) vaccination with the parents of preteens who are due to receive the vaccine. That's the conclusion of a new study that asked a diverse group of US parents what they felt are the most compelling reasons to get their children vaccinated.

Certain types of HPV cause virtually all cervical cancers, as well as most anal cancers, many oropharyngeal, vaginal, and vulvar cancers, and some penile cancers.

In the United States, the Centers for Disease Control and Prevention (CDC) recommends routine HPV vaccination for girls and boys starting at age 11 or 12. But in 2016, only 43% of US adolescents were up to date with the vaccine. Numerous studies have shown that this sub-optimal level of vaccine coverage is due in part to the way health care providers communicate about HPV vaccination.

CDC, the President's Cancer Panel, and other groups recommend that providers tell parents that cancer prevention is the most important reason for HPV vaccination. But "as far as I know, this is the first published study to test and provide evidence that this is the most important message," said Sarah Kobrin, Ph.D., M.P.H., of NCI's Division of Cancer Control and Population Sciences, who was not involved in the study.

Results of the NCI-funded study were published in the July 2018 Cancer Epidemiology, Biomarkers & Prevention.

Study Surveyed Diverse Group of Parents

A research team led by Melissa Gilkey, Ph.D., of the University of North Carolina at Chapel Hill, conducted the online survey of 1,259 parents of 11- to 17-year-old males and females. Survey participants were 51% female and 49% male, were from all regions of the United States, and had a wide range of education and income levels.

Using a method known as "best-worst scaling," the researchers asked parents to select the best and worst of 11 reasons that a doctor might give for a 12-year-old child to get the HPV vaccine. The researchers then combined the results from the 1,177 parents who completed the survey to come up with a ranking of all 11 reasons. The survey also included questions to assess parents' confidence in adolescent vaccination in general.

In the overall sample, parents ranked "It can prevent some types of cancer" as the best reason for HPV vaccination.

"Parents thought this was the best reason by far, and the finding was consistent across many different types of parents," Dr. Gilkey said.

Perhaps most notably, both parents with low confidence in adolescent vaccination and those with high confidence said that cancer prevention was the best reason. These two groups of parents also ranked the other possible reasons similarly overall, which was contrary to what Dr. Gilkey's team had predicted.

Other reasons that parents ranked highly included "It can prevent a common infection" and "It has lasting benefits."

Reasons that parents ranked lowest included "Your child is due for it" and "I got it for my own child."

These reasons "aren't necessarily bad messages," Dr. Gilkey said, "but they do not appear to be broadly compelling to parents."

Motivating More Parents to Vaccinate is Key

As the study authors and outside experts noted, however, asking parents which reason for HPV vaccination they think is best is different from determining which message would motivate a parent to vaccinate in an actual encounter with their child's doctor.

"The trust and other dynamics that exist when a person is talking to their own child's health care provider can't be captured in a survey [like this]," noted Rebecca Perkins, M.D., of Boston University School of Medicine, an HPV vaccine researcher who was not involved in the study.

Those distinctions, between the preferences people state in a survey and what happens in the real world, Dr. Kobrin said, might explain why the study did not find a difference between parents with low versus high confidence in vaccination.

Dr. Perkins and her colleagues recently published a study that analyzed audio recordings of interactions among primary care providers, parents or guardians, and adolescents. They found that for many parents or guardians, especially those who were undecided about vaccination beforehand, a simple statement by the provider that the vaccine is "due" or "needed" was persuasive.

"Being clear that HPV vaccination and other adolescent vaccines are the standard of care is the first step when talking to parents," Dr. Gilkey said. For those parents who have questions or want to talk more about the HPV vaccine, emphasizing the cancer message may be particularly helpful.

"That's where studies like our survey come in," she continued.

Researchers can use information about the most promising messages from such studies to design and test real-world interventions aimed at increasing HPV vaccination rates. Those interventions include strategies for training health care providers to improve the way they communicate about HPV vaccination.

To reach the Healthy People 2020 goal of an 80% HPV vaccination coverage level, Dr. Perkins said, "We need to focus on how to get that [prevention] message to every parent of every child who is eligible for the HPV vaccine and every provider who takes care of kids who are eligible for the vaccine."

    Cancer Centers Endorse Goal of Increasing HPV Vaccination

    Last month, experts from NCI-Designated Cancer Centers from across the United States issued a statement endorsing the goal of eliminating cancers caused by HPV through HPV vaccination, evidence-based cancer screening, and treatment of cervical precancers.

    The June 1, 2018, statement urged health care providers to make clear and strong recommendations for HPV vaccination and cervical cancer screening. "These practices offer a rare opportunity to prevent 12,000 cervical cancers and nearly 40,000 other HPV-related cancers ... among men and women annually in the United States," the statement said.

© 2018 The National Cancer Institute

Can Age Affect Response to Immune Checkpoint Inhibitors?

by NCI Staff

The National Cancer Institute -- July 6, 2018

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Credit: iStock

Immune checkpoint inhibitors-drugs that unleash an immune response against cancer-work astonishingly well for some people with advanced melanoma but do not work at all for many others. Clinicians and researchers are eagerly searching for factors that can help identify patients that are most likely to have good responses.

Now researchers believe they have found a simple characteristic that may be associated with how well somebody with melanoma will respond to checkpoint inhibitors: age.

In an analysis of more than 500 patients, researchers found that older people with melanoma appeared to respond better to checkpoint inhibitor treatment than younger people. A follow-up study in mice suggested that the pattern might be due, in part, to an age-related shift in the kinds of immune cells found inside melanoma tumors.

The researchers also identified a potential strategy to improve responses to checkpoint inhibitors in younger people. Giving young mice a drug that eliminates one type of immune cell before treating them with a checkpoint inhibitor substantially improved their responses. This combination treatment approach "might have great benefit in young patients," the investigators wrote June 13 in Clinical Cancer Research.

Elad Sharon, M.D., M.P.H., of NCI's Cancer Therapy Evaluation Program, who was not involved in the research, said that although the findings are interesting, they are preliminary and that clinicians shouldn't alter their approach to immunotherapy treatment just yet.

Age Affects Immunotherapy Response

The research team, led by Ashani Weeraratna, Ph.D., of the Wistar Institute in Philadelphia, evaluated data on people with metastatic melanoma who had been treated with the immune checkpoint inhibitor pembrolizumab (Keytruda) at several cancer centers around the world.

More people age 62 or older had tumor shrinkage (they responded) or had stable disease after pembrolizumab treatment than did people younger than age 62 (63% versus 51%). The researchers observed a similar pattern in both women and men, as well as in people who either had or hadn't been previously treated with a targeted therapy against a gene that is commonly mutated in melanoma tumors.

For every decade of age, the probability that a patient was resistant to pembrolizumab treatment dropped by 13%, the researchers observed.

They observed a similar pattern in mice implanted with melanoma tumors. Treatment with a checkpoint inhibitor slowed tumor growth in older mice but not in younger mice bearing genetically identical melanoma tumors.

These results came as a surprise, said Dr. Weeraratna, because the activity of the immune system generally declines with age. But "because the [clinical] data came from different [cancer centers], it really spoke to the robustness of this effect," she noted.

What the findings call for, said Dr. Sharon, "is more translational research to understand the differences between patients that respond or fail to respond" to checkpoint inhibitor treatment.

Cytotoxic T cells are a type of immune cell that recognize and kill infected and cancer cells. Because these cells can damage healthy tissues if not kept in check, their activity is tightly controlled by another type of immune cell, known as regulatory T cells.

The protective role of regulatory T cells also means that they can interfere with immunotherapy treatments, however. For example, regulatory T cells can prevent the activation of cancer-fighting cytotoxic T cells that is triggered by checkpoint inhibitors. A recent study suggested that people whose tumors contained fewer regulatory T cells than cytotoxic T cells had better responses to immunotherapy treatment.

When Dr. Weeraratna and her team examined melanoma tumors of both young and old mice, they found that the total number of immune cells inside the tumors was similar. However, the tumors of young mice had more regulatory T cells and fewer cytotoxic T cells than the tumors of older mice. They did not observe this age-related shift in T cell types in the other organs of mice.

And in an analysis of melanoma tumor samples from a separate group of more than 200 patients, the tumors of younger patients also had more regulatory T cells and fewer cytotoxic T cells than those of older patients.

The findings suggest that cytotoxic T cell activity is suppressed by regulatory T cells in melanoma tumors of younger patients, the researchers wrote, limiting the effectiveness of immune checkpoint inhibitors.

The researchers wondered if altering the ratio of regulatory to cytotoxic T cells in mice would change the response to checkpoint inhibitors. To find out, they treated young mice with either a drug that eliminates regulatory T cells, a checkpoint inhibitor, or both drugs together. When given alone, both the regulatory T cell-depleting drug and the checkpoint inhibitor delayed tumor growth compared with control treatment. But the combination of the two drugs was even more effective at delaying tumor growth and it did not cause any toxic side effects.

Why older people have fewer regulatory T cells in their melanoma tumors than younger people is still unknown. Because older individuals tend to have more regulatory T cells in other organs, the researchers hypothesized that the recruitment of regulatory T cells to melanoma tumors specifically may lessen as we age.

In a follow-up study, they are investigating the role of the skin's architecture in this process. "The skin has a very stiff, defined matrix that starts to break down as we age. This is part of what we think is affecting the way immune cells migrate" to melanoma tumors, said Dr. Weeraratna.

There are also specific kinds of regulatory T cells that inhabit the skin, Dr. Weeraratna explained. "We think those change with age, too, so that's something else that we're exploring," she said.

How age affects the types of T cells found in tumors of the lung or stomach, for example, may be completely different, she added.

Concerns About Autoimmune Reactions

A critical role of regulatory T cells is to suppress the activity of cytotoxic T cells that accidentally attack heathy tissues. So some scientists are concerned that therapies that eliminate regulatory T cells might allow these "self-reactive" cytotoxic T cells to fire away at healthy tissues, potentially leading to autoimmune diseases.

But, so far, such effects haven't been observed. In a handful of small clinical trials, regulatory T cell--depleting drugs did not cause autoimmune responses. However, one such drug-known as daclizumab (Zinbryta)-was recently withdrawn over concerns about brain toxicity.

Several ongoing trials are evaluating the efficacy of other T cell--depleting drugs in combination with immunotherapies, Dr. Sharon noted. For instance, investigators of an NCI-funded phase 2 clinical trial are testing varlilumab, a drug that appears to deplete regulatory T cells when used in combination with the immune checkpoint inhibitor nivolumab (Opdivo).

Another trial, also sponsored by NCI, is evaluating the regulatory T cell--depleting drug mogamulizumab in combination with pembrolizumab for the treatment of people with diffuse large B-cell lymphoma. The investigators of both trials plan to study the role of regulatory T cells in treatment response by examining tumor biopsy specimen from participants.

© 2018 The National Cancer Institute

Dr. Alan S. Rabson, Long-Time NCI Deputy Director and Cancer Research Stalwart, Dies

by NCI Staff

The National Cancer Institute -- July 5, 2018

companies img Alan Rabson, M.D., in his office on the NIH campus in Bethesda, MD.

Credit: National Cancer Institute

Many in the cancer research and NIH community are mourning the loss of long-time NCI senior leader Alan Rabson, M.D., who passed away July 4, at the age of 92.

With a distinguished scientific career that spanned six decades and included research on tumor virology and cancer pathology as well as senior leadership roles at NCI, Dr. Rabson was highly respected at NIH and well beyond.

Honored time and again for his commitment to science and to advancing cancer research, Dr. Rabson was equally known for treating everybody he encountered-whether a member of Congress, a young researcher in training, or a patient needing advice-with kindness and respect.

"There have been few people like Alan Rabson," said NCI Director Norman Sharpless, M.D. "The stories of his remarkable history at NCI, his immense dedication to his work, and his love for his family are truly inspiring. It is no overstatement to say that we have lost a giant."

Dr. Rabson's wife of 59 years, Ruth Kirschstein, M.D., also was a highly respected and accomplished scientist at NIH. Dr. Kirschstein, who passed away in 2009, helped organize the research response to the AIDS epidemic and was the first woman to direct an NIH institute, leading the National Institute of General Medical Sciences for two decades.

The couple were known for their deep devotion to NIH and each other. In a 1998 interview, Dr. Rabson recounted: "I started [at NIH] by finishing my last year of pathology training at the Clinical Center. My wife and I liked the place so much that we stayed here for the next 42 years."

From Brooklyn to Bethesda

Born in Brooklyn in 1926, Dr. Rabson spent his first two decades mostly in New York, including completing his undergraduate degree at the University of Rochester and his medical degree at the State University of New York.

Remarkably, Dr. Rabson's first attempt to come to NCI was unsuccessful. Still in medical school, he applied to spend the summer at the institute working for well-known NCI biochemist Jesse Greenstein, Ph.D. However, it was not to be. Washington, DC, was simply too hot in the summer and there was no air conditioning at NIH, the eminent scientist explained in response to the young medical student's request, so he usually worked in Berkeley, California, during those months.

During the Korean War, Dr. Rabson joined the Public Health Service's Commissioned Corps, studying virology, at the Communicable Disease Center (now known as the Centers for Disease Control and Prevention) and the University of Michigan, and pathology, at the US Public Health Service Hospital in New Orleans.

He finally arrived at NIH in 1955, as a pathology anatomy resident. Dr. Rabson's career at NCI began not long after, when he was recruited to study tumor-causing viruses and serve as a staff member in NCI's pathology department at the NIH Clinical Center.

companies img Dr. Alan Rabson with his wife, Dr. Ruth Kirschstein, and their son, Arnold.

Credit: National Cancer Institute

For many years, the NCI Laboratory of Pathology performed the pathology for most of the NIH institutes conducting research at the Clinical Center. The mindset that Dr. Rabson and his colleagues had towards the many people who participated in Clinical Center studies was simple. He said: "We owed them the very, very best we could give them."

Dr. Rabson was also legendary in his willingness to help people facing a cancer diagnosis to find the best options for their care, said NIH Director Francis Collins, M.D., Ph.D. Whether it was a member of Congress or a young mother from the heartland, Dr. Collins recalled, Dr. Rabson always took time to understand the situation, build a relationship with the patient and family, and help them sift through a myriad of possible clinical trials.

"Every year since 2012, the NIH Director's Award ceremony has included the Alan S. Rabson Award for Clinical Care," Dr. Collins said. "It goes to a deserving employee who demonstrates an exceptional commitment to assisting patients and their families who look to the NIH for help. Al's half-century of service stands as the epitome of personal dedication to patient care at the National Institutes of Health."

After 20 years in the pathology department, Dr. Rabson was named director of the forerunner to what is now NCI's Division of Cancer Biology. During that time, he oversaw the division's transition from an intramural research group that performed its own research to one that also managed the funding of cancer research performed by NCI-supported investigators at institutions across the country.

A Long-Time Leader and Role Model

The final stage of Dr. Rabson's distinguished career at NCI began in 1995, when he was named deputy director of the institute by then-NCI Director Richard Klausner, M.D.

"He came down to my office on the third floor and he said, 'Would you be willing to be my deputy?' And I said, 'I can't think of anything nicer,'" Dr. Rabson recounted.

Over the following several decades, he was asked by each new director to continue on in the deputy director role. Current NCI Deputy Director Doug Lowy, M.D., described Dr. Rabson's invaluable service as a sounding board for each director and other NCI leaders on decisions both small and large as among his most important duties.

"He had an inimitable leadership style," Dr. Lowy said. "When you talked with him, he spent most of the time trying to understand what you needed, so he could help you, rather than spending it figuring out how you could help him. He truly believed that if you were successful, he was successful."

Dr. Rabson held clinical professorships at George Washington University and Georgetown University, and received multiple awards from the Public Health Service for his clinical work and scientific contributions. He officially retired from federal service in 2015. That same year he was named a Scientist Emeritus at NCI.

© 2018 The National Cancer Institute

Melody Management

Cancer Research & APP Development

Study Provides Closer Look at Postmenopausal Bleeding and Endometrial Cancer

by NCI Staff

The National Cancer Institute -- August 29, 2018

companies img Women experiencing abnormal vaginal bleeding may undergo a transvaginal ultrasound, biopsy, or both, to determine if an endometrial tumor is the cause.

Credit: National Cancer Institute

In the largest analysis to date looking at the extent to which vaginal bleeding is associated with endometrial cancer in women who have gone through menopause, 90% of women diagnosed with endometrial cancer reported bleeding before their cancer diagnosis. Approximately 9% of postmenopausal women who saw a doctor for bleeding later received a diagnosis of endometrial cancer.

Unlike many other cancer types, the rate of endometrial cancer has increased in recent years and is expected to continue rising worldwide over the coming decade. This rise is thought to be largely due to factors that affect hormones, such as rising obesity rates and changes in how many children women are likely to have.

If endometrial cancer is found early, a woman has a 95% chance of surviving the cancer for at least 5 years. By contrast, for women diagnosed after their cancer has spread outside the uterus, the chance of surviving for at least 5 years is much lower, ranging from 16-45%.

In most cancers, by the time a person develops symptoms, their disease is usually advanced and harder to treat, explained Megan Clarke, Ph.D., of NCI's Division of Cancer Epidemiology and Genetics (DCEG), who led the analysis. "With endometrial cancer it's quite different, and [recognizing symptoms] gives us an opportunity to intervene" and improve the odds of long-term survival, she added.

Typically, postmenopausal women who experience bleeding are referred for further testing to either rule out or diagnose endometrial cancer. While vaginal bleeding has been known to be a symptom of endometrial cancer, this large study confirms the practice of referring women for further testing, explained Christina Chu, M.D., of Fox Chase Cancer Center, who was not involved with the research.

"If you have bleeding after menopause, you should call your doctor and let them know," said Dr. Chu. "For the majority of women, it's a benign problem, but there are simple things that can be done to rule out endometrial cancer."

Examining Endometrial Cancer Worldwide

To get a comprehensive picture of the relationship between endometrial cancer and postmenopausal vaginal bleeding, researchers led by DCEG's Dr. Clarke and Nicolas Wentzensen, M.D., Ph.D., performed a meta-analysis of 129 studies, which included more than 40,000 women. Data for the studies-which were conducted in Europe, North America, and Asia-were collected between 1977 and 2017.

The researchers estimated the overall prevalence of endometrial cancer among women with postmenopausal bleeding across all the studies combined and within different regions of the world. They also examined whether factors such as use of hormone replacement therapy affect the prevalence of endometrial cancer.

Overall, the analysis showed that, consistent with what had been seen in earlier studies, 90% of women diagnosed with endometrial cancer had experienced postmenopausal bleeding.

The number of women with postmenopausal bleeding who were diagnosed with endometrial cancer varied around the globe. While the rate was 9% overall, it ranged from 5% in North America to 13% in Western Europe.

Among the studies included in the analysis, the risk of endometrial cancer in women with postmenopausal bleeding was lower in studies that included women using hormone replacement therapy. This may be due, in part, to the fact that hormone replacement therapy itself can cause bleeding, especially during the first 6 months of use, explained Dr. Clarke.

"It's only if there's persistent bleeding after the initial 6 months of [hormone replacement] that it may be more concerning" and should trigger testing for endometrial cancer, she said.

Current Testing Practices Supported

Currently, testing for endometrial cancer in women experiencing abnormal vaginal bleeding consists of transvaginal ultrasound imaging, biopsy, or both.

Although people tend to think of biopsies as invasive and frightening, an endometrial biopsy is a simple procedure similar to a Pap smear, Dr. Chu explained. Like a Pap smear, it can be done in the doctor's office and doesn't require anesthesia.

In their study, the researchers ran simulations in which they estimated how many women with postmenopausal bleeding would need to undergo additional testing to detect one case of endometrial cancer, based on varied levels of risk and different testing strategies. Assuming a 10% risk of endometrial cancer (similar to that observed in the meta-analysis) and that women underwent subsequent testing with ultrasound, they estimated that 7 women would need to have a biopsy to find 1 cancer.

Before sending a woman for testing, doctors should ask themselves: "If she has postmenopausal bleeding, how high is her risk of cancer?" explained Dr. Wentzensen. "Our estimate of 10% supports the current practice of further evaluating these women."

Extending the Benefit

The findings confirm that "postmenopausal women with [vaginal] bleeding have a low risk of endometrial cancer, but the vast majority of women with endometrial cancer present with bleeding. It's just a way to think about it from two different directions," explained Dr. Chu.

Although they don't want to alarm anyone with these results, added Dr. Clarke, women should know that getting tested if they have postmenopausal bleeding "gives us an opportunity to [potentially] detect endometrial cancer early, which provides a high likelihood of cure."

The DCEG team is currently performing another study in collaboration with the Mayo Clinic, looking prospectively at the number of diagnoses of endometrial cancer in women with postmenopausal bleeding. They also hope to use data from the study to identify molecular markers of risk and build better models that could more accurately determine which women need to be tested.

Additionally, the researchers have launched a study with the University of Alabama to examine racial disparities in endometrial cancer diagnosis. "Currently, African American women are more likely to be diagnosed with aggressive disease and more likely to die from endometrial cancer than white women," explained Dr. Clarke.

With these disparities and the increasing incidence of the disease, "it's a growing problem, but increased awareness and better early detection may improve endometrial cancer mortality going forward," concluded Dr. Wentzensen.

Related Resources

Endometrial Cancer Screening (PDQ)-Patient Version

© 2018 The National Cancer Institute

Statement from NCI Director Dr. Norman E. Sharpless on the Death of Senator John McCain

by NCI Staff

The National Cancer Institute -- August 27, 2018

companies img Senator John McCain

The passing of Senator John McCain is a moment of true sadness for our country. Few have served this country for so long and with such commitment and distinction.

Even as he underwent treatment for an aggressive brain cancer, Sen. McCain continued to play an active role in Congress-something that comes as no surprise, given his lifelong legacy of dedication and service.

Shortly after his diagnosis in July 2017, Sen. McCain received treatment at the NIH Clinical Center, under the care of NCI physicians and nurses. In November of last year, in a kind and gracious speech on the Senate floor, he thanked those at NCI who directly provided that care.

During that speech, he also took the time to thank all of those engaged in cancer research and care, hailing what he called the "patient forms of bravery exemplified by our doctors and nurses and research scientists."

To be called brave by a courageous and upstanding man like Sen. McCain is very high praise.

Sen. McCain, and his upholding of the ideals of commitment to a greater good, will be dearly missed. His family will continue to be in the thoughts of NCI staff, just as they are among those of millions of Americans across the country.

© 2018 The National Cancer Institute

$50 million awarded by CPRIT to MD Anderson and its projects

Funds support research, facilities, recruitment, prevention and drug development efforts

The MD Anderson Cancer Center -- August 24, 2018

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HOUSTON -- The University of Texas MD Anderson Cancer Center today was awarded $30 million to support research, core facilities, recruitment and prevention efforts from the Cancer Prevention and Research Institute of Texas (CPRIT). An additional $19.9 million was awarded to a company co-founded by MD Anderson to support the development of a novel targeted therapy to treat neurological conditions caused by chemotherapy. In total, MD Anderson and its projects received 28 percent of the $177 million in awards announced by CPRIT.

MD Anderson awards included $11.9 million for multi-investigator research including awards for breast cancer and pre-clinical studies; $12.5 million for core facilities support; $4 million for new faculty recruitment; $1.3 million for cancer prevention; and $200,000 for high-impact high-risk research. CPRIT awarded $19.9 million to Korysso Therapeutics, Inc., doing business as Magnolia Tejas Corporation, the wholly owned Houston-based subsidiary of Magnolia Neurosciences Corporation, launched by MD Anderson and Accelerator Life Science Partners.

"These CPRIT awards are vital to our mission as they allow us to fund transformational research and prevention projects, to recruit stellar talent and to more quickly advance novel therapeutics developed by our experts," said Stephen Hahn, M.D., chief medical executive of MD Anderson. "We're grateful to CPRIT and the people to Texas for this much-needed support that will help us work to improve the treatment and prevention of cancer for our patients and beyond."

Since its inception, CPRIT has awarded $2.15 billion in grants for cancer research, of which MD Anderson and its projects have received $428 million, or nearly 20 percent. The agency began making awards in 2009 after Texas voters overwhelmingly approved a 2007 constitutional amendment committing $3 billion to the fight against cancer. Programs made possible with CPRIT funding have reached Texans from all 254 counties of the state, brought 159 distinguished researchers to Texas, advanced scientific and clinical knowledge, and provided more than 4.7 million life-saving education, training, prevention and early detection services to Texans.

"CPRIT has reached a significant milestone, which is only possible due to the support of Texans, their elected representatives, and our partner institutions and grantees," said Wayne Roberts, CPRIT chief executive officer. "As a result of this historical undertaking, Texas is developing into a world class center of cancer research and prevention as our state's institutions grow in international prominence.

CPRIT awards to MD Anderson and its projects include:

Multi-Institutional Investigator Awards

  • BRCA answers from cancer interactome structures or BACIS (John Tainer, Ph.D., Molecular and Cellular Oncology) - $5,969,140
  • Rational combination treatment options to reverse resistance in hormone receptor-positive breast cancer refractory to standard therapy (Kelly Hunt, M.D., Breast Surgical Oncology) - $5,992,274

High-Impact High-Risk Awards

  • Targeted proteolysis of glucocortoid receptor as therapeutic strategy in antiandrogen treatment-resistant prostate cancer (Yonathan Lissanu Deribe, Ph.D., Genomic Medicine) - $199,999

Core Facility Support Awards

  • Integrated single-cell genomics core facility (Nicholas Navin, Ph.D., Genetics) - $4,897,577
  • Pediatric solid tumors comprehensive data resource core (Richard Gorlick, M.D., Pediatrics) - $5,005,246
  • Protein array and analysis core or PAAC (Mark Bedford, Ph.D., Epigenetics and Molecular Carcinogenesis - $2,594,107

Recruitment of First-Time, Tenure-Track Faculty Member Awards

  • Recruitment of two experts in cell biology - $4 million

Tobacco Control and Lung Cancer Screening Awards

  • Increasing access to smoking cessation and smoke-free home services for low-income pregnant women in northeast Texas (Janice Blalock, Ph.D., Behavioral Science) - $1,346,919

Texas Company Product Development Awards

  • Development of a novel targeted therapy, based on discoveries made by MD Anderson's Therapeutics Discovery division, for the prevention of chemotherapy-induced peripheral neuropathy and chemo brain (Korysso Therapeutics, Inc) - $19,953,624

© 2018 The University of Texas MD Anderson Cancer Center

Enhancements to NCI's SEER Program Creating New Research Opportunities

by Lynne Penberthy, M.D.

The National Cancer Institute -- August 23, 2018

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When NCI launched the Surveillance, Epidemiology, and End Results (SEER) program 45 years ago, few could have anticipated that one day it would rely on powerful supercomputers to scan electronic pathology reports to collect real-time information about patients' tumors.

And, yet, this is exactly what is happening in one of a series of innovative SEER pilot studies that represent a fundamental rethinking of what this long-running program can and should be. These pilot studies are setting the stage for SEER to routinely collect far more clinically relevant pieces of data at the population level than previously-data that the research community as well as patients want and need to better understand cancer and its impact.

Although many of these new data collection efforts are in their early stages, they represent a true sea change for SEER. We should no longer consider SEER as just a tool for conducting population-based observational studies. I believe it can also become an invaluable resource for performing and informing clinical and even basic research.

More Data on Treatments, Genomics, and Recurrences

When we set about to enhance SEER, we worked with and sought feedback from many groups and experts. This outreach allowed us to better understand the cancer research community's needs and the opportunities that could be created through strategic, targeted enhancements to SEER.

In those discussions and forums, the main data needs that were identified included those that cover:

  • All treatments received by individual patients from diagnosis until their death
  • Outcomes other than incidence and mortality-in particular, recurrences
  • The genomic composition of patients' tumors

As might be expected, enabling SEER to collect these data is complicated. Doing so requires capturing information over an extended time period from a massive, fragmented US health care system that relies on a wide variety of records systems that are not designed for easy information sharing.

Take, for example, a woman with early-stage breast cancer diagnosed and successfully treated in 2010 but who then had a recurrence in 2015. Ideally, we want to capture data concerning her primary treatment (e.g., surgery, radiation); any prescribed adjuvant treatments (e.g., chemotherapy, hormonal therapy) and whether they were actually administered; important clinical factors (e.g., non-cancer health problems, age, race/ethnicity); where in the body her recurrence occurred and how it was diagnosed; the outcomes of germline and tumor genomic tests done at the time of recurrence; and what treatments she received for that recurrence.

Some of these data may be in free-form notes (general notes for which there are no specific data fields) in an electronic record. Some may be in pharmacy records, or a primary care physician's notes, or insurance records. And if the woman moved to a different state during this period, that presents a whole new layer of challenges.

Trying to collect such data, and ensure that they are accurate, is an extremely complex undertaking. It's because of that great complexity that we are moving forward with these enhancements in a thoughtful and systematic way-one that we believe will lay the foundation for successfully integrating them into the broader SEER program.

companies img Lynne Penberthy, M.D. Associate Director, Surveillance Research Program, Division of Cancer Control & Population Sciences

More Cases, More Diversity

Among the most important enhancements to the SEER program is the expansion of the size and diversity of the population it covers.

SEER now covers 34% of the US population, covering 19 different geographic areas. With this expansion, SEER is collecting data on approximately 550,000 new individual cancer cases (without any personally identifying information) each year.

This expansion was implemented with a strategic focus: adding US cancer registries that include more underserved and ethnic/racial minorities. That means SEER is capturing data on cancer that more fully represents the US population.

Of course, it's always good to have more data to work from. In practice, the expanded population covered by SEER means that researchers will be able to perform better studies-those that allow us to more completely understand how cancer affects different patient subgroups and inform the development of interventions intended to address the shortcomings and disparities that we know exist in the current system of cancer care.

Pilot Studies and a Virtual Biorepository

Unfortunately, we can't immediately start collecting every type of data we'd like SEER-wide. That is why we have launched a series of pilot studies that can help us better understand the barriers and challenges to collecting these new types of data.

Take, for example, the aforementioned supercomputers. They are part of a pilot effort being conducted in collaboration with the US Department of Energy (DOE).

Under this partnership, we are working with DOE scientists to develop tools that will allow SEER to collect the data elements it has traditionally captured (e.g., cancer type and grade) as well as new data elements (e.g., biomarkers, recurrences) from patient medical records. Compared with the manual collection that is often used now, automated data collection would be far more reliable and rapid, even if some cases still require manual coding.

This pilot with the DOE will allow us to assess the feasibility of this automated data collection and refine these new data collection tools, ensuring, for example, that they are accurately capturing the data we're looking for.

Another SEER pilot study is focusing on collecting data on the use of oral cancer drugs. Such data have traditionally been difficult to amass because these treatments are not given at hospitals or at doctors' offices but are obtained through pharmacies and taken by patients at home. Little is known about the use of these drugs and adherence to prescribed regimens in a real-world population-that is, outside of a clinical trial setting.

In one such pilot study being conducted with the SEER registry in Georgia, linkages have been established between the registry and all Walgreens and CVS pharmacies in the state. These linkages connect a patient's information in the pharmacy's records to the same patient in the SEER registry, allowing for the real-time collection of data on filled prescriptions for oral cancer therapies.

Having these types of real-world data readily available would be invaluable. From them, researchers could glean important insights into usage patterns that, for example, can identify whether certain subgroups of patients are not getting the therapies they need.

Similar pilot efforts are creating linkages between SEER registries and health insurance claims data from some of the largest health insurance companies in the country. These linkages are similar to those that enable the SEER-Medicare Linked Database, which was established in the early 1990s. This database has been the primary data source for more than 1,600 published studies, including those that have provided information on important new cancer incidence trends and long-term survivorship issues.

Creating these linkages with commercial health insurance claims will allow SEER to capture much more information on people diagnosed with cancer who are under the age of 65 (i.e., not yet in Medicare), including critical data on treatments that patients receive over time. Such information can offer a window into real-world clinical practice and its potential implications for patients and the health care system at large.

Other pilot linkage efforts underway involve collecting data on the results of genomic tests, including multigene panels like the Oncotype DX test used in the TAILORx breast cancer trial. As oncology continues on the road to precision medicine, the ability to systematically collect these data would go a long way toward informing this movement.

Although these linkage pilots are noteworthy, another exciting enhancement to SEER under active evaluation is on the other end of the research spectrum: the development of a "virtual biorepository."

The aim of this repository is to provide information on tumor samples stored at institutions across the country. This will allow investigators to search for samples from patients with certain demographic or clinical characteristics or certain outcomes, and then request those samples (including all related clinical data on that patient) via an honest broker for use in their research.

Currently, six SEER registries are participating in a pilot study of the virtual biorepository, focusing on specific survivor groups for breast and pancreatic cancer. The lessons learned from this pilot will inform our efforts to eventually scale up to a larger virtual biorepository.

New Data, Important Opportunities

The enhancements planned for SEER are exciting and much needed.

Of course, patience will be an important ally moving forward. It will take time to implement these ambitious plans, and there is always the possibility that-given the scale of these efforts-they won't always go according to plan. In fact, performing these activities using small pilots allows us to understand where the barriers and challenges might be and to realistically assess whether they can move past the pilot phase.

That said, we are taking the necessary steps to eventually make these new tools and resources integral parts of SEER. In so doing, we will be opening up new doors to cancer researchers and greatly expanding the value of this unique and needed program.

Over the coming decade, stay tuned to hear more about a remarkable array of new scientific opportunities. As always, we welcome ideas and feedback from the cancer community about ways to strengthen the utility and usability of SEER data for both cancer research and cancer control planning.

© 2018 The National Cancer Institute

Combination immunotherapy shrinks melanoma brain metastases

Ipilimumab, nivolumab provide durable responses in stage 4 patients with worst prognosis

The MD Anderson Cancer Center -- August 22, 2018

companies img Hussein Tawbi, M.D., Ph.D.

HOUSTON -- Combination immunotherapy shrank melanoma that has spread to the brain in more than half of the patients in a clinical trial reported in the New England Journal of Medicine led by an investigator at The University of Texas MD Anderson Cancer Center.

Of 94 patients in the single-arm study combining checkpoint inhibitors ipilimumab and nivolumab, at a minimum follow-up of nine months and a median of 14 months, 24 (26 percent) had a complete response, 28 (30 percent) had a partial response and 2 (2 percent) had stable disease.

"As treatment for stage 4 melanoma has improved greatly in recent years, our patients with metastases to the brain have remained the group most in need, they've had the worst prognosis, so we are very excited about these results," said the national study's principal investigator and lead author Hussein Tawbi, M.D., Ph.D., associate professor of Melanoma Medical Oncology at MD Anderson.

"This practice-changing study proved that you can start with immunotherapy first with these patients, tackling both brain and extracranial disease at the same time," Tawbi said. "And it opens up new opportunities for development of systemic therapies for metastatic melanoma."

About 40 percent of patients with stage 4 melanoma have brain metastases at diagnosis, and 75 percent eventually develop the condition, which previously was so intractable to treatment that these patients were routinely excluded from clinical trials of new drugs. Median overall survival of patients with brain metastases has been four to five months.

Durable responses

At nine months, 59.5 percent of patients with brain tumors had not progressed.

"The absence of progression for that long with brain metastases is huge," Tawbi said. "Historically, the overall one-year survival rate for patients with brain metastases is less than 20 percent, with the immunotherapy combination in this study, it's 82 percent."

Tawbi and colleagues note in the paper that the immunotherapy combination results should cause reconsideration of the current standard of care for brain metastases: surgery or targeted radiation for a small number of tumors and whole-brain radiation for more extensive disease.

Stereotactic radiation is quite effective when used to treat small metastases before immunotherapy can begin, Tawbi says, with a four-week wait between treatments. What often occurs, he says, is the original metastases are destroyed but others arise during the four weeks, further delaying systemic treatment.

"We've shown you don't have to wait for radiation, you can initiate immunotherapy early for all patients and expect the tumors in the brain to respond as well as those outside the brain," he said. "Current efforts focus on adding radiation at the right time for lesions that have not responded or progress. Neurosurgeons, radiation oncologists and medical oncologists will continue to work together to recommend the best initial approach for our patients and the best timing for subsequent treatments as needed."

For tumors outside the brain, 56.4 percent of study patients had their tumors either shrink or remain stable. Nine-month progression-free survival was 56.6 percent. Median progression-free and overall survival have not been reached.

All patients were treated with ipilimumab, which blocks the CTLA-4 checkpoint on T cells, in combination with nivolumab, which inhibits activation of the PD1 checkpoint. Both checkpoints otherwise shut down T cells and thus block the anti-tumor immune response.

Brain-related side effects

Patients in the trial had untreated brain metastases that also had not caused neurological symptoms, such as impaired thinking, vision or memory. A second arm added to the trial to enroll 20 patients who had neurological symptoms had not been open long enough to analyze the results.

Historically, one reason patients with brain metastases had been excluded from clinical trials is that the blood-brain barrier, tight vascular construction, prevents drugs from reaching tumors. Since immunotherapy empowers T cells rather than treating tumors directly, the immune system cells can defeat the barrier, but there were concerns about immune-related side effects.

"We were quite concerned going into the study about immunotherapy causing inflammation and swelling in the brain, so this was closely monitored," Tawbi said. "In the end, only 5 percent of patients had swelling in the brain."

Overall, 34 patients (36.2 percent) had some type of central nervous system side effect, with headache being the most prominent, experienced by 21 patients. Seven of the 34 patients had the more serious grade 3 or 4 toxicities - three headaches, two with brain swelling, one with a brain hemorrhage and one with syncope (a loss of consciousness).

The side effect profile was otherwise similar to those caused by the combination in patients without brain metastases. Fifty-two patients (55 percent) had a grade 3 or 4 side effect, with 19 patients (20 percent) having to leave the trial. One patient died of treatment-related inflammation of the heart.

The most common grade 3 or 4 side effects were increased alanine aminotransferase in 15 patients and increased aspartate aminotransferase in 16 patients, both signs of potential liver damage.

Previous small studies showed that either ipilimumab or anti-PD1 drugs alone had response rates of around 20 percent in brain metastases. A smaller Australian study showed a 46 percent response rate for the combination.

An earlier clinical trial of combination targeted therapies, also led by MD Anderson investigators, showed high response rates for brain metastases but at shorter durations, with median progression-free survival of 5.8 months.

"Including these patients in clinical trials will accelerate progress for this patient population," Tawbi said.

The clinical trial was sponsored by Bristol-Myers Squibb, which developed and markets both drugs.

Tawbi reports receiving past research funding for MD Anderson and consulting fees from Bristol-Myers. Potential conflicts of interest for all authors are listed at the New England Journal of Medicine web site.

Co-authors with Tawbi are: Peter Forsyth, M.D., and Nikhil Khushalani, M.D., of Moffitt Cancer Center and Research Institute, Tampa; Alain Algazi, M.D., University of California-San Francisco; Omid Hamid, M.D., of The Angeles Clinic and Research Institute, Los Angeles; F. Stephen Hodi, M.D., and David Reardon, M.D., of Dana-Farber Cancer Institute, Boston; Stergios Moschos, M.D., University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill, N.C.; Karl Lewis, M.D., of University of Colorado Comprehensive Cancer Center, Aurora, Colo.; Christopher Lao, M.D., of the University of Michigan, Ann Arbor, Mich.; Michael Postow, M.D., of Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York; Michael Atkins, M.D., of Georgetown-Lombardi Comprehensive Cancer Center, Washington D.C.; Marc Ernstoff, M.D., and Igor Puzanov, M.D., of Roswell Park Cancer Institute, Buffalo, N.Y.; Ragini Kudchadkar, M.D., of Winship Cancer Institute of Emory University, Atlanta; Reena Thomas, M.D., Ph.D., of Stanford University Hospital, Palo Alto, Calif.; Ahmad Tarhini, M.D., Ph.D., of University of Pittsburgh Medical Center, Pittsburgh; Anna Pavlick, D.O., of New York University, Lake Success, N.Y.; Joel Jiang, Ph.D., Alexandre Avila, M.D., Ph.D., Sheena Demelo, M.D., of Bristol-Myers Squibb, Princeton, N.J.; and Kim Margolin, M.D., City of Hope, Duarte, Calif.

© 2018 The University of Texas MD Anderson Cancer Center

Ribociclib Approval Expanded for Some Women with Advanced Breast Cancer

by NCI Staff

The National Cancer Institute -- August 20, 2018

companies img A breast cancer cell undergoing cell division.

Credit: National Cancer Institute

The Food and Drug Administration (FDA) has expanded the approval for ribociclib (Kisqali) for some women with advanced breast cancer.

Under the July 18 approval, ribociclib can now be used in combination with some types of hormone therapy for the treatment of advanced hormone receptor-positive (HR+), HER2-negative (HER2-) cancer in women who haven't yet reached menopause. Most breast cancers are HR+ and HER2-.

FDA also expanded ribociclib's approval for use in postmenopausal women with this type of advanced breast cancer. Previously, it had been approved for use in combination with a type of hormone therapy called an aromatase inhibitor. With the expanded approval, ribociclib can now also be used with fulvestrant (Faslodex), a different type of hormone therapy.

The approval for premenopausal and perimenopausal women was based on results from a randomized clinical trial called MONALEESA-7. The expanded approval for postmenopausal women was based on results of a related trial, called MONALEESA-3. Both trials were sponsored by Novartis, the maker of ribociclib.

The new approvals for ribociclib were the first granted through a new FDA pilot program launched earlier this year called Real-Time Oncology Review. The program allows FDA to begin reviewing a drug after results from trials are first available but before a company has officially submitted an approval application.

Under the pilot program, the expanded approval of ribociclib was granted less than a month after Novartis filed its formal approval application, FDA Commissioner Scott Gottlieb, M.D., explained in a statement.

Slowing Disease Progression

Ribociclib works by inhibiting molecules called CDK4 and CDK6 that help control cell division. These enzymes are commonly activated by a variety of molecular mechanisms in breast cancer cells. Other FDA-approved CDK4/6 inhibitors include palbociclib (Ibrance) and abemaciclib (Verzenio).

MONALEESA-7 enrolled 672 pre- and perimenopausal women with recurrent or metastatic breast cancer. Women who had previously received hormone therapy for early-stage breast cancer, but not for advanced disease, could enroll in MONALEESA-7. Women who had received a single course of chemotherapy for advanced disease were also eligible to participate.

The researchers randomly assigned participants to receive ribociclib plus hormone therapy or a placebo plus hormone therapy. The type of hormone therapy used was based on factors such as patient and doctor preference and previous treatments, and it could be letrozole (Femara), anastrozole (Arimidex), or tamoxifen. All participants also received a monthly injection of goserelin (Zoladex), which suppresses hormone production in premenopausal women and allows hormone therapy to work better. Goserelin is usually given with standard hormone therapy for premenopausal women with breast cancer.

Women who received ribociclib plus hormone therapy lived longer without their disease progressing (progression-free survival) than women who received placebo plus hormone therapy: a median of 24 months compared with 13 months. The improvement in progression-free survival in women treated with ribociclib was about the same regardless of what type of hormone therapy was used.

Earlier trials of other CDK4/6 inhibitors had included some premenopausal women but weren't exclusively designed for them, explained Jairam Krishnamurthy, M.D., from the University of Nebraska Medical Center, who was not involved in MONALEESA-7.

Based on results from the earlier trials, many doctors were already using CDK4/6 inhibitors in premenopausal women (with ovarian suppression), said Dr. Krishnamurthy. "MONALEESA-7 is a confirmation for that [practice]," he added.

A similar relative improvement in progression-free survival was seen in the MONALEESA-3 trial, which tested the combination of ribociclib and fulvestrant in postmenopausal women with advanced or metastatic disease.

In MONALEESA-7, more cases of a potentially dangerous change in the heart's electrical conduction (called QT interval prolongation) were seen in women who received tamoxifen, even without ribociclib, than in women who received the other forms of hormone therapy, explained Debu Tripathy, M.D., of the University of Texas MD Anderson Cancer Center, who led the trial. As a precaution the new approval does not include the use of ribociclib in combination with tamoxifen, he added.

Some of the most common side effect seen in women in both trials included a drop in the number of white blood cells, infection, fatigue, and nausea. Quality of life remained higher for longer in the ribociclib group.

What Therapy for Which Patients?

Follow-up for both trials is still ongoing, to see if a difference in overall survival emerges over time.

"Typically, in HR+, HER2- disease, it has been difficult to show an overall survival advantage because these patients have so many other lines of therapy available" if their disease progresses, explained Dr. Krishnamurthy. "[Improved] overall survival is something that's been kind of the holy grail" in advanced breast cancer, he added.

In both trials, patients' quality of life remained high during treatment. This is important for advanced cancer, said Dr. Krishnamurthy.

"A common misconception among patients [with advanced disease] and their families is they feel that we should administer chemotherapy, because we have to be 'aggressive.'

"On the contrary, for HR+, HER2- disease, you have to target the estrogen receptor," for as long as possible, he added. This strategy has the potential to be both more effective and produce fewer side effects than chemotherapy, he explained.

Two trials in progress (PEARL and PASIPHAE) are testing whether giving a CDK4/6 inhibitor and hormone therapy instead of chemotherapy as an initial, or first-line, treatment for women with metastatic breast cancer improves progression-free survival.

Other questions about the best way to use CDK4/6 inhibitors remain to be answered. For instance, further studies are needed to understand which patients with advanced or metastatic breast cancer may do just as well with a hormone therapy alone and which patients have tumors that are resistant to CDK4/6 inhibition, explained Dr. Tripathy. Neither of these groups would benefit from a combination of CDK4/6 inhibitors and hormone therapy.

And for tumors that are resistant to CDK4/6 inhibitors, more research is needed to tease out "what the mechanisms of resistance are and how we can use this information-not only to make better choices for our patients, but also to discover newer drugs that might reverse resistance or perform better in these patients," Dr. Tripathy said.

But "clinicians should at least discuss the possibility of adding a CDK4/6 inhibitor with everybody who's getting first-line or second-line hormone therapy [for advanced disease]," he concluded. "Because, for most patients, CDK4/6 inhibitors appear to be of benefit in terms of delaying progression. . .and may also delay the time that they need to go on more aggressive treatment, like chemotherapy."

© 2018 The National Cancer Institute

NCI-led research team develops predictor for immunotherapy response in melanoma

by NCI Staff

The National Cancer Institute -- August 20, 2018

companies img Researchers developed a gene expression predictor that can indicate which melanoma patients will respond to immunotherapy.

Credit: iStock

In a new study, researchers developed a gene expression predictor that can indicate whether melanoma in a specific patient is likely to respond to treatment with immune checkpoint inhibitors, a novel type of immunotherapy. The predictor was developed by Noam Auslander, Ph.D., with other researchers in the Center for Cancer Research (CCR) at the National Cancer Institute (NCI), part of the National Institutes of Health, and colleagues at Harvard University, Cambridge, Mass.; the University of Pennsylvania, Philadelphia; and the University of Maryland, College Park. The study was published August 20, 2018 in Nature Medicine.

"There is a critical need to be able to predict how cancer patients will respond to this type of immunotherapy," said Eytan Ruppin, M.D., Ph.D., of NCI's newly established Cancer Data Science Laboratory, who led the study. "Being able to predict who is highly likely to respond and who isn't will enable us to more accurately and precisely guide patients' treatment."

Treatment with checkpoint inhibitors is effective for some patients with late-stage melanoma and certain other types of cancer. However, not all patients with melanoma respond to this treatment, and it can have considerable side effects. Being able to predict which patients are likely to respond and which are not would be a major clinical advance. But developing a predictor of response has been challenging, partly because of the limited number of patients who have received this relatively new form of treatment.

In this study, the investigators developed a predictor by first looking for clues in cases where the immune system appears to mount an unprompted, successful immune response to cancer, causing spontaneous tumor regression. They analyzed neuroblastoma, a type of cancer that frequently undergoes spontaneous regression in young children, and were able to define gene expression features that separated patients with non-regressing disease from those with regressing disease.

These features enabled the researchers to compute what they called an IMmuno-PREdictive Score (IMPRES) for each patient sample. The higher the IMPRES score for a sample, the more likely it was to undergo spontaneous regression. To see if IMPRES could be used to predict melanoma patients' responses to checkpoint inhibitors, the authors analyzed 297 samples from several studies. They found that the predictor could identify nearly all patients who responded to the inhibitors and more than half of those who did not, making it significantly superior to all other existing published predictors. Importantly, unlike other existing predictors, IMPRES was accurate across many different melanoma patient data sets.

"We now know that immunotherapy works, but we do not understand well why a particular therapy will work for some patients but not others," said Tom Misteli, Ph.D., director of CCR at NCI. "This study is a step forward in developing tools to address this challenge, which is of practical importance to patients."

Dr. Ruppin said that while the results obtained are encouraging, they will need to be carefully evaluated in additional patient datasets. The authors also wrote that further study of this kind of predictor is now warranted in other cancer types for which checkpoint inhibitors have been approved.

About the Center for Cancer Research (CCR): CCR comprises nearly 250 teams conducting basic, translational, and clinical research in the NCI intramural program-an environment supporting innovative science aimed at improving human health. CCR's clinical program is housed at the NIH Clinical Center-the world's largest hospital dedicated to clinical research. For more information about CCR and its programs, visit ccr.cancer.gov.

About the National Cancer Institute (NCI): NCI leads the National Cancer Program and NIH's efforts to dramatically reduce the prevalence of cancer and improve the lives of cancer patients and their families, through research into prevention and cancer biology, the development of new interventions, and the training and mentoring of new researchers. For more information about cancer, please visit the NCI website at cancer.gov or call NCI's Contact Center (formerly known as the Cancer Information Service) at 1-800-4-CANCER (1-800-422-6237).

About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit nih.gov.

© 2018 The National Cancer Institute

Liquid Biopsy May Predict Risk of Breast Cancer Returning Years Later

by NCI Staff

The National Cancer Institute -- August 15, 2018

companies img Circulating tumor cells, or CTCs, are cells that are shed by tumors into the blood.

Credit: APMIS June 2014. doi: 10.1111/apm.12183. Creative Commons.

Women who had cancer cells detected in their blood 5 years after a breast cancer diagnosis were 13 times more likely to have their cancer return than women who did not, results from an ongoing study have shown.

Most women who are diagnosed with hormone receptor-positive breast cancer that has not spread will not have a recurrence. Among those who do have a recurrence, more than half have a late recurrence, meaning their disease will return 5 or more years after diagnosis.

Doctors do not currently have a reliable method to predict who is likely to have a late recurrence and is a candidate for therapies that might prevent or delay it. According to the study findings, a blood test-a type of liquid biopsy-may help classify patients according to their recurrence risk.

"This [finding] is not something that should change practice now," said lead investigator Kathy Miller, M.D., of Indiana University Melvin and Bren Simon Cancer Center. "But it gives us the potential for future clinical trials that identify patients at higher risk [of late recurrence] and study whether having that information could change treatment and improve outcomes," she added.

Though there are limitations, "this is a really well-conducted study," said Lyndsay Harris, M.D., of NCI's Division of Cancer Treatment and Diagnosis, who has conducted similar research but was not involved in the study. "It's part of a clinical trial and therefore was carefully controlled."

The finding that detection of tumor cells in blood is associated with late recurrence of breast cancer "is a really important observation that had not been clearly shown in the setting of a large clinical trial," she added.

The study, funded in part by NCI, was reported in JAMA Oncology on July 26.

Detecting Breast Cancer Cells in Blood

Tumors are solid masses, but they aren't static. In addition to growing, spreading, and changing the environment around them, tumors also shed cells into nearby blood vessels. Studies have suggested that measuring and analyzing these so-called circulating tumor cells may reveal important information about the tumor that could benefit the patient.

Liquid biopsies are being widely studied as a way to improve early detection of cancer, monitor disease progression, and help guide treatment decisions.

Dr. Miller and her colleagues wanted to determine whether a liquid biopsy test for circulating tumor cells was associated with late recurrence in women with breast cancer.

More than 700 women who were participating in a large NCI-funded clinical trial of adjuvant therapy for breast cancer also enrolled in this new study. At the time that they enrolled-around 5 years after their original breast cancer diagnosis-the women did not have any evidence of a recurrence.

The researchers used a liquid biopsy test to identify and count tumor cells in a sample of blood collected from participants at the time of enrollment. The test is cleared by the Food and Drug Administration to assess disease progression in patients with metastatic breast, prostate, and colon cancer. However, it has not been proven that using the test to inform treatment decisions improves patient outcomes, Dr. Harris stressed.

Of the 547 women whose samples could be analyzed, 26 had at least one detectable circulating tumor cell. The researchers did not observe any major differences in characteristics such as tumor size or age at diagnosis between the women who had detectable circulating tumor cells and those who didn't. The proportion of women with hormone receptor-positive (HR+) and hormone receptor-negative (HR-) breast cancer who had detectable circulating tumor cells was similar.

At a median follow up of 2.6 years after the test was performed, cancer had returned in 24 women in the study, including 7 women who had detectable circulating tumor cells and 17 who did not. For all women in the study, the detection of circulating tumor cells was associated with a 12.7-fold higher risk of recurrence.

Late recurrences are typically more common among women with HR+ than HR- breast cancer. Dr. Miller and her colleagues observed the same pattern: cancer returned in 6.5% of women with HR+ breast cancer and 0.5% of those with HR- breast cancer.

Of the 23 women with HR+ breast cancer who had a late recurrence, 7 had detectable circulating tumor cells. For women with HR+ breast cancer, the detection of circulating tumor cells was associated with a 13.1-fold higher risk of recurrence.

Among women with HR+ breast cancer who had detectable circulating tumor cells, those who had a recurrence had higher numbers of circulating tumor cells than those who did not have a recurrence.

None of the eight women with HR- disease who had detectable circulating tumor cells had a recurrence. It's not clear why circulating tumor cells are associated with recurrence only for women with HR+ disease, Dr. Miller said.

Though there's no evidence yet, one idea is that the immune system may be better at attacking and eliminating HR- tumors before they have a chance to grow back, she added.

Predicting At-Risk Patients

The research team acknowledged that the study population is small and that they need to follow the participants for a longer time. They are continuing to follow these participants.

"More patients may have a recurrence with further follow up," Dr. Miller said.

The researchers also plan to determine if testing patients more than once is a more accurate way to predict recurrence. Circulating tumor cells might be detected later in women who had a recurrence but did not test positive at the 5-year mark, said Dr. Miller.

In addition, the team will evaluate other tumor biomarkers-such as certain proteins in the blood-that might be associated with the risk of recurrence "to see if we can do an even better job of segregating patients based on their risk," Dr. Miller explained.

Dr. Harris noted that the question of how the detection of circulating tumor cells might change patient treatment and, ultimately, outcomes, still needs to be addressed.

Women with HR+ breast cancer are sometimes treated with hormone therapy for more than 5 years in an effort to prevent or delay a late recurrence. But it isn't clear if all patients with HR+ breast cancer need such treatment, which comes with the risk of serious side effects, for that length of time.

Having a test that could predict which HR+ breast cancer patients are most at risk for a late recurrence and might be good candidates for extended therapy, or another treatment approach, would be helpful, Dr. Harris added.

Dr. Miller and her colleagues are beginning to talk about just such a study, using the liquid biopsy test to determine patient treatment.

© 2018 The National Cancer Institute

PARP inhibitor improves progression-free survival in patients with advanced breast cancers and BRCA mutations

MD Anderson-led Phase III trial meets primary endpoint with talazoparib over chemotherapy

MD Anderson Cancer Center -- August 15, 2018

companies img Jennifer Litton, M.D.

HOUSTON - In a randomized, Phase III trial led by researchers at The University of Texas MD Anderson Cancer Center, the PARP inhibitor talazoparib extended progression-free survival (PFS) and improved quality-of-life measures over available chemotherapies for patients with metastatic HER2-negative breast cancer and mutations in the BRCA1/2 genes.

The results of the EMBRACA trial were published today in the New England Journal of Medicine. The findings were first presented at the 2017 San Antonio Breast Cancer Symposium by Jennifer Litton, M.D., associate professor of Breast Medical Oncology, also corresponding author of the study.

"The trial found that talazoparib provides a significant clinical benefit to all patient subgroups, including those with hormone receptor-positive and triple-negative disease," said Litton. "The results of this trial are quite exciting and indicate talazoparib is a novel treatment option for patients with metastatic breast cancer and BRCA mutations."

Mutations in the BRCA1/2 genes, which account for 5 to 10 percent of all breast cancers, cause defects in normal DNA damage repair. PARP inhibitors block an additional DNA repair pathway, and the anti-tumor effects of PARP inhibitors can be intensified in patients with BRCA mutations. Talazoparib works by not only inhibiting the PARP enzyme, but by trapping the enzyme on DNA to further prevent DNA repair.

The international Phase III clinical trial, EMBRACA, enrolled 431 patients with locally advanced or metastatic and hereditary BRCA1/2 gene mutations. Patients with HER2-positive disease were excluded as there are approved targeted therapies for those cancers. Patients could have had up to three previous chemotherapies, including platinum-based therapies.

Participants were randomized 2:1 to receive either talazoparib (287) or physician's choice of treatment (PCT) of single-agent therapy (144), either capecitabine, eribulin, gemcitabine or vinorelbine. Fifty-four percent of participants had HR+ disease and 46 percent had TN breast cancer; BRCA1 and BRCA2 mutations were split at 45 and 55 percent, respectively.

"Importantly, the trial met its primary endpoint of progression-free survival. Patients were nearly 46 percent less likely to have progressed on talazoparib compared to physician's choice," said Litton. "Secondary endpoints also were promising, including a dramatic improvement in time to clinical deterioration among patients receiving talazoparib."

The median PFS, assessed by blinded independent review, was 8.6 months in the talazoparib arm, compared with 5.6 months in the PCT arm, a statistically significant improvement. The overall response rate, or percentage of patients with tumor shrinkage, was 62.6 percent and 27.2 percent in the talazoparib and PCT arms, respectively. Twelve participants had complete responses, all in the talazoparib arm.

Patient-reported quality-of-life measures revealed a prolonged time to deterioration of overall health, 24.3 months in the talazoparib arm compared to 6.3 months for the PCT arm.

Grade 3-4 hematological adverse events occurred in 55 percent of patients receiving talazoparib and 39 percent of those on chemotherapy, but talazoparib was associated with fewer high-grade non-hematological events, including gastrointestinal and skin/subcutaneous tissue disorders. Grade 3-4 serious events occurred in 26 and 25 percent of patients receiving talazoparib and PCT, respectively. Adverse events resulting in death occurred in 2.1 percent of patients on talazoparib and 3.2 percent on PCT.

Final overall survival will be reported at a later date when the data fully matures, said Litton.

"It is encouraging to see this oral PARP inhibitor was well-tolerated and superior to chemotherapy alone. We look forward to seeing how overall survival is affected, but I think talazoparib will be an excellent option for patients with metastatic disease and BRCA mutations," said Litton.

Litton hopes to continue investigating the utility of PARP inhibitors in additional breast cancer patients with BRCA mutations, including those with early-stage disease, as well as possibilities for enhancing the activity of PARP inhibitors in patients without inherited BRCA mutations.

The study was sponsored by Pfizer. Litton has research funding with EMD Serono, Astra-Zeneca, Pfizer and Genentech, and she serves on advisory boards for Pfizer and Astra-Zeneca, all uncompensated.

As follow up, a Phase I talazoparib in combination trial is ongoing at MD Anderson; Litton hopes that this study and other combination studies may expand who can benefit from PARP inhibitors and improve responses for more patients.

In addition to Litton, co-investigators on the study include: Hope S. Rugo, M.D., UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco; Johannes Ettl, M.D., TU Muenchen III, Munich; Sara Hurvitz, M.D., University of California, Los Angeles; Anthony Goncalves, M.D., Ph.D., Institut Paoli-Calmettes, Marseille; Kyung-Hun Lee, M.D., Ph.D., Seoul National University Hospital, Seoul; Louis Fehrenbacher, M.D., Kaiser Permanente, Northern California, Velljo, CA; Rinat Yerushalmi, M.D., Rabin Medical Center, Beilinson Hospital, Petah Tikva, Israel; Lida A. Mina, M.D., Banner Health, Phoenix; Miguel Martin, M.D., Instituto de Investigacion Sanitaria Gregorio Maranon, Ciberonc, Universidad Complutense, Madrid; Henri Roche, M.D., Ph.D., Institut Universitaire du Cancer Toulouse, Toulouse, France; Young-Hyuck Im, M.D., Samsung Medical Center, Seoul; Ruben G. W. Quek, Ph.D., Denka Markova, Ph.D., Iulia C. Tudor, Ph.D., and Alison L. Hannah, M.D., all of Pfizer, Inc., San Francisco; Wolfgang Eiermann, M.D., Interdisziplinares Onkologisches Zentrum Muenchen, Muenchen, Germany; and Joanne L. Blum, M.D., Ph.D., Baylor Sammons Cancer Center, Texas Oncology, US Oncology, Dallas.

© 2018 The University of Texas MD Anderson Cancer Center

Cetuximab with radiation found to be inferior to standard treatment in HPV-positive oropharyngeal cancer

by NCI Staff

The National Cancer Institute -- August 14, 2018

companies img Anatomical illustration of the oropharynx.

Credit: National Cancer Institute

An interim analysis of data from a randomized clinical trial of patients with human papillomavirus (HPV)-positive oropharyngeal cancer found that treatment with radiation therapy and cetuximab is associated with worse overall and progression-free survival compared to the current standard treatment with radiation and cisplatin. The trial was designed to see if cetuximab with radiation would be less toxic than cisplatin with radiation without compromising survival for patients with the disease.

The phase 3 trial, which closed enrollment in 2015, was funded by the National Cancer Institute (NCI), part of the National Institutes of Health, and led by NRG Oncology, part of NCI's National Clinical Trials Network. The data monitoring committee overseeing the trial recommended releasing the data after an interim data analysis showed that cetuximab with radiation was associated with inferior overall and progression-free survival, compared to cisplatin and radiation. The U.S. Food and Drug Administration has previously approved cetuximab with radiation for patients with head and neck cancer, including oropharyngeal cancer. Cetuximab with radiation is an accepted standard of care, especially for patients who cannot tolerate cisplatin.

"The goal of this trial was to find an alternative to cisplatin that would be as effective at controlling the cancer, but with fewer side effects," said Andy Trotti, M.D., of the Moffitt Cancer Center in Tampa, Florida, a lead investigator of the trial. "We were surprised by the loss of tumor control with cetuximab."

There has been a lot of recent interest in the cancer clinical research community in evaluating the "de-escalation" of therapies for cancers that have a good prognosis, such as HPV-positive cancer of the oropharynx (the part of the throat at the back of the mouth, including the soft palate, the base of the tongue, and the tonsils). The goal is to improve patients' quality of life and reduce long-term toxic effects without compromising treatment efficacy. HPV-positive oropharyngeal cancer is frequently diagnosed in individuals in their 50s and 60s, and is associated with high survival rates, providing the incentive for this trial. Moreover, the incidence of this type of cancer has increased rapidly in recent years in the United States.

"Clinical trials designed to test less toxic treatment strategies for patients without compromising clinical benefit are a very important area of interest for NCI and the cancer research community," said Shakun Malik, M.D., of NCI's Division of Cancer Treatment and Diagnosis.

This trial's primary objective was to determine whether the substitution of cetuximab for cisplatin with radiation would result in comparable overall survival while reducing toxic side effects with improved long-term quality of life. The trial enrolled 849 patients with HPV-positive oropharyngeal cancer who were randomly assigned to receive either cetuximab or cisplatin with radiation. The study had three planned interim analyses.

The third and final interim analysis, done after a median follow-up of 4.5 years, found that overall survival on the cetuximab arm was significantly inferior to the cisplatin arm. Overall rates of serious (grade 3-5) adverse events were similar for patients in both groups. However, as the researchers expected, toxic side effects were different, with adverse events of renal toxicity, hearing loss, and bone marrow suppression more common in patients in the cisplatin arm, while body rash was more common in the cetuximab arm. All patients in this trial had completed therapy at the time of this analysis.

"This trial is the first randomized clinical trial specifically designed for patients with HPV-positive oropharyngeal cancer, and it establishes cisplatin with radiation as the standard of care," said Maura Gillison, M.D, Ph.D., of the University of Texas MD Anderson Cancer Center in Houston, the other lead investigator of the trial.

Full study details will be presented in the plenary session at the American Society for Radiation Oncology (ASTRO) Annual Meeting in San Antonio, Texas on Oct. 22 at 2:15 pm CT. Findings from the trial will later be published in a peer-reviewed journal.

For more information on the trial: https://clinicaltrials.gov/ct2/show/NCT01302834

About the National Cancer Institute (NCI): NCI leads the National Cancer Program and NIH's efforts to dramatically reduce the prevalence of cancer and improve the lives of cancer patients and their families, through research into prevention and cancer biology, the development of new interventions, and the training and mentoring of new researchers. For more information about cancer, please visit the NCI website at cancer.gov or call NCI's Contact Center (formerly known as the Cancer Information Service) at 1-800-4-CANCER (1-800-422-6237).

About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit nih.gov.

About NRG Oncology: NRG Oncology conducts practice-changing, multi-institutional clinical and translational research to improve the lives of patients with cancer. Founded in 2012, NRG Oncology is a Pennsylvania-based nonprofit corporation that integrates the research of the NSABP Foundation, the Radiation Therapy Oncology Group (RTOG), and the Gynecologic Oncology Group (GOG). The research network seeks to carry out clinical trials with emphases on gender-specific malignancies, including gynecologic, breast, and prostate cancers, and on localized or locally advanced cancers of all types. NRG Oncology's extensive research organization comprises multidisciplinary investigators, including medical oncologists, radiation oncologists, surgeons, physicists, pathologists, and statisticians, and encompasses more than 1,300 research sites located world-wide with predominance in the United States and Canada. NRG Oncology is supported primarily through grants from the National Cancer Institute (NCI) and is one of five research groups in NCI's National Clinical Trials Network. www.nrgoncology.org

© 2018 The National Cancer Institute

MD Anderson ranked No. 1 for cancer care in national survey

MD Anderson Cancer Center -- August 13, 2018

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HOUSTON - The University of Texas MD Anderson Cancer Center again has been ranked No. 1 for cancer care by U.S. News & World Report's annual "Best Hospitals" survey. Since the survey began in 1990, MD Anderson has been named one of the top two cancer hospitals, and it has ranked first 14 times in the last 17 years.

"MD Anderson is proud and grateful to be recognized once again as the leading cancer center in the nation, an honor that reflects our team's commitment to ending cancer," said Peter WT Pisters, M.D., president of MD Anderson. "It is a privilege for our 20,000 employees and 1,000 volunteers to serve those counting on us and to work alongside supportive friends, donors, leaders and advocates in the community."

In addition to MD Anderson's top ranking for cancer care, the Head and Neck Surgery service was ranked No. 14 in the Ear, Nose and Throat specialty. Orthopedics and Urology also were rated as "High Performing" areas.

For more than 75 years, MD Anderson has been a global leader in the fight to end cancer. Its extraordinary mission calls for bold approaches that allow MD Anderson to continue setting the standard in cancer prevention, education, research and care. Last year alone, more than 137,000 patients sought MD Anderson's expertise and nearly 11,000 patients enrolled in clinical trials, making it home to the largest cancer clinical trials program in the world. Through industry partnerships and its Therapeutics Discovery division, MD Anderson is working to develop innovative treatment options with the goal of bringing transformational, life-saving medicines to patients quickly, safely and effectively.

"Through a collective culture of team science and team-based clinical care, MD Anderson tackles challenges along the entire cancer care continuum to ensure the best possible outcomes for our patients," said Pisters. "We are grateful for our patients and their families who entrust us with their care and inspire us every day. We are committed to partnering with them in Making Cancer History."

© 2018 The University of Texas MD Anderson Cancer Center

Targeted Drug Approved for Acute Myeloid Leukemia with IDH1 Gene Mutations

by NCI Staff

The National Cancer Institute -- August 13, 2018

companies img Approximately 6-10% of people with AML have a mutation in the IDH1 gene.

Credit: Adapted from PLOS One Sept. 15, 2015. https://doi.org/10.1371/journal.pone.0133813. CC BY 4.0

On July 20, the Food and Drug Administration (FDA) approved ivosidenib (Tibsovo) for the treatment of adults with acute myeloid leukemia (AML) that has a specific mutation in a gene called IDH1. The approval covers patients whose AML has returned after earlier treatment (relapsed) or has not responded to standard therapies (refractory).

Ivosidenib is a tablet that patients take orally once a day.

FDA also approved a companion diagnostic test called the Abbott RealTime IDH1 assay, which can identify patients with IDH1 mutations who may benefit from ivosidenib. Approximately 6% to 10% of patients with AML have the specific IDH1 mutation.

Ivosidenib is the first FDA-approved treatment that inhibits abnormal proteins produced by mutated IDH1 genes. Blocking these proteins may help keep cancer cells from growing.

Last year, FDA approved an oral drug that inhibits abnormal forms of the IDH2 protein in patients with AML. The drug, enasidenib (Idhifa), was the first IDH2 inhibitor approved for AML, and there is a companion diagnostic test to identify specific mutations in the IDH2 gene.

Both enasidenib and ivosidenib are molecularly targeted therapies for AML that were approved based on the results of single-arm phase 1 studies, noted Roland Walter, M.D., Ph.D., an AML specialist at Fred Hutchinson Cancer Research Center in Seattle.

In these trials, the effectiveness of the drugs and their side effect profiles were "virtually identical," Dr. Walter said. He noted that the effectiveness of the drugs was measured by the proportion of patients achieving morphologically-defined remission, which means they had less than 5% myeloblasts in the bone marrow and either a full or partial recovery of blood counts, and the durations of those remissions.

Dr. Walter cautioned, however, that more research is needed to compare enasidenib and ivosidenib with salvage therapy (treatments that are used when other therapies for AML fail).

"There are currently no comparative data available, and it is not clear whether-and to what degree-treatment outcomes are better with these molecularly targeted therapies compared with conventional salvage therapy," he added.

Testing an IDH1 Inhibitor in Patients with AML

FDA's approval of ivosidenib was based on results from a 174-patient clinical trial. All patients in the trial were adults with relapsed or refractory AML whose blood or bone marrow had a mutation in the IDH1 gene. Agios Pharmaceuticals, the maker of ivosidenib, funded the trial.

With a median follow-up of 8.3 months, following treatment with ivosidenib, nearly a third of the patients (32.8%) experienced complete remissions. The median duration of response was 8.2 months.

Additional results from the trial appeared in the New England Journal of Medicine on June 21.

Common side effects of ivosidenib included fatigue, increase in white blood cells, joint pain, diarrhea, shortness of breath, and swelling in the arms or legs. Approximately 19% of patients experienced a side effect called differentiation syndrome, which includes fever and respiratory distress and can be fatal if not treated.

Physicians will have to become familiar with the side effects of this drug, such as differentiation syndrome, noted Dr. Walter. "There is still much to learn about ivosidenib and enasidenib, including how best to combine these drugs with others," he added.

© 2018 The National Cancer Institute

MD Anderson and Accelerator Life Science Partners launch Magnolia Neurosciences to speed development of neuroprotective therapies

Company to explore new treatments uncovered by MD Anderson's Therapeutics Discovery team

MD Anderson Cancer Center -- August 13, 2018

companies img Tumor cells with DNA repair defects, including microsatellite instability, may be particularly susceptible to immune checkpoint inhibitors.

Cancer Immunol Immunother 2016. CC BY 4.0.

HOUSTON - The University of Texas MD Anderson Cancer Center and Accelerator Life Science Partners, a leading life science investment and management firm, today announced the launch of Magnolia Neurosciences Corporation, a company developing a new class of neuroprotective medicines, with $31 million in Series A funding. The company will develop novel therapeutics based on discoveries made by researchers in MD Anderson's Therapeutics Discovery division, including the Institute for Applied Cancer Science (IACS) and the Neurodegeneration Consortium (NDC).

"By developing new treatments, Magnolia Neurosciences will address a critical need for patients suffering from neurodegenerative conditions, such as Alzheimer's disease and chemotherapy-induced neuropathy in cancer patients," said Jim Ray, Ph.D., director of the NDC. "These conditions are driven by similar biological pathways, and it is our hope that we can improve the lives of patients across disease types based upon new drug candidates discovered by the MD Anderson Therapeutics Discovery team."

Annually, more than 700,000 Americans with cancer are treated with chemotherapy, and many experience a variety of neural and cognitive impairments as a result of their treatment. More than 200,000 patients each year will suffer from a condition known as "chemobrain," characterized by general cognitive and memory problems, which can last for years. Additionally, roughly two-thirds of patients undergoing chemotherapy treatment develop peripheral neuropathy, in which nerve damage causes pain, numbness and tingling in the hands and feet.

The development of medicines to prevent these conditions in patients receiving chemotherapy would not only improve patients' quality of life, but also would avoid the need for dose reductions or breaks from therapy, resulting in improved survival, explained Philip Jones, Ph.D., vice president of Therapeutics Discovery and head of drug discovery at IACS.

Neurodegenerative diseases include a range of conditions characterized by progressive deterioration of neurons in the human brain. These conditions affect millions of Americans and are largely untreatable.

The NDC is a multi-institutional initiative launched to better understand the biology of neurodegenerative diseases and translate that knowledge into effective therapeutics interventions. Established in 2012 by an inaugural $25 million gift from the Robert A. and Renee E. Belfer Family Foundation, the NDC brings researchers from Baylor College of Medicine, the Massachusetts Institute of Technology and the Icahn School of Medicine at Mount Sinai together with drug discovery and development experts from MD Anderson's Therapeutics Discovery division.

The Therapeutics Discovery division is a unique group of more than 100 clinicians, researchers and drug discovery scientists at MD Anderson working to develop innovative treatment options, including small molecules, biologics and cell-based therapies. The goal of the Therapeutics Discovery team is to bring transformational, life-saving medicines to patients quickly, safely and effectively by working closely with patients and clinicians.

"Our team is inspired by the needs we see in our patients, and we learned from MD Anderson's physicians that some cancer treatments can cause significant neurocognitive and neuropathy challenges for survivors," said Jones. "Therefore, we set out to discover new therapies to combat these issues and, hopefully, a variety of other neurodegenerative conditions."

Under the leadership of Giulio Draetta, M.D., Ph.D., senior vice president and head of Therapeutics Discovery and co-leader of MD Anderson's Moon Shots Program, Ray and Jones established a multi-disciplinary team of scientists to identify and advance new targeted therapies to treat neural damage, which now form the basis of Magnolia Neurosciences. Ray and Jones also will serve as members of the Magnolia Neurosciences Scientific Advisory Board.

"This project is a stellar example of the patient-focused drug development model that drives Therapeutics Discovery and exemplifies MD Anderson's commitment to caring for our patients throughout their entire cancer journey, from diagnosis to survivorship," said Draetta. "We're excited to see these new therapeutics progress into clinical trials through the launch of Magnolia Neurosciences."

Investors participating in the $31 Million Series Afinancing include AbbVie Ventures, Alexandria Venture Investments, ARCH Venture Partners, Eli Lilly and Company, Innovate NY Fund, Johnson & Johnson Innovation - JJDC, Inc., the Partnership Fund for New York City, Pfizer Ventures, Watson Fund, L.P., WuXi AppTec's Corporate Venture Fund and 180 Degree Capital Corp.

The preclinical research to identify and develop the novel drug candidates being advanced by Magnolia Neurosciences was funded by the NDC, through support from the Robert A. and Renee E. Belfer Family Foundation; and IACS, part of MD Anderson's Moon Shots Program, a collaborative effort to accelerate the development of scientific discoveries into clinical advances that save patients' lives.

About Magnolia Neurosciences Corporation

Magnolia Neurosciences Corporation is a drug discovery and development company focused on the creation of a novel class of neuroprotective medicines. The company was launched by a $31 million Series A investment by Accelerator Life Science Partners in 2018 and was co-founded by world-class researchers at The University of Texas MD Anderson Cancer Center. The company endeavors to make life-changing medicines for the benefit of patients and their families suffering from serious CNS diseases. The company's offices are located in the Alexandria Center for Life Science, New York City's first and only premier life science campus. For more information, please visit www.magnolianeurosciences.com.

© 2018 The University of Texas MD Anderson Cancer Center

Tailored Psychotherapy Eases Depression in People with Advanced Cancer

by NCI Staff

The National Cancer Institute -- August 9, 2018

companies img In a large clinical trial, tailored psychotherapy sessions helped to reduce depression symptoms in people with advanced cancer.

Credit: iStock

People diagnosed with advanced cancer can face a host of challenges and stresses, from navigating the health care system to dealing with relationship disruptions and figuring out how to spend the time they have left, that can leave them vulnerable to depression. Yet cancer centers and clinics don't routinely provide psychological support to all advanced cancer patients to help them cope.

In a new clinical trial, just three to six sessions of a tailored psychotherapy approach known as Managing Cancer and Living Meaningfully, or CALM, helped to lessen symptoms of depression in people recently diagnosed with advanced cancer. Results from the trial also showed that the approach may help prevent the onset of depression in those with advanced disease.

"We know there's a lot of distress [among people with advanced cancer], and we've shown previously that, without treatment, the symptoms of depression get worse," said study leader Gary Rodin, M.D., head of the Department of Supportive Care at Princess Margaret Cancer Centre in Toronto, Canada.

"The idea of CALM is to intervene proactively rather than just waiting for people to get distressed, anxious, depressed, and overwhelmed," he said.

The sustained improvement among patients after as few as three CALM sessions was impressive, said Ann O'Mara, Ph.D., R.N., M.P.H., head of palliative research in NCI's Division of Cancer Prevention, who was not involved in the study.

CALM therapy "addresses many issues that are above and beyond what palliative care services may [currently] provide," Dr. O'Mara said. "If incorporated into a palliative care setting, this intervention could really help our patients with advanced cancer."

Results of the randomized clinical trial were published June 29 in the Journal of Clinical Oncology.

Providing a Roadmap to Reduce Stress and Live Meaningfully

Dr. Rodin and colleagues Sarah Hales, M.D., Ph.D., and Chris Lo, Ph.D., developed CALM to help patients in four key areas: symptom management and communication with health care providers; changes in self and close personal relationships; spiritual well-being and a sense of meaning and purpose in life; and concerns about mortality and the future.

"We try to help people understand that there are many ways to think about their situation and many ways to live meaningfully," Dr. Rodin said.

CALM therapy consists of three to six 45- to 60-minute sessions over 3-6 months. The patient's primary informal caregiver is invited to one or more sessions when acceptable to both patient and therapist.

The approach provides a general framework or "roadmap" that therapists can modify based on their own personal style and culture and on a patient's individual needs and concerns, Dr. Rodin explained.

A wide range of cancer care and palliative care providers, including nurses, physicians, psychologists, and social workers, can provide CALM therapy after receiving the necessary training, which consists of an intensive 2-day workshop and ongoing supervision on at least three cases. These clinicians have typically had experience engaging in conversations with people with advanced cancer but may not have prior formal training in psychotherapy.

"CALM is meant to be initiated as soon as possible after diagnosis of an advanced cancer, to help people live their lives as well as they can," Dr. Rodin said. "Sometimes people get so swallowed up by the cancer care system, or they feel so hopeless, that they give up on life while they're still relatively well physically. That's what we're trying to prevent."

Reducing and Preventing Symptoms of Depression

To measure the effects of CALM on symptoms of depression, Dr. Rodin's team enrolled 305 patients recently diagnosed with advanced or metastatic cancer and an expected survival of 12-18 months. Participants were randomly assigned to receive either usual care (154 patients) or usual care plus CALM (151 patients). Usual care may include specialized psychosocial oncology services, but a previous study by Dr. Rodin's team showed that less than 10% of patients with advanced cancer received any form of structured psychotherapy at the cancer center where the trial took place.

Participants in CALM were still being actively treated for their cancer, and most therapy sessions took place in outpatient clinics.

The team used a standard nine-item questionnaire, known as PHQ-9, to measure symptoms of depression when patients first entered the study (baseline) and at 3 and 6 months. A PHQ-9 score of 5-9 points out of a 27-point maximum is considered mild depression and a score of 10-14 is considered moderate depression.

The researchers also assessed other outcomes not central to the trial, including distress about death, via standard questionnaires that participants completed at the time they entered the study, and again at 3 and 6 months after study entry.

At both 3 and 6 months, CALM participants reported less-severe symptoms of depression, on average, than those reported by participants in the usual care group. The benefits of CALM therapy appeared greater at 6 months than at 3 months, with a mean reduction in PHQ-9 scores of 1.29 and 1.09, respectively.

Although the overall difference in depressive symptoms between the two groups at 3 and 6 months was small, the ability to provide measurable improvement with the CALM approach is still notable, Dr. O'Mara said, because not all people with advanced cancer, like those in the study, are likely to experience depression.

To clarify the clinical meaning of their findings, the team performed additional analyses of the data in specific subgroups of patients. They found that CALM was more likely than usual care to provide a "clinically important" PHQ-9 reduction in depression of at least 5 points for participants who entered the study with a PHQ-9 score of at least 8 points at baseline.

These analyses also suggested "that not only does CALM reduce depression in some patients, it may also prevent the onset of depression" in participants who were not depressed at baseline, Dr. Rodin said.

Furthermore, the authors wrote, "The study findings suggest that participants with moderate levels of distress about dying and death benefited most from CALM therapy."

Assessing the Universality of CALM

The optimal timing of CALM and the most appropriate and meaningful ways to assess its outcomes require further research, the study authors said.

In an earlier pilot study, people with advanced cancer described multiple benefits of CALM therapy. For instance, Dr. Rodin said, patients reported that CALM provided a safe place to talk about their feelings, allowed them to face their fears, and helped them face the end of life and live their lives meaningfully.

And, he continued, his team believes that the qualitative data from patient interviews is also very important when judging the potential benefits of a program such as CALM. Such data provide valuable information about the experience of CALM therapy and about the mechanisms by which it may exert its effect.

One key limitation of the new trial, the authors noted, is that it was conducted at a single, urban cancer center with primarily English-speaking, white, well-educated participants.

Dr. Rodin's team has launched a global initiative to disseminate CALM in 20 countries to find out whether it can be generalized to people of diverse ethnicities and cultures.

Dr. Rodin's team also is working with colleagues in Germany to develop an online version of CALM, which he said could make it available to people with more limited access to oncology and palliative care services, such as those living in rural areas.

© 2018 The National Cancer Institute

MD Anderson and Jazz Pharmaceuticals collaborate to evaluate potential treatment options for hematologic malignancies

MD Anderson Cancer Center -- August 6, 2018

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HOUSTON and DUBLIN - The University of Texas MD Anderson Cancer Center and Jazz Pharmaceuticals plc today announced a five-year collaboration agreement with a goal of evaluating therapies for multiple hematologic malignancies, including acute myeloid leukemia (AML) and myelodysplastic syndromes.

The joint effort brings together MD Anderson's translational medicine and clinical research capabilities with Jazz's hematology/oncology portfolio, including its FDA-approved medicines as well as current and potential future investigational therapies.

"This collaboration represents a significant opportunity to efficiently develop innovative therapies and therapeutic combinations," said Tapan Kadia, M.D., associate professor of Leukemia at MD Anderson. "Our aim is to always provide leading-edge care for our leukemia patients, and it is our hope that this joint effort will result in new treatment solutions."

MD Anderson and Jazz will pursue research opportunities in areas of high unmet need. The initial focus of the collaboration is to evaluate and generate additional data for Vyxeos (daunorubicin and cytarabine) liposome for injection, in new patient populations and in combination with other therapies.

"Jazz is committed to providing meaningful medicines for people with hematologic cancers, particularly those with serious unmet clinical needs," said Allen Yang, M.D., Ph.D., vice president and acting chief medical officer of Jazz Pharmaceuticals. "We look forward to collaborating with MD Anderson to help advance treatment options for patients as part of our growing hematology oncology therapeutic area."

Vyxeos received FDA approval in August 2017 for the treatment of adults with newly diagnosed therapy-related (t-AML) or AML with myelodysplasia-related changes (AML-MRC), which represents part of high-risk or secondary AML populations. AML-MRC is more common in older patients who often do not respond well to intensive chemotherapy; while t-AML can occur as a result of previous chemotherapy or radiation therapy.

About Jazz Pharmaceuticals plc

Jazz Pharmaceuticals plc (Nasdaq: JAZZ) is an international biopharmaceutical company focused on improving patients' lives by identifying, developing and commercializing meaningful products that address unmet medical needs. The company has a diverse portfolio of products and product candidates with a focus in the areas of sleep and hematology/oncology. In these areas, Jazz Pharmaceuticals markets Xyrem (sodium oxybate) oral solution, Erwinaze (asparaginase Erwinia chrysanthemi), Defitelio (defibrotide sodium) and Vyxeos (daunorubicin and cytarabine) liposome for injection in the U.S. and markets Erwinase and Defitelio (defibrotide) in countries outside the U.S. For country-specific product information, please visit www.jazzpharmaceuticals.com/products. For more information, please visit www.jazzpharmaceuticals.com and follow us on Twitter at @JazzP

© 2018 The University of Texas MD Anderson Cancer Center

Comprehensive CAR T-cell therapy pediatric guidelines developed by MD Anderson in collaboration with the Pediatric Acute Lung Injury and Sepsis Investigators network

MD Anderson Cancer Center -- August 6, 2018

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HOUSTON -- Almost one year after the U.S. Food and Drug Administration (FDA) approval of chimeric antigen receptor (CAR) T-cell therapy for children with acute lymphoblastic leukemia (ALL), researchers at The University of Texas MD Anderson Cancer Center and the Pediatric Acute Lung Injury and Sepsis Investigators Network (PALISI) today published treatment guidelines for managing the treatment in the online issue of Nature Reviews Clinical Oncology. These guidelines outline lessons learned by leading experts in various fields to identify early signs and symptoms of treatment-related toxicity and detail ways in which to manage it.

CAR T-cell therapy involves removing patient T cells, re-engineering them, and introducing them back into the body, where they attack cancer cells. The FDA approved the first CAR T-cell therapy for children and young adults with ALL last year. Ongoing research aims to expand its use for other cancers.

"CAR T-cell therapy has been associated with remarkable response rates for children and young adults with ALL, yet this innovative form of cellular immunotherapy has resulted in unique and severe toxicities which can lead to rapid cardiorespiratory and/or neurological deterioration," said Kris Mahadeo, M.D., associate professor of Pediatrics and Chief of Stem Cell Transplant and Cellular Therapy at MD Anderson. "This novel therapy requires the medical vigilance of a diverse multi-disciplinary team and associated clinical infrastructure to ensure optimal patient outcomes."

As CAR T-cell therapy becomes more widely used, treatment guidelines, comprehensive training of multi-disciplinary staff, and other measures should facilitate the appropriate management of toxicities that may occur following this new treatment, added Mahadeo.

MD Anderson's CAR T-cell-therapy-associated Toxicity (CARTOX) program collaborated with PALISI and its Hematopoietic Stem Cell Transplantation (HSCT) sub-group in creating the comprehensive guidelines for treating children with cancer receiving CAR T-cell therapy. By bringing together experts from many areas, including pediatric intensivists, pharmacy, neurology, and translational immunotherapy research, the guidelines offer key learnings to providers and aim to help improve the patient experience and outcome.

"CARTOX, which oversees care for MD Anderson CAR T-cell therapy patients, is the first stand-alone immune effector cellular therapy program to earn accreditation from the Foundation for the Accreditation of Cellular Therapy (FACT)," said Elizabeth Shpall, M.D., professor of Stem Cell Transplantation and Cellular Therapy and one of the senior authors on the Natures Reviews Clinical Oncology paper. "The program provides oversight for more than 20 active immune effector cell research protocols and two approved standard of care therapies at MD Anderson, and it is clear these new guidelines will serve as an important new model for care of CAR T-cell patients."

In 2017, MD Anderson's CARTOX Program published guidelines in Nature Reviews Clinical Oncology on management of adult patients receiving CAR T-cell therapy. However, early signs and symptoms of toxicity in children brought attention to pediatric-specific monitoring including escalation of care based on parent and caregiver concerns.

Some examples of the recommendations include:

  • Monitoring for cytokine release syndrome (CRS) using pediatric normal ranges for organ function.

  • Promptly addressing parent and/or caregiver concerns as early signs or symptoms of CRS can be subtle and best recognized by those who know the child best.

MD Anderson team members who collaborated on development of the guidelines included Elizabeth Shpall, M.D.; Katy Rezvani, M.D., Ph.D.; and Partow Kebriaei, M.D.; all of the Department of Stem Cell Transplantation and Cellular Therapy; Sattva Neelapu, M.D., of the Department of Lymphoma and Myeloma; Sajad Khazhal, M.D.; David McCall, M.D.; Demetrios Petrepolous, M.D.; Joan O'Hanlon Curry; Sarah Featherston; Jessica Fogelsong, M.D.; Lisa Hafemeister; Cathy Nguyen; Rodrigo Mejia, M.D.; and John Slopis, M.D.; all of the Division of Pediatrics; and Alison Gulbis; and Maria Mireles, Pharm.D.; of the Department of Pharmacy.

Other participating institutions included the Keck School of Medicine, University of Southern California, Los Angeles; University of Pennsylvania Perelman School of Medicine, Philadelphia; University of Washington Seattle Children's Hospital; George Washington University and Children's National, Washington D.C.; Baylor College of Medicine, Houston; Dana-Farber Cancer Institute, Harvard University, Boston; Weill Cornell Medical College Presbyterian Hospital, New York; University of Minnesota Masonic Children's Hospital, Minneapolis; Duke Children's Hospital, Duke University, Durham, N.C.; Nationwide Children's Hospital, Ohio State University, Columbus; St. Jude's Children's Research Hospital, Memphis, Tenn.; and Children's Hospital at Montefiore, Albert Einstein College of Medicine, Bronx, N.Y.

© 2018 The University of Texas MD Anderson Cancer Center

Combination of Immunotherapy Drugs Approved for Metastatic Colorectal Cancer

by NCI Staff

The National Cancer Institute -- August 3, 2018

companies img Tumor cells with DNA repair defects, including microsatellite instability, may be particularly susceptible to immune checkpoint inhibitors.

Cancer Immunol Immunother 2016. CC BY 4.0.

On July 10, the Food and Drug Administration (FDA) approved the combination of two immunotherapy drugs-ipilimumab (Yervoy) and nivolumab (Opdivo)-for the treatment of some patients with metastatic colorectal cancer who have been treated previously with standard chemotherapy drugs.

The accelerated approval covers patients 12 years of age and older whose tumors have one of two genetic features that prevent cells from repairing damaged DNA: mismatch repair deficiency (dMMR) or high microsatellite instability (MSI-H).

Tumors that have either of these genetic features tend to have high rates of DNA mutations. Some of these mutations may lead to the production of many abnormal antigens that can be targeted by immune cells.

Researchers have found that several immune checkpoint inhibitors are effective in patients with MSI-H or dMMR tumors, and this work has led to FDA approvals.

In 2017, FDA approved the checkpoint inhibitor pembrolizumab (Keytruda) for the treatment of MSI-H or dMMR tumors, regardless of where in the body the cancer started. This was the first FDA approval based solely on the presence of a genetic feature in a tumor.

The approval was a step forward for precision medicine, noted James Gulley, M.D., Ph.D., head of the immunotherapy section of NCI's Center for Cancer Research.

A few months later, FDA approved nivolumab for patients with MSI-H or dMMR metastatic colorectal cancer that has progressed after chemotherapy.

The CheckMate-142 Study

The new FDA approval was based on results from the CheckMate-142 study, which was funded by Bristol-Myers Squibb, the manufacturer of ipilimumab and nivolumab.

The clinical trial is testing nivolumab alone and in combination with other anticancer drugs, including ipilimumab, in patients with dMMR or MSI-H metastatic colorectal cancer that had progressed after treatment with fluoropyrimidine- and oxaliplatin-containing chemotherapy or fluoropyrimidine- and irinotecan-containing chemotherapy.

Among 82 patients in the trial who received the combination immunotherapy, 3 had complete responses and 35 had partial responses, for an overall response rate of 46%. In addition, 89% of the responses lasted 6 months or longer, according to FDA.

The FDA statement noted that the overall response rate among a similar group of 58 patients who received nivolumab alone was 28%, with 67% of the responders having responses that lasted 6 months or more.

The most common side effects among the patients receiving ipilimumab and nivolumab included fatigue, diarrhea, fever, musculoskeletal pain, and abdominal pain. The combination immunotherapy had a "manageable safety profile," the researchers wrote in a report on the CheckMate-142 study earlier this year.

Assessing the Various Treatment Options for Patients

Although CheckMate-142 did not include an arm testing pembrolizumab in the same patient population, Dr. Gulley noted that the response rates for both are similar (46% for the combination and 40% for pembrolizumab alone)-and higher than that for nivolumab alone (28%).

"This combination immunotherapy is an important additional option for patients," he said, noting that pembrolizumab, as a single agent, may have fewer side effects than the two-drug combination.

"We don't know if there are patients who would respond to nivolumab and ipilimumab who wouldn't respond to pembrolizumab or vice versa," Dr. Gulley continued.

He also noted that prospective studies would need to be done to see whether patients with dMMR or MSI-H metastatic colorectal cancer who didn't respond to checkpoint inhibitors, like pembrolizumab, that block the protein PD-1 would respond to the addition of checkpoint inhibitors, like ipilimumab, that target the protein CTLA-4.

© 2018 The National Cancer Institute

New Immunotherapy Option Approved for Cervical Cancer, Rare Lymphoma

by NCI Staff

The National Cancer Institute -- August 2, 2018

companies img Metastatic cervical cancer cells.

Credit: National Cancer Institute

In June, the Food and Drug Administration (FDA) further expanded the approved uses of the immunotherapy drug pembrolizumab (Keytruda). The two recent approvals cover the use of pembrolizumab for some women with advanced cervical cancer and for adults and children with relapsed or treatment-resistant primary mediastinal large B-cell lymphoma (PMBCL), a rare type of aggressive non-Hodgkin lymphoma.

Both actions by FDA were accelerated approvals, meaning further studies are needed to confirm the drug's clinical benefit in patients with these cancers.

Pembrolizumab is a type of immunotherapy called an immune checkpoint inhibitor. It works by blocking the binding of PD-1, a protein expressed on cytotoxic T cells, to the PD-L1 protein expressed on some cancer cells, an interaction that acts as a brake on the immune system and prevents T cells from attacking the cancer.

First Approval of a PD-1 Inhibitor for Cervical Cancer

On June 12, FDA approved pembrolizumab to treat women with cervical cancer that has recurred or spread (metastasized) to other parts of the body and gotten worse during or after chemotherapy. The approval makes pembrolizumab the first immune checkpoint inhibitor approved to treat cervical cancer.

Under the approval, patients' tumors must express PD-L1, as determined by an FDA-approved laboratory test. FDA simultaneously approved the PD-L1 IHC 22C3 pharmDx test (manufactured by Dako North America, Inc.), as a companion diagnostic test for women with cervical cancer.

The accelerated approval was based on results from a single cohort of 98 women with cervical cancer who were enrolled in an ongoing phase 2 clinical trial of pembrolizumab for the treatment of several cancer types. The trial, called Keynote-158, is sponsored by Merck, the drug's manufacturer.

Of the 98 women, 77 had tumors that expressed PD-L1. Two of these women had their tumors disappear completely (complete responses) and nine had their tumors shrink by 30% or more (partial responses), for an overall response rate of 14.3%. In 10 of the 11 women who responded to pembrolizumab, the responses lasted 6 months or longer, and after nearly 12 months of follow-up, the median duration of response had not been reached. None of the women with PD-L1-negative tumors responded to pembrolizumab.

Nearly 40% of the women experienced serious side effects, including anemia (7%), fistula (4%), infection (4%), or hemorrhage (4%), and 8% of the patients had to stop treatment because of them. The most common side effects included fatigue, pain, nausea and vomiting, and difficulty breathing (dyspnea).

The current standard of care for women with cervical cancer that has recurred or metastasized after previous treatment is chemotherapy in combination with bevacizumab (Avastin). FDA approved the combination regimen in 2014 based on results of an sponsored randomized phase 3 trial showing a 3.7-month improvement in median overall survival with the addition of bevacizumab to chemotherapy.

The clinical trials that led to the approvals of bevacizumab and pembrolizumab for cervical cancer that recurs or spreads and worsens during or after chemotherapy had different designs and goals, so "it's not possible to compare the two regimens given the data currently available," said Elise Kohn, M.D., Gynecologic Cancer Therapeutics Lead in NCI's Cancer Therapy Evaluation Program.

"We now have two very different approved therapeutic options for these patients," she said, "so patients should discuss the pros and cons of each regimen with their physicians before deciding on their treatment."

Dr. Kohn stressed that patients and clinicians need to weigh the risks of side effects when considering the treatment options.

"Although the patterns of toxicity are different, they are not insignificant for either option," she explained.

New Treatment Option for Rare Lymphoma

On June 13, FDA approved pembrolizumab for the treatment of adult and pediatric patients with PMBCL that is resistant to available treatments (refractory) or returned following treatment with two prior therapies.

The accelerated approval was based on results from a multicenter single-arm phase 2 trial called Keynote-170. The trial, sponsored by Merck, included 53 patients between the ages of 20 and 61 with relapsed or refractory PMBCL.

Although there were no children in the trial, "efficacy for pediatric patients with PMBCL was extrapolated from the results in the adult PMBCL population," according to a Merck news release, and safety was determined based on "a study of 40 pediatric patients with advanced melanoma, lymphoma, or PD-L1-positive advanced, relapsed, or refractory solid tumors" who were treated with pembrolizumab.

The overall response rate in the Keynote-170 trial was 45%, with 11% of patients achieving a complete response and 34% experiencing a partial response. At an average follow-up of nearly 10 months, the median duration of response had not yet been reached.

In its approval notice, FDA stated that pembrolizumab should not be used in patients who have an urgent need for surgery to reduce a PMBCL mass that may be compressing a major blood vessel or other critical structure within the mediastinum.

The most common side effects of pembrolizumab in the Keynote-170 trial included musculoskeletal pain, upper respiratory tract infection, fever, fatigue, and dyspnea. Serious side effects occurred in 26% of patients, causing 15% to interrupt therapy and 8% to discontinue treatment with pembrolizumab entirely. Twenty-five percent of patients had side effects that required treatment with corticosteroids.

"In the short follow-up thus far, there haven't been signs of increased toxicity compared to other trials of PD-1 inhibitors," said Mark Roschewski, M.D., of the Lymphoid Malignancies Branch in NCI's Center for Cancer Research. "But PMBCL patients are often young and female, so longer follow-up will be important for these patients because their lifetime risk of developing autoimmune diseases is much higher" than older patients treated with PD-1 inhibitors, he emphasized.

The distinction between patients with refractory PMBCL after first-line therapy and those who have relapsed or still have refractory disease following two previous lines of therapy is important, said Dr. Roschewski. Patients who have not been cured despite two previous lines of therapy-the patients covered by this approval-have a very poor prognosis.

"These patients need better therapies," he said. "Now that we have an approved drug in PMBCL, it opens the possibility of combination therapy studies, such as pembrolizumab and CAR T-cell therapy, for example.

© 2018 The National Cancer Institute

Melody Management

Cancer Research & APP Development

Vaccine, anti-PD1 drug show promise against incurable HPV-related cancers

Immunotherapy combination yields high response rate compared to earlier single-agent trials

The MD Anderson Cancer Center -- September 27, 2018

companies img Bonnie Glisson, M.D.

HOUSTON -- A tumor-specific vaccine combined with an immune checkpoint inhibitor shrank tumors in one third of patients with incurable cancer related to the human papilloma virus (HPV) in a phase II clinical trial led by investigators at The University of Texas MD Anderson Cancer Center and reported in JAMA Oncology.

"That encouraging response rate is about twice the rate produced by PD1 checkpoint inhibitors in previous clinical trials, so these results will lead to larger, randomized clinical trials of this combination," said principal investigator Bonnie Glisson, M.D., professor of Thoracic/Head and Neck Medical Oncology and Abell-Hanger Foundation Distinguished Professor at MD Anderson.

Vaccines specific to HPV antigens found on tumors had previously sparked a strong immune response, but had not, by themselves, been active against established cancers, Glisson said.

"Vaccines are revving up the immune system, but the immunosuppressive tumor microenvironment probably prevents them from working," Glisson said. "Our thinking was that inhibition of PD-1 would address one mechanism of immunosuppression, empowering the vaccine-activated T lymphocytes to attack the cancer."

The team combined the vaccine ISA101, which targets important peptides produced by the strongly cancer-promoting HPV16 genotype of the virus, along with nivolumab, a checkpoint inhibitor that blocks activation of PD-1 on T cells.

Of the 24 patients with recurrent HPV16-related cancers, 22 had oropharyngeal (back of the throat) cancer, one had cervical cancer and one had anal cancer.

  • Eight (33 percent) had a tumor response, two were complete. All eight had oropharyngeal cancer. Median duration of response was 10.3 months
  • Overall median survival was 17.5 months, progression-free survival was 2.7 months and 70 percent of patients survived to 12 months.
  • Five of the eight responders remain in response.
  • Develop new approaches to treat and prevent ovarian cancer

"The median survival of 17.5 months for these patients is promising and provides further support for randomized trials testing the contribution of ISA101 to PD-1 inhibition," Glisson said.

HPV causes nearly all cervical cancers, and most oropharyngeal, anal, penile, vulvar and vaginal cancers. HPV16 and HPV18 are the leading viral genotypes that increase cancer risk. Given the viral cause of these cancers, immunotherapy has been considered a strong potential approach. The researchers note that three previous clinical trials of PD1 inhibitors alone for recurrent HPV-related cancers yielded response rates ranging from 16 to 22 percent.

Two patients had grade 3 or 4 side effects -- elevated enzyme levels -- that required them to discontinue nivolumab. Glisson said the team observed side effects expected from the two treatments separately, but the researchers were encouraged to see no sign of synergistic side effects caused by the combination.

"That's important as we develop rational combination immunotherapy," Glisson said. This clinical trial was among the first to combine vaccination with PD1 inhibition.

Randomized clinical trials of the vaccine and anti-PD1 combination for cervical and oropharyngeal cancer are being organized.

The single-arm trial was an investigator-initiated effort originated at MD Anderson, Glisson noted.

This study was supported by MD Anderson's Moon Shots Program, a collaborative effort to accelerate the development of scientific discoveries into clinical advances that save patients' lives, and MD Anderson's Cancer Center Support Grant from the National Cancer Institute (P30 CA016672). Philanthropic support also was provided by Mr. and Mrs. Charles W. Stiefel and the Abell-Hanger Foundation Distinguished Professorship.

Bristol-Myers Squibb provided nivolumab and ISA Pharmaceuticals provided the ISA101 vaccine.

Co-authors with Glisson are Erminia Massarelli, M.D., of City of Hope National Medical Center, Duarte, Calif.; William, M.D., Faye Johnson, M.D., Ph.D., Merrill Kies, M.D., Renata Ferrarotto, M.D., and Hai Tran, PharmD., of MD Anderson Thoracic/Head and Neck Medical Oncology; Ming Guo, M.D., of Pathology; Lei Feng and J. Jack Lee, Ph.D., of Biostatistics; Young Uk Kim, Ph.D., and Chantale Bernatchez, Ph.D., of Melanoma Medical Oncology; Cara Haymaker, Ph.D., Tomas Zecchini Barrese, M.D., Jaime Rodriguez Canales, M.D., and Ignacio Wistuba, M.D., of Translational Molecular Pathology; Michael Curran, Ph.D., of Immunology; Lerong Li and Jing Wang, Ph.D., of Bioinformatics and Computational Biology; and Sjoerd H. van der Burg, Ph.D., and Cornelis Melief, Ph.D., of Leiden University Medical Center, Leiden, the Netherlands. Melief is also employed by ISA Pharmaceuticals.

© 2018 The MD Anderson Cancer Center

Stimulating the Immune System Shrinks Some Slow-Growing Lymphomas

by NCI Staff

The National Cancer Insitute -- September 26, 2018

companies img A treatment approach that incorporates a drug that spurs the activity of immune cells called dendritic cells, pictured above, has shown efficacy in two small clinical trials.

Credit: National Cancer Institute

In a small clinical trial, the combination of low-dose radiation and a compound that stimulates the immune system shrank tumors in most patients with slow-growing (indolent) B-cell lymphomas.

Even though the compound, called SD-101, was injected directly into a single tumor (a procedure called in situ vaccination), tumors elsewhere in the body frequently shrank as well, indicating that the immune-stimulating compound helped to induce a body-wide, or systemic, immune response.

The findings were published August 28 in Cancer Discovery.

No serious side effects were reported during the trial. Although limiting treatment-related side effects is always important, the study's lead investigator, Ronald Levy, M.D., of Stanford University, explained that it's particularly important in people with indolent lymphomas, because they usually live for years after diagnosis without their cancer progressing or causing serious symptoms. If patients are going to receive treatment before symptoms arise or any evidence of their disease progressing, Dr. Levy added, it shouldn't negatively affect their quality of life.

Christopher Melani, M.D., of NCI's Center for Cancer Research, who was not involved with the trial, noted that the trial's findings were promising. He explained that a small number of people with indolent lymphoma do go into remission spontaneously.

"But the degree of responses seen with this combination of the vaccine and radiation was much higher than would be expected by either spontaneous remission or focal radiation therapy [alone]," he added.

Instead of Watching and Waiting

Slow-growing, low-grade B-cell lymphomas can include subtypes such as follicular lymphoma, marginal zone lymphoma, and cutaneous B-cell lymphoma. No current treatments can eliminate these lymphomas entirely, explained Dr. Levy. Available treatments, including chemotherapy and targeted therapies, can only slow disease progression.

Because the available treatments can have side effects, doctors often suggest a "watch and wait" approach for people with indolent lymphoma who aren't experiencing symptoms. In this approach, treatment is delayed until symptoms worsen or imaging shows that the cancer is progressing, said Dr. Melani.

Studies have not shown that giving these therapies early, before an indolent lymphoma progresses, extends how long patients live. But "it can be hard for some patients to be diagnosed with a cancer and be told 'we're not going to do anything about it yet,'" he added.

For their trial, Dr. Levy and his colleagues enrolled 29 patients with indolent B-cell lymphomas whose tumors were being monitored but not treated. Most participants (21) had follicular lymphoma.

All participants received a low dose of radiation to their largest tumor, followed by injections of SD-101 into the same tumor once a week for 5 weeks. This process is called in situ vaccination because the injections are given directly into the tumor tissue.

SD-101 contains a synthetic version of a substance that is released by the immune system during an infection by some bacteria or viruses. When immune cells called dendritic cells detect SD-101, they undergo a maturation process and alert other immune cells to the presence of a threat.

The delivery of radiation to the tumors before SD-101 is injected destroys some of the lymphoma cells, causing them to release proteins that can be identified by the immune system (called antigens). Dendritic cells, alerted by the presence of SD-101, can take up these antigens and show them to other immune cells, which then travel through the bloodstream and identify and kill lymphoma cells elsewhere in the body.

The trial was funded by NCI and Dynavax Corporation, the manufacturer of SD-101.

Triggering an Immune Response

Because radiation alone is known to shrink low-grade lymphomas, all participants were expected to receive some benefit from the treatment, explained Dr. Levy.

As expected, the treated tumor shrank in 26 of the 29 participants. In 7 patients, the treated tumor shrank enough to be considered a partial response. One patient's tumor disappeared entirely (a complete response).

Tumors elsewhere in the body also shrank in 25 participants. People whose treated tumors shrank substantially also tended to have the strongest responses at tumors elsewhere in the body. Five of these 25 patients had a partial response, and one had a complete response.

Patients whose tumors shrank tended to have an increase in two types of immune cells involved in attacking tumor cells and a decrease in a type of cell that can suppress the immune response.

The most common side effects after the SD-101 injections were flu-like symptoms, including chills, headache, and fever, that lasted for a day or two. No serious side effects were seen. One patient discontinued treatment because of a fever and confusion, which improved quickly after treatment was stopped.

Finding the Best Combinations for Immunotherapy

These results "were tantalizing, but not yet good enough," said Dr. Levy. Only about 25% of participants had their tumors shrink substantially. "We think we can do better by adding additional immune-stimulating agents to the platform that we've established here," he continued.

Dr. Levy and his colleagues are conducting two additional early-phase trials of SD-101 in people with indolent lymphoma. One is adding the targeted therapy ibrutinib (Imbruvica) to SD-101 and radiation for patients who have already received treatment for their lymphoma. The second is testing an antibody that stimulates T cells, in addition to SD-101 and radiation, for patients who have opted for a watch-and-wait approach.

Other researchers are investigating the in situ vaccination approach in other cancer types. In another small clinical trial published alongside the lymphoma study, tumors shrank in 7 of 9 patients with advanced melanoma who received the combination of SD-101 injections and the immune checkpoint inhibitor pembrolizumab (Keytruda).

None of these patients had received pembrolizumab previously, and the response rate exceeded what is typically seen with pembrolizumab alone, the trial investigators noted. Two patients had a complete response to the combination therapy.

Other ongoing studies are also testing different immune-system stimulants-injected into tumors or given through the bloodstream-in other cancer types. "We're still trying to figure out the best [treatment] combinations for immunotherapy; it's a very active area of research," concluded Dr. Melani.

© 2018 The National Cancer Insitute

The Penn Ovarian Cancer Research Center

Penn Medicine - The University of Pennsylvania -- September 24, 2018

companies img Ron Drapkin, MD, PhD - Director

As we recognize World Cancer Research Day today, which aims to raise public awareness of the importance of cancer research, it's fitting that NCI is releasing its Fiscal Year 2020 Annual Plan and Budget Proposal on this same day.

The plan, which represents our best professional judgement on the optimum funding needed to make the most rapid progress against cancer, is prepared every year for the President and Congress to inform congressional budget planning and priority setting.

I encourage you to take a look at the plan-the first during my term as NCI director-to learn more about key scientific areas of opportunity where additional support could fuel progress and improve the outlook for people with cancer and those at increased risk.

The plan also highlights the promising results of the nation's investment in biomedical research. Of special interest are the stories of impact about several patients, our most important partners in cancer research, and two researchers whose efforts are having a tremendous impact.

This is, without a doubt, a time of great hope in cancer research. It's an honor to be part of a cancer research community whose commitment and painstaking efforts have led to groundbreaking discoveries that have resulted in steadily declining rates for most cancers and better options for more effective, less toxic therapies.

Nonetheless, our successes and optimism are paired with many challenges. Clearly, there are still too many cancers that we don't understand well enough to improve outcomes. And for some cancers for which we do have effective therapies, the side effects can be intolerable, the costs are too high for many patients, or the availability is limited.

The annual plan presents our vision to tackle these and other challenges to accelerate progress in cancer research and fulfill NCI's mission to help all people live longer, healthier lives.

This is, without a doubt, a time of great hope in cancer research. It's an honor to be part of a cancer research community whose commitment and painstaking efforts have led to groundbreaking discoveries that have resulted in steadily declining rates for most cancers and better options for more effective, less toxic therapies.

Nonetheless, our successes and optimism are paired with many challenges. Clearly, there are still too many cancers that we don't understand well enough to improve outcomes. And for some cancers for which we do have effective therapies, the side effects can be intolerable, the costs are too high for many patients, or the availability is limited.

The annual plan presents our vision to tackle these and other challenges to accelerate progress in cancer research and fulfill NCI's mission to help all people live longer, healthier lives.

companies img Research and Clinical Team

The Penn Ovarian Cancer Research Center (OCRC), established in 2007, serves as a catalyst to promote comprehensive and interdisciplinary research on ovarian cancer in collaboration with the Jordan Center for Gynecologic Cancer, the Abramson Cancer Center, the Basser Center for BRCA, the Wistar Institute, and the Penn Immunotherapy Program, as well as numerous local, national and international investigators and clinicans.

The OCRC has five major goals:

  • Develop new methods for early detection of ovarian cancer
  • Develop a comprehensive understanding of ovarian cancer pathogenesis
  • Characterize the genetic factors that drive the development of hereditary and sporadic forms of ovarian cancer
  • Develop new approaches to treat and prevent ovarian cancer
  • Support clinical trials to assess safety and efficacy of new treatments

The ultimate goal of these programs is to improve the quality of life for women with ovarian cancer and provide guidance and support to their families.

Patient care and clinical trials are conducted in the Jordan Center for Gynecologic Cancer on the 3rd floor (west) in the Perelman Center for Advanced Medicine. Our translational and basic research program is located in the Smilow Center for Translational Research, immediately adjacent to the Perelman Center, and the Biomedical Research Building. These state of the art facilities encourage our "bench to bedside" approach to ovarian cancer and support our multidisciplinary approach to patient care and research.

To learn more about our program, our team and ovarian cancer, click on the links below:

Research and Clinical Team

Research Team

  • Robert A. Burger, MD
  • Ron Drapkin, MD, PhD - Director
  • Andrea Facciabene, PhD
  • Carl H. June, MD
  • Lana Kandalaft, PharmD, PhD
  • Chunseng Li, PhD
  • Mark A. Morgan, MD
  • Daniel J. Powell, Jr., PhD
  • Fiona Simpkins, MD
  • Janos Tanyi, MD, PhD
  • Wei-Ting Hwang, PhD
  • Lin Zhang, MD

Clinical Research Team

  • Andrew Best
  • Vijaya Dandamudi
  • Euihye Jung
  • Jessica Marchesi
  • Sureya Sufian
  • Qunrui Ye, PhD

© 2018 The Trustees of the University of Pennsylvania

Poziotinib maintains high response rate against harmful lung cancer mutation

MD Anderson clinical trial tests drug against exon 20 EGFR- and HER2-positive cancer

The MD Anderson Cancer Center -- September 24, 2018

companies img John Heymach, M.D., Ph.D.

HOUSTON -- A drug revived by researchers at The University of Texas MD Anderson Cancer Center continues to provide unprecedented response rates among stage 4 non-small cell lung cancer patients with genetic mutations that have previously defied treatment.

Early results from a phase 2 clinical trial, reported today at the IASLC 19th World Conference on Lung Cancer hosted by the International Association for the Study of Lung Cancer, show 24 of 44 patients (55 percent) with exon 20 mutations in the epidermal growth factor receptor (EGFR) and six of 12 patients (50 percent) with exon 20 mutations in the human epidermal growth factor receptor (HER2) had their tumors shrink at eight weeks after treatment with poziotinib.

"These findings confirm earlier observations that poziotinib is highly active against this previously untargetable mutation and durable responses are observed, with some patients on treatment now for more than a year," said principal investigator John Heymach, M.D., Ph.D., professor and chair of Thoracic/Head and Neck Medical Oncology.

Nineteen patients remain on treatment, six for more than a year. All responses so far are partial responses.

Previous early results had been reported for 11 EGFR patients. Heymach's presentation is the first to include HER2 patients. Researchers estimate exon 20 EGFR mutations occur in about 1-2 percent of non-small cell lung cancer patients and HER2 exon 20 variations occur in about 3 percent.

The MD Anderson investigator-initiated clinical trial provides the largest data set among exon 20 lung cancer patients worldwide. Spectrum Pharmaceuticals, which makes poziotinib, has opened a multi-center phase II trial.

Response rates of exon 20 patients to other targeted therapies aimed at EGFR and HER2 have been 12 percent or less, the researchers note. There are no approved therapies for these patients.

  • Median progression free survival on the EGFR arm of the poziotinib trial was 5.5 months. It has not been reached in the HER2 arm.
  • In the EGFR cohort, 56 percent of patients had a side effect of grade 3 or higher, most commonly skin rash (34.9 percent), diarrhea (17.5 percent) and inflammation around the fingernails and toenails called paronychia (9.5 percent); one patient stopped treatment due to grade 3 skin rash and 60 percent had dose reductions. Side effects in HER2 cohort were similar. One death from pneumonitis in the HER2 cohort was considered to be possibly drug-related.

MD Anderson Lung Cancer Moon Shot resurrects poziotinib

Heymach's team decided to focus on exon 20 patients while selecting projects for MD Anderson's Moon Shots Program, a collaborative effort to accelerate the development of scientific discoveries into life-saving advances. Review of a patient database found exon 20 patients had a median progression-free survival of just two months.

In a series of cell line and mouse model experiments, combined with structural modeling of both EGFR and HER2 mutations and available drugs to target them, the researchers found that poziotinib's structure made it a good fit for exon 20-mutated disease, even though it had largely failed against other mutations. The tighter target pocket on EGFR and HER2 tumors with exon 20 mutations also explained why other targeted therapies had been unable to bind with and inhibit the proteins.

Heymach and colleagues contacted Spectrum Pharmaceuticals and collaborated to launch the first phase II trial at MD Anderson in 2017.

Heymach, Jacqulyne Robichaux, Ph.D., postdoctoral fellow, Shuxing Zhang, PHARMD, Ph.D., associate professor of Experimental Therapeutics, and colleagues published their results this year in Nature Medicine.

The MD Anderson team continues to study resistance mechanisms to poziotinib and work with colleagues to study exon 20 insertions in other types of cancer. They have identified about 20 other cancer types that include exon 20 EGFR or HER2 mutations and plan a basket clinical trial of poziotinib against other cancers.

Spectrum and MD Anderson signed a licensing agreement covering MD Anderson discoveries about poziotinib earlier this year.

© 2018 The MD Anderson Cancer Center

Hope and Challenge: The NCI Annual Plan and Budget Proposal for Fiscal Year 2020

by Norman E. Sharpless, M.D.

The National Cancer Institute -- September 24, 2018

companies img The FY 2020 Annual Plan and Budget Proposal includes several stories about patients, including Mike (right), a former patient of Dr. Sharpless.

Credit: National Cancer Institute

As we recognize World Cancer Research Day today, which aims to raise public awareness of the importance of cancer research, it's fitting that NCI is releasing its Fiscal Year 2020 Annual Plan and Budget Proposal on this same day.

The plan, which represents our best professional judgement on the optimum funding needed to make the most rapid progress against cancer, is prepared every year for the President and Congress to inform congressional budget planning and priority setting.

I encourage you to take a look at the plan-the first during my term as NCI director-to learn more about key scientific areas of opportunity where additional support could fuel progress and improve the outlook for people with cancer and those at increased risk.

The plan also highlights the promising results of the nation's investment in biomedical research. Of special interest are the stories of impact about several patients, our most important partners in cancer research, and two researchers whose efforts are having a tremendous impact.

This is, without a doubt, a time of great hope in cancer research. It's an honor to be part of a cancer research community whose commitment and painstaking efforts have led to groundbreaking discoveries that have resulted in steadily declining rates for most cancers and better options for more effective, less toxic therapies.

Nonetheless, our successes and optimism are paired with many challenges. Clearly, there are still too many cancers that we don't understand well enough to improve outcomes. And for some cancers for which we do have effective therapies, the side effects can be intolerable, the costs are too high for many patients, or the availability is limited.

The annual plan presents our vision to tackle these and other challenges to accelerate progress in cancer research and fulfill NCI's mission to help all people live longer, healthier lives.

© 2018 The National Cancer Insitute

Heart Problems: Investigating the Cardiac Side Effects of Cancer Treatments

by NCI Staff

The National Cancer Institute -- September 21, 2018

companies img

Credit: National Cancer Institute

In June, approximately 100 researchers attended a workshop on the campus of the National Institutes of Health (NIH) in Bethesda, MD, about an important but underappreciated side effect of some treatments for cancer: heart problems.

Certain cancer treatments can damage the heart and the cardiovascular system. These side effects, including high blood pressure, abnormal heart rhythms, and heart failure, can be caused or exacerbated by chemotherapy and radiation therapy, as well as by newer forms of cancer treatment, such as targeted therapies and immunotherapies.

"Cancer therapies affect a number of organs and organ systems, including the heart," said Saro Armenian, D.O., M.P.H., at the meeting. Dr. Armenian, who treats children with cancer at City of Hope Comprehensive Cancer Center, noted that when a patient develops cardiac side effects during treatment, a doctor may modify the dose of a therapy or stop the therapy altogether.

Some cardiac side effects, however, go undetected for years or even decades after a patient's treatment has ended. "Patients diagnosed with cancer are living longer today than in the past, and many of these survivors are living long enough to develop late cardiovascular effects," said Lori Minasian, M.D., deputy director of NCI's Division of Cancer Prevention, in an interview.

In recent years, Dr. Minasian continued, researchers have begun systematically to document the longer-term cardiovascular side effects of cancer treatments, also known as cardiotoxicities.

At the workshop on improving outcomes in treatment-related cardiotoxicity, participants from government, academia, and the private sector identified gaps in current knowledge and discussed priorities for future research. NCI and the National Heart, Lung, and Blood Institute (NHLBI) cosponsored the meeting.

Investigating a Range of Treatment-Related Cardiac Side Effects

companies img Heart tissue from a patient treated with an immune checkpoint inhibitor showing T cells (blue dots) invading muscle fibers in the heart.

Credit: Dr. Javid Moslehi, Vanderbilt University

The workshop highlighted a challenge for the field, which is known as cardio-oncology: identifying and investigating cardiac side effects that are associated with a rapidly changing landscape of cancer treatments and combinations of therapies.

For example, as more and more immunotherapies have entered the clinic in recent years, researchers have begun to detect specific cardiac side effects that can occur during treatment with some of these agents.

A recent study showed that a small percentage of patients who receive immunotherapy drugs called immune checkpoint inhibitor develop inflammation of the heart muscle known as myocarditis. In this study, about half of the patients who developed severe myocarditis died of it.

"In a small but significant number of patients, there is a fatal outcome from immune checkpoint inhibitors that is directly related to the heart," said Javid Moslehi, M.D., who directs the Cardio-Oncology Program at Vanderbilt-Ingram Cancer Center and led the study. (Other studies have estimated that the incidence of myocarditis in patients receiving checkpoint inhibitors is around 1%.)

While research on myocarditis from checkpoint inhibitors has "created a buzz," many other cancer therapies can cause cardiovascular adverse events, he noted.

"We're not paying enough attention to the other forms of cardiovascular toxicities from cancer drugs beyond doxorubicin," Dr. Moslehi continued, referring to the commonly used chemotherapy drug that has been the focus of much cardiotoxicity research over the past decade. "We need to have a broader perspective."

Susan Dent, M.D., who codirects Cardio-Oncology at Duke University, agreed. Doctors and patients, she noted, need information about the potential cardiac side effects of cancer drugs when these agents enter the clinic.

"We don't want to wait until a decade has passed and then design a study to learn about the cardiotoxicities associated with a cancer drug," she said.

    Sharing Stories of Patients Who Died Prematurely

    To illustrate the serious nature of cardiotoxicities and to put a human face on the issue, several speakers at the workshop shared the stories of individuals who died prematurely of heart problems related to cancer therapies, including Ellen Stovall.

    A prominent advocate for cancer survivors who served on an NCI advisory board, Stovall had been treated for three different cancers over many years. Some of the therapies led to chronic health problems, and about 2 years ago, at the age of 69, Stovall died suddenly. The cause of her death was complications of cardiovascular disease related to her cancer treatments.

    Another example discussed at the meeting was a woman who developed heart disease related to treatments for multiple cancers that led to emergency triple-bypass surgery. She died at age 47.

    "We cannot cure patients of one cancer, only to have them develop a second cancer and treatment-related cardiac problems that result in a triple bypass" before age 50, Dr. Dent commented.

Studies Needed to Inform Clinical Decisions

More research is also needed to help inform clinical decisions about cancer treatments and cardiac side effects. "Oncologists and cardiologists want to be able to implement evidence-based guidelines for patient care, but more studies are needed," said Dr. Minasian.

Chau Dang, M.D., a medical oncologist at Memorial Sloan Kettering Cancer Center, summarized the critical questions as "who, when, and how." That is, who should be monitored for cardiovascular problems, when should they be monitored, and how should they be monitored?

The workshop included discussions of biomarkers of cardiac or cardiovascular damage, such as troponin, which is a complex of proteins that is released when heart muscle is damaged. These biomarkers were developed for patients with heart disease rather than for patients with cancer who may experience treatment-induced cardiac side effects.

As a result, it's not clear whether biomarkers of cardiovascular damage could be used to assess the risk of cardiac side effects or to monitor cardiovascular health in patients being treated for cancer or in long-term survivors. "We don't know if the patterns of injury from anti-cancer drugs are the same as the patterns of injury of de novo heart disease," said Dr. Minasian.

Nonetheless, several speakers emphasized the need to establish the usefulness of biomarkers for assessing whether patients are experiencing cardiovascular damage from cancer therapies and how such biomarkers should be used, particularly given the existence of other tests, such as imaging tests.

"Right now, it's not clear which combinations of biomarker and imaging tests should be used for which patients and when," said Dr. Dent.

Understanding How Cancer Therapies Harm the Cardiovascular System

Aarti Asnani, M.D., a cardiologist in the Cardio-Oncology Program at Beth Israel Deaconess Medical Center, said in an interview, "What we have now are broad and relatively nonspecific biomarkers of cardiac injury."

She noted that developing new biomarkers will require "a deeper understanding of the mechanisms of cardiotoxicity as well as larger randomized clinical trials for validation."

At the workshop, several participants also stressed the importance of learning more about how cancer treatments may harm the cardiovascular system. This information could be used to develop much-needed research tools, such as better ways to predict which patients are at risk of developing cardiac side effects as well as strategies for reducing this risk, Dr. Dent noted.

"Each cancer drug causes different cardiovascular issues through different mechanisms," said Dr. Moslehi. "To move forward, we need to know the nature of the cardiovascular toxicity."

Large clinical trials that follow patients over time would allow researchers to gain insights into how and when longer-term cardiac side effects develop, Dr. Armenian noted.

One Example: Cardiac Side Effects and Breast Cancer

companies img Researchers are using zebrafish to study how the cancer drug doxorubicin affects the heart. Normal fish (left) and a fish that developed cardiomyopathy after treatment with doxorubicin (right).

Credit: Dr. Aarti Asnani, Beth Israel Deaconess Medical Center

Over the past decade, breast cancer has been a focus of research on cardiac side effects, in part because certain treatments for the disease are known to cause these side effects.

Based on this evidence, the American Heart Association recently issued a rare scientific statement on cardiovascular disease and breast cancer. For some breast cancer survivors-older individuals in particular-the risk of dying from cardiovascular disease may exceed the risk of dying from cancer, the authors of the statement noted.

Dawn L. Hershman, M.D., who studies breast cancer at the Herbert Irving Comprehensive Cancer Center at Columbia University Medical Center, agreed. "The reality is we've made a huge amount of progress in treating breast cancer, and today women diagnosed with early-stage breast cancer are more likely to die of cardiac disease than of cancer," she said in an interview.

Although some breast cancer treatments, such as HER2-targeted therapies, doxorubicin, and radiation therapy, are known to cause cardiac side effects, other factors can affect a patient's cardiovascular health as well, Dr. Hershman pointed out.

"A big part of the problem is that cardiac and vascular risk factors are not always well managed in patients with cancer," she explained. "When a woman is diagnosed with breast cancer, her adherence to treatments for other health conditions often goes down, such as the management of cholesterol or keeping diabetes under control."

The dual risks of cancer and heart disease in cancer survivors have created a challenge for both oncologists and cardiologists, noted Dr. Minasian. "The question is, can we manage the risk of both diseases to help people live healthy and productive lives?" she said.

The goal, she explained, is to understand a patient's risk of cardiovascular disease when cancer is diagnosed and then to manage that risk throughout the treatment for cancer and beyond. If a patient already has cardiovascular disease, then the disease would be managed along with the cancer, Dr. Minasian added.

Increasing Awareness of Cardiac Side Effects

With an aging US population and continued advances being made in cancer care, some researchers warned that cardiotoxicities are likely to become a larger concern in the coming decades.

Yet, several speakers noted that many of their colleagues in cardiology and oncology were generally unfamiliar with the cardiac side effects of cancer treatments.

"We need to engage all members of the health care team, including doctors, pharmacists, and nurses, to convey the importance of cardiovascular health in cancer survivors," said Dr. Dent

Patients and survivors need to be informed as well, added Dr. Minasian, noting that collaboration among researchers will be critical to making progress against cardiotoxicities. "We need cardiologists and oncologists to work together to answer basic questions about cardiotoxicities that neither group could answer working alone," she said.

    Surgeons Help Patients Get the Treatments They Need

    Some hospitals and cancer centers have developed multidisciplinary teams to facilitate the treatment of patients with cancer while mitigating the risk of cardiac side effects.

    At the University of Texas MD Anderson Cancer Center, for example, Cezar A. Iliescu, M.D., is part of a new field known as interventional cardio-oncology. These physicians and researchers specialize in complex procedures that allow patients who have both cancer and heart disease to receive the cancer treatments they need.

    "We're able to do any cardiovascular procedure that patients with cancer-including frail patients-need, irrespective of their comorbidities," said Dr. Iliescu. "We can say with strong confidence that the patient will not die from cardiovascular disease."

    The MD Anderson researchers have been publishing their results, including a review of the clinical management of acute coronary syndrome in patients with cancer.

    "There are not a lot of data out there on how to manage the care of these types of patients, so we want to share our experience," said Dr. Iliescu. "This is a very interesting and dynamic field."

© 2018 The National Cancer Insitute

NCI and FDA Address Common Concerns: A Win-Win for Making Progress against Cancer

by Norman E. Sharpless, M.D.

The National Cancer Institute -- September 17, 2018

companies img NCI and FDA are sponsoring a challenge to spur the development of methods that use proteomic and other "omics" data to accurately detect and correct mislabeled tumor and tissue samples.

Credit: National Cancer Institute

I am a big believer in strategic partnerships as a key step toward making advances against cancer. That's one of the reasons why I am particularly excited about NCI's latest collaborative effort with the Food and Drug Administration (FDA): the Multi-omics Enabled Sample Mislabeling and Correction Challenge.

This challenge is launched in coordination with DREAM Challenges, a community of researchers from a variety of organizations who crowdsource solutions to fundamental biomedical questions. This challenge invites participants to propose solutions that address a serious and long-standing problem in the analysis of human samples: namely, the mislabeling of tissue samples caused by human error.

In the research setting, sample mislabeling can result in irreproducible study findings or invalid study conclusions. In the clinic, it can lead to patients potentially getting the wrong treatments, which could have severe consequences. Mislabeling errors are becoming more prevalent because large-scale studies of the molecular characteristics that drive cancers, which rely on tumor and tissue samples, are highly complex and have multiple points during which mislabeling errors can occur.

The goal of the challenge, which launches at the end of September, is to encourage the development of innovative algorithmic solutions that rely on "-omics" (for example, genomic and proteomic) datasets to accurately detect and correct mislabeled samples. (More information on the challenge is available in this commentary published September 7 in Nature Medicine).

This challenge, just the most recent example of FDA and NCI's long history of successful collaborations, demonstrates how government agencies with shared concerns can leverage expertise and resources to expedite progress and benefit patients.

Our agencies are continuing that tradition of strong and strategic partnerships, expanding these into the research and regulatory realms with the goal of spurring more rapid progress. I'd like to share a few more examples of successful FDA-NCI collaborations that show the tangible benefits of working together in diverse areas.

Partnering on Workforce Training and Development

Building a competitive, diverse, and innovative research workforce for the decades ahead is one of NCI's most important responsibilities. NCI and FDA have long recognized that progress requires investing in a sustainable pipeline of highly qualified scientists who understand research, medicine, and the regulatory process.

Over the past dozen years, FDA and NCI have participated in a joint initiative called the Interagency Oncology Task Force (IOTF) fellowship program.

The goal of the IOTF program, which also includes NIH and HHS as partners, is to develop a cadre of scientists with a skill set that bridges research and regulatory science.

IOTF fellows gain expertise in the regulatory requirements for developing new cancer therapies and related devices so that they can properly evaluate their efficacy, safety, quality, and performance. They also learn strategies to improve planning for the various steps throughout the research and regulatory review process, which covers rules concerned with the development, testing, approval, manufacturing, quality control, and marketing of drugs and devices.

The fellows emerge from the IOTF program equipped with the skills to more quickly and efficiently move new drugs and devices from the bench to the bedside.

Since the launch of IOTF in 2005, the program has supported 55 fellows, all of whom went on to jobs at FDA, NIH, or industry. Of the 37 fellows who went to FDA, 15 are now in leadership roles.

Collaborating to Modernize Assessment of Safety and Tolerability of Treatments

companies img NCI Director Dr. Norman E. Sharpless

Credit: National Institutes of Health

As any oncologist can tell you, treatment-related side effects not only can harm patients' quality of life, but they can also keep patients from completing their treatment. We owe it to patients to do a better job of understanding how new therapies affect the quality of their life beyond measures of tumor size or how long they live without their tumors growing.

For years, clinicians and investigators have used the Common Terminology Criteria for Adverse Events (CTCAE) to help document their assessments of how patients in clinical trials are tolerating therapy. To better capture the patient perspective, NCI developed the complementary Patient Reported Outcomes (PRO) version of the CTCAE (PRO-CTCAE). NCI and FDA's Oncology Center of Excellence (OCE) are participating in working groups to further explore the use of PRO-CTCAE in cancer drug development.

Building on this work, NCI and the FDA are also investigating the development of tools that objectively measure clinical outcomes such as pain, cognitive function, quality of life, and other indicators of patients' tolerability of therapy. Recently developed tools include biometric sensors and computer vision and voice recognition technologies. Such tools are able to capture the experience of all patients, not just those who are able to respond to questionnaires, and will ultimately provide a more comprehensive picture of the side effects of cancer treatments.

Accelerating Childhood Cancer Drug Development

In August 2017, Congress passed the FDA Reauthorization Act (FDARA), which included several provisions from a previously introduced bill known as the Research to Accelerate Cures and Equity (RACE) for Children Act.

These provisions, which were incorporated into FDARA as Section 504, Development of drugs and biological products for pediatric cancers, amend current requirements for pediatric studies so that they are based on relevant molecular targets rather than cancer site of origin. NCI collaborates with FDA to implement Section 504.

Prior to this law going into effect, investigators would be required to develop pediatric study plans for a therapy only if it was indicated for the same type of cancer that the drug was being evaluated for in adults. However, as NCI-supported research has shown, some molecular targets are shared between these cancers and pediatric cancers. Going forward, Section 504 mandates that shared molecular targets will drive the development of study plans, rather than cancer type.

FDARA requires FDA, in consultation with NCI, to develop and maintain a list of relevant molecular targets to inform the development and review of pediatric study plans. To meet this requirement, FDA's OCE and NCI convened public meetings of the childhood cancer community to help develop the list of molecular targets. NCI also issued a Request for Information to collect additional input on potential molecular targets.

FDA published the list of targets last month, and NCI will continue to collaborate with FDA to keep the list up-to-date. Additionally, several NCI programs, including the Pediatric Early Phase Clinical Trials Network and Pediatric Preclinical Testing Consortium, continue to conduct research that will inform the list of molecular targets.

Working Hand in Hand to Reduce Tobacco Use

Smoking rates in the United States have dropped substantially over the past several decades, thanks to the implementation of policies and programs-many of which are based on NCI-supported research-at the local, state, and federal levels. But, with nearly 40 million Americans still smoking cigarettes, tobacco use is an ongoing challenge. Public health agencies must do more.

Both NCI and FDA's Center for Tobacco Products have long been committed to reducing tobacco use in the United States and globally, and tobacco use reduction is an area of close collaboration.

NCI has funded innovative research on the interplay between nicotine content and smoking behavior since the 1980s and has built a robust scientific evidence base to help better understand how modifying nicotine content in cigarettes could impact smoking behavior. This research provided part of the scientific foundation for FDA's estimate that reducing nicotine in cigarettes to nonaddictive or minimally addictive levels could potentially decrease the smoking rate from 15% to 1.4% of adults. In addition, current smokers could more easily quit and millions of youth would never start smoking.

Based on these estimates, last year, FDA Commissioner Scott Gottlieb announced FDA's intent to pursue regulatory action to reduce nicotine in cigarettes to nonaddictive or minimally addictive levels.

Tackling the problem of tobacco use also means we must consider the factors that contribute to its use, including the proliferation of new tobacco products such as e-cigarettes, which are now the most commonly used tobacco product among middle and high school students. Moreover, studies have suggested that teens who use e-cigarettes are more likely to go on to smoke conventional cigarettes.

In response to these findings, FDA has made new efforts to prevent tobacco product use among teens, including the launch last year of a Youth Tobacco Prevention Plan that includes an emphasis on e-cigarettes. Research supported by NCI's Tobacco Control Research Branch has provided and will continue to provide an evidence base for FDA's activities in this area.

Many Opportunities Ahead

I've highlighted just a few areas in which FDA and NCI are currently collaborating, but our shared concerns on a number of public health issues open up many opportunities on which we can and do work together.

I've always believed that a multipronged, multidisciplinary team approach is the best way to accelerate progress in public health, and I think our collaborations have demonstrated that. I plan to have ongoing discussions with FDA about other partnerships and cultivating more opportunities to advance cancer research and care.

Related Resources

FDA Approvals - Cancer Currents Blog

Partners and Collaborators

© 2018 The National Cancer Insitute

Moxetumomab Approved by FDA for Hairy Cell Leukemia

The National Cancer Institute -- September 14, 2018

companies img Moxetumomab pasudotox (Moxe) binds CD22 receptors on the surface of cancerous B cells, where it is internalized and processed to release its toxic payload.

Credit: National Cancer Institute

The Food and Drug Administration (FDA) has approved moxetumomab pasudotox (Lumoxiti), a bacterial toxin-based drug, for the treatment of some patients with hairy cell leukemia (HCL). The approval covers the use of moxetumomab in patients with HCL who have already undergone at least two lines of standard treatments.

The action by FDA makes moxetumomab the first treatment approved for this group of patients. The approval was based on the findings from an 80-patient clinical trial sponsored by the drug's manufacturer, MedImmune.

In the trial, approximately 30% of patients had a complete disappearance of their cancer (complete response) that lasted for a long period, and side effects from the therapy were few and mostly minor. Overall, 75% of patients in the trial had either a partial response or complete response.

Moxetumomab was originally discovered by Ira Pastan, M.D., and colleagues in NCI's Center for Cancer Research (CCR), and later licensed to MedImmune/AstraZeneca for clinical development.

"This is an important example of conceptually innovative research conducted at NCI that has come to practical fruition with a commercial partner," said CCR Director Tom Misteli, Ph.D. "It's the kind of work made possible by our ability at NCI to pursue long-term, high-risk research, including on rare forms of cancers such as hairy cell leukemia. Moxetumomab will make a difference in the lives of patients with this incurable disease."

Many people diagnosed with HCL will achieve remission with current treatments, explained the trial's lead investigator, Robert Kreitman, M.D., of CCR's Laboratory of Molecular Biology.

"But about 30%-40% of those patients will relapse 5 to 10 years after their first treatment," Dr. Kreitman continued.

As patients receive further treatments, although they may go into remission again, the length of those remissions gets shorter and shorter, and the toxicities of the treatments accumulate, he explained. For these patients, few effective treatments exist, which is what makes this new approval so important.

"Moxetumomab represents a promising nonchemotherapeutic treatment for HCL, addressing an unmet medical need for patients," Dr. Kreitman said.

Moxetumomab includes a special boxed warning for clinicians and patients about the risk of capillary leak syndrome, in which fluid and proteins leak out of tiny blood vessels into surrounding tissues.

Further details on moxetumomab and the clinical trial on which FDA's approval was based are available in this June 2018 Cancer Currents post.

© 2018 The National Cancer Insitute

Appendix Cancers Are Genetically Distinct from Other Gastrointestinal Cancers, Study Shows

The National Cancer Institute -- September 12, 2018

companies img The appendix is located at the end of the large intestine.

Credit: National Cancer Institute

The largest-ever study of DNA changes in cancer of the appendix shows that this rare cancer is distinct from colorectal cancer and other cancers of the gastrointestinal (GI) system. Moreover, the study authors reported that specific genetic mutations found in the tumors may help predict whether they are likely to be aggressive.

When cancer of the appendix cannot be removed completely with surgery, the standard treatment is to give patients the same chemotherapy regimens used to treat colorectal cancer.

But recent studies analyzing the molecular characteristics of appendiceal cancers have suggested that approaching them as if they are the same as other GI cancers may be a mistake. The new study confirms that appendix cancer is "very different from colon cancer," said John Paul Shen, M.D., one of the leaders of the study and a postdoctoral fellow at the University of California, San Diego (UCSD).

"It stands to reason," Dr. Shen continued, "that we should develop treatments specifically for appendix cancer, rather than give these patients chemotherapy that was tested on colon cancer patients."

The study was published online on August 8 in JCO Precision Oncology.

One Tumor Is Not Like the Other

The new study analyzed the DNA sequences of more than 300 cancer-associated genes in appendix tumor tissue from 703 patients using a test developed by the company Foundation Medicine. Last November, the Food and Drug Administration approved the Foundation Medicine gene panel as one of the first comprehensive genome-profiling tests for tumors.

The frequency of mutations in important cancer genes clearly differed in the appendiceal cancers compared with colorectal and pancreatic cancers analyzed in earlier studies, Dr. Shen and his colleagues reported. For example, the TP53 and APC genes were far less likely to be mutated in appendiceal cancers than in colorectal cancer.

Mutation frequencies also differed among appendiceal cancer subtypes (as defined by their appearance, or histopathology). For example, mutations in the KRAS gene were common in adenocarcinomas, which begin in the lining of the appendix, but were much less frequent in a subtype known as goblet cell carcinoids.

Mutation Profiles Associated with Prognosis

One of the most striking findings was the difference in prognosis for patients whose tumors had mutations in the GNAS gene compared with patients whose tumors had mutations in the TP53 gene.

In a group of 76 patients who were treated at UCSD, those with GNAS mutations had a life expectancy of 10 years after diagnosis, whereas patients with TP53 mutations had a life expectancy of 3 years. Patients whose tumors had neither mutation had a life expectancy of 6 years.

Dr. Shen said he doesn't expect this data to change clinical practice yet, but added, "Given that so much of the time as an oncologist you have so little data to guide you, especially for a rare tumor, I think any data is helpful."

Carmen Allegra, M.D., head of GI Cancer Therapeutics in NCI's Cancer Therapy Evaluation Program, commented that it is "of great value to have this sort of information" for a cancer that is relatively rare and not well understood. This kind of work can drive more research and the search for "specific and better" treatments, Dr. Allegra said.

To develop more effective treatments for appendiceal cancer, Dr. Shen suggested that researchers may need to begin classifying these cancers by molecular type, rather than considering all appendix tumors as a single cancer type or a type of colorectal cancer.

The addition of molecular typing may also serve as way to simplify tumor classification, Dr. Shen said. A 2017 study showed that pathologists give conflicting classifications for appendix cancer tumors nearly 30% of the time.

Anirban Maitra, M.B.B.S., a professor of pathology specializing in pancreatic cancer at The University of Texas MD Anderson Cancer Center, agreed that "it is absolutely critical that a tumor is, first and foremost, correctly classified." He added that while "histopathology still remains the gold standard," molecular typing is complementary and is increasingly helping provide "more refined subtyping."

Ramifications and Future Directions

While the study provides evidence that analyzing fewer than 10 genes can be very informative in classifying an appendiceal tumor, the study didn't unearth "actionable mutations," or mutations in genes for which targeted drugs are already available, both Drs. Shen and Maitra pointed out.

However, a small proportion of patients' tumors had an alteration known as microsatellite instability high (MSI-H), which can cause tumors to develop many genetic mutations. Pembrolizumab (Keytruda) has been approved by the Food and Drug Administration for the treatment of patients with MSI-H tumors, regardless of their cancer type, and Dr. Shen suggested that this treatment option should be considered for people with appendix cancers whose tumors are MSI-H.

The study raises other prospects for further investigation. For example, Dr. Shen would like to know whether surgical removal alone is enough to cure appendiceal cancers with GNAS mutations. Dr. Shen also noted that more work is needed to address how best to treat advanced appendix cancers with TP53 mutations, which he said should be studied separately from other tumors.

Researchers are beginning to develop cell line models of different appendiceal cancer subtypes based on their molecular profiles, Dr. Shen said, so they can begin testing therapies that might work best against each subtype.

© 2018 The National Cancer Insitute

Integrating Geriatric Assessment into Cancer Care: A Conversation with Dr. Supriya Mohile

The National Cancer Institute -- September 11, 2018

companies img Credit: iStock

    More than 60% of patients with cancer are age 65 and over. Despite the relatively high prevalence of cancer in older adults, there is a gap in knowledge about the safest and most effective cancer treatments for patients in this age group.

    In this interview, Supriya G. Mohile, M.D., who directs the Geriatric Oncology Research Program at the University of Rochester's James Wilmot Cancer Institute, discusses the unique issues experienced by older adults with cancer and the recent publication of guidelines on incorporating geriatric assessment into patient care.

What unique challenges do older people with cancer face?

Most cancer patients in the United States are older than 65. Older patients also have the highest mortality from cancer. Nevertheless, there has not been as much of a focus on effectively managing their care as there should be. So, these patients face a lot of challenges.

First, there is a lack of safety and efficacy data on treating older patients, because they are typically not well represented in clinical trials. For example, oncology is moving toward targeted therapies, and these treatments tend to have different side effects than traditional chemotherapy. Some of these side effects, such as cardiotoxicity, can be more dangerous for many older adults with cancer. This creates problems when treating older patients, because there just isn't enough data to support the safety of many of these new treatments in older patients, especially those age 75 and over.

Second, older patients tend to have other medical problems in addition to their cancer-not just other health conditions, or comorbidities, but also disabilities, including cognitive, physical, and functional disabilities.

Disabilities are important to outcomes because they are associated with increased toxicity from treatment and early mortality. And many oncologists, surgeons, and primary care doctors who care for older adults aren't sufficiently trained in assessing disability and how a disability may affect the efficacy and safety of a particular cancer treatment.

Third is access to care, especially for those older patients who are frail or have difficulty getting to appointments. Older patients also often have difficulty with care coordination, managing their medicine, or even their ability to be safe at home during treatment.

What is unique about the caregiver experience of older cancer patients?

Caregivers are often the patient's children who are working, or spouses who are also older with their own medical issues. These factors can make care management even more complex.

In an ongoing clinical trial-funded by NCI's Community Oncology Research Program (NCORP) and the Patient-Centered Outcomes Research Institute (PCORI)-that is testing incorporating geriatric assessments into clinical practice, we're also enrolling patients' caregivers. Most are spouses and many also have comorbidities and high levels of distress, which we found to be common among caregivers of this age group. In fact, caregivers often report more distress than the patients themselves.

We also found that the caregivers rarely tell doctors that they are overwhelmed because they really take pride in caring for their loved one. Oncologists must often read between the lines to see how stressed caregivers are. It can be helpful for clinicians to ask the caregivers, "how are you doing?" or "how can we help you?" when they suspect the patient's medical status is weighing heavily on them.

Unfortunately, we don't have many caregiver interventions we can offer. The few in existence, such as cognitive behavioral therapy, are often not paid for by insurance. Caregivers, especially those of older patients with cancer, have a lot of unmet needs and through this trial we hope we can begin to identify possible solutions.

What is a geriatric assessment? What's being done to encourage more physicians to use them?

The geriatric assessment helps providers collect information about comorbidities and disabilities that are not otherwise captured in routine oncological care. It's intended to assist with the prediction of toxicity from treatments and their impact on outcomes for older adults.

Robust data now support geriatric assessment in the care delivery for older patients with cancer. In fact, the Practical Assessment and Management of Vulnerabilities in Older Patients Receiving Chemotherapy Guidelines from the American Society of Clinical Oncology (ASCO) recommend performing a geriatric assessment for every older adult with cancer receiving chemotherapy.

However, there is a lot of work still to be done with how the geriatric assessment is implemented in clinical practice. One is informing policy, including working with ASCO to develop these new guidelines. The second is to better integrate geriatric assessment into standard oncology practice.

In our NCORP and PCORI-funded trial and a similar trial, we have found that oncology teams can effectively perform this assessment and that it's feasible to do so in everyday practice. We are also trying to encourage oncology practices to incorporate a geriatric assessment into electronic medical records to make it even more seamless in practice.

companies img Supriya G. Mohile, M.D. James Wilmot Cancer Institute University of Rochester

What is the SOCARE Clinic at Wilmot?

The Specialized Oncology Care and Research for the Elderly, or SOCARE, is one of the first multi-disciplinary geriatric cancer clinics in the United States. I helped start SOCARE at the University of Rochester to provide direct geriatric assessment consultations. These consultations can be with primary care physicians or oncologists or others who have older patients with cancer and want us to help identify risks and communicate treatment options to the patient.

We started the clinic in 2011 in collaboration with the University of Chicago, which also opened a parallel clinic led by Dr. William Dale. All data from these clinics are collected and assembled in a registry, which allows us to look at things like treatment challenges, barriers, and outcomes from more than 1,000 patients.

The Rochester clinic now has four geriatric oncology faculty and an active fellowship program; it also includes input from a dietician, occupational therapist, physical therapist, social worker, and others. Collectively, the team makes recommendations-guided by the geriatric assessment-for the doctors, patients, and caregivers who request our help.

There are not currently enough clinics and groups like SOCARE throughout the country, which is why it is so important for all oncologists to be trained in using the geriatric assessment.

What is a toxicity prediction tool and how is it used?

Two chemotherapy prediction models are included in the ASCO guidelines, and we recommend that at least one of these models is used during decision making for chemotherapy for older patients with cancer.

The Cancer and Aging Research Group's (CARG) toxicity tool consists of 12 very simple questions, half of which address clinical variables routinely captured in oncology care and half of which address variables captured in the geriatric assessment. This tool creates a score that estimates the chemotherapy toxicity for the patient. It is intended to help guide discussions and show patients data that demonstrates their risk of toxicity in a way that they can easily understand.

The other tool is the Chemotherapy Risk-Assessment Scale for High-Age Patients (CRASH) score, which is more like a geriatric assessment, so it takes longer. Both are available on the web.

As a standard approach in our SOCARE clinic, we do one of these toxicity risk calculations for every patient being considered for chemotherapy treatment.

What efforts are underway to encourage more oncologists to specialize in geriatric oncology?

Geriatrics is actually one of the fastest growing fields of medicine in the United States in general, so there is already increasing interest. Geriatric oncology does require a different kind of training, which includes an American Board of Internal Medicine accredited geriatric oncology fellowship. The number of people being trained now is growing because they know this field is important and is becoming much more popular at meetings like ASCO and others.

I still don't think there are going to be enough geriatric oncologists to meet the future demand. So what needs to happen next is to integrate geriatric training throughout all oncology fellowships, so that every oncologist coming out of their fellowships know the importance of appropriate care management for older adults and how to do geriatric assessment.

© 2018 The National Cancer Insitute

MD Anderson immunotherapy expert Sharma wins Coley Award

The MD Anderson Cancer Center -- September 11, 2018

companies img Padmanee Sharma, M.D., Ph.D.

HOUSTON -- Padmanee Sharma, M.D., Ph.D., professor of Genitourinary Medical Oncology and Immunology at The University of Texas MD Anderson Cancer Center, has been recognized for her innovative work understanding factors that enhance and hinder cancer immunotherapy. Sharma will receive the William B. Coley Award for Distinguished Research in Tumor Immunology, awarded annually by the Cancer Research Institute (CRI), at an annual meeting co-sponsored by CRI in New York Sept. 30 to Oct. 3.

"CRI has played an inspiring and central role in advancing cancer immunotherapy, so I'm honored and excited to earn this recognition," says Sharma. "Immune checkpoint therapy has improved survival and provided durable clinical responses for thousands of advanced-stage patients with different cancer types, yet there's more for us to learn in order to increase the number of patients who benefit from this novel treatment."

Immune checkpoint drugs enable T cells, the soldiers of the immune system, to work better by blocking inhibitory proteins on T cells that normally act to limit T cell responses.

"Science-driven efforts led by Dr. Sharma and recognized by CRI are crucial for identifying mechanisms of response and resistance to immune checkpoint inhibitors so we can develop rational combination therapy strategies to further enhance anti-tumor immune responses for the benefit of patients," said Giulio Draetta, M.D., Ph.D., interim Chief Science Officer at MD Anderson. "Dr. Sharma's research, excellent patient care, and leadership have been vital in establishing MD Anderson's essential role in advancing cancer immunotherapy."

For Sharma, the key to understanding the dynamics between immune response, tumors and their surrounding environment has been in-depth longitudinal analyses of patients' tumors prior to and after treatment with immune checkpoint therapy.

CRI notes Sharma's pioneering use of immune checkpoint therapy, such as anti-CTLA-4 therapy, before surgery to evaluate the immunologic impact of these drugs on the tumor microenvironment. Two such clinical trials led by Sharma - in bladder and prostate cancer - established the vital role of the immune-stimulating ICOS molecular pathway promoting tumor destruction after anti-CTLA-4 checkpoint therapy. These findings opened ICOS stimulation as a potential target for immunotherapy.

Pre-surgical trials also helped determine the safety profile of immune checkpoint inhibitors in combination with surgery, a treatment strategy under development in a number of cancers for earlier-stage disease.

Sharma is scientific director of MD Anderson's immunotherapy platform, which supports biopsy-based analysis before, during and after immunotherapy treatment in more than 100 clinical trials.

"That's the basis for the translational research platform, to make sure we evaluate human immune responses in patients treated with immunotherapy agents, which helps us to understand the biological mechanisms at work, not just the clinical endpoints," she says.

One recent project led Sharma and colleagues to successfully propose a checkpoint blockade combination clinical trial for prostate cancer - a disease that has resisted immunotherapy.

Sharma also continues preclinical research to identify and characterize other molecules that act as checkpoints or immune stimulators. As a clinician, Sharma has led clinical trials that helped advance immune checkpoint blockade to U.S. Food and Drug Administration approval for advanced bladder and kidney cancer.

Coley Award honorees receive a $5,000 prize and a gold medallion bearing the likeness of Coley. Sharma will deliver the William B. Coley Lecture on Sept. 30 during this year's CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference (CICON).

The Cancer Research Institute (CRI), established in 1953, is the world's leading nonprofit organization dedicated exclusively to transforming cancer patient care by advancing scientific efforts to develop new and effective immune system-based strategies to prevent, diagnose, treat, and eventually cure all cancers. The Coley award was established in 1975 in honor of Dr. William B. Coley, a pioneer of cancer immunotherapy, whose daughter, Helen Coley Nauts, founded CRI.

© 2018 The University of Texas MD Anderson Cancer Center

Study links BAP1 protein to tumor suppression in kidney, eye, bile duct and mesothelioma cancers

The MD Anderson Cancer Center -- September 10, 2018

companies img Boyi Gan, Ph.D.

HOUSTON -- Researchers at The University of Texas MD Anderson Cancer Center have shown how BRCA-associated protein 1 (BAP1) serves as a tumor suppressor gene in kidney, eye, bile duct, mesothelioma and other cancers by regulating a form of cell death called ferroptosis, opening up a potential new area of therapy research. Findings from the study, led by Boyi Gan, Ph.D., associate professor, Department of Experimental Radiation Oncology, were published in the Sept. 10 online issue of Nature Cell Biology.

"Although BAP1 is frequently mutated or deleted in a variety of cancers, the process by which it suppresses tumors remains unclear," said Gan. "Our study achieved a comprehensive identification of BAP1-regulated target genes and relevant biological processes in cancer cells, and identified a BAP1-mediated epigenetic mechanism linking ferroptosis to tumor suppression."

Ferroptosis is a recently identified form of regulated cell death caused by depletion of cystine, an amino acid vital to cancer cell growth and survival, and by overproduction of molecular carriers of oxygen known as reactive oxygen species (ROS) on lipids, which have been linked to cancer and are targets of some therapies.

"Ferroptosis is structurally, genetically and biochemically distinct from other forms of regulated cell death such as apopotosis," said Gan. "It is well established that cell death, most notably apoptosis, plays important roles in tumor suppression. The roles of and regulatory mechanisms of ferroptosis in tumor biology, however, still remain largely unexplored."

Gan's team described how BAP1 encodes a key enzyme which interacts with other enzymes and cellular components to regulate genes, resulting in tumor suppression via ferroptosis. The researchers found that treatment with a ROS inducer resulted in substantially more ferropotosis-related cell death in BAP1 cancer cells than in other similar cancer cells which do not express BAP1. They also discovered that BAP1 promotes ferroptosis by mediating repression of a cystine 'transporter' called SLC7A11.

"We showed that BAP1 inhibits tumor development partly through SLC7A11 and ferroptosis and that cancer-associated BAP1 mutants lose their abilities to repress SLC7A11 and to promote ferroptosis," said Gan. "Together, our results uncover a previously unappreciated mechanism coupling ferroptosis to tumor suppression."

MD Anderson study team participants included: Yilei Zhang, Ph.D.; Xiaoguang Liu, Ph.D.; Zihua Gong, M.D., Ph.D.; Pranavi Koppula, Kapil Sirohi, Ph.D.; Xu Li, Ph.D.; Hyemin Lee, Ph.D.; Li Zhuang; Zhen-Dong Xiao, Ph.D.; and Junjie Chen, Ph.D., all of the Department of Experimental Radiation Oncology; Li Feng, Gang Chen, Ph.D., and Peng Huang, M.D., Ph.D., of the Department of Translational Molecular Biology; and Yongkun Wei, Ph.D., Mien-Chie Hung, Ph.D., of the Department of Molecular and Cellular Oncology.

Other participating institutions included: Baylor College of Medicine, Houston; Cleveland Clinic; China Medical University, Taichung, Taiwan; Westlake University, Hangzhou, China; and Sun Yat-Sen University, Guangzhou, China.

The study was funded by the National Institutes of Health (R01 CA181196, R01HG007538, R01CA193466, R01CA172724, and P30CA016672); the Cancer Prevention and Research Institute of Texas (RP170067); the Sister Institute Network Fund and Institutional Research Grant, MD Anderson; the Andrew Sabin Family Fellow Award; and the Ellison Medical Foundation New Scholar Award.

© 2018 The University of Texas MD Anderson Cancer Center

Exosomes May Help Tumors Evade Immune System

by NCI Staff

The National Cancer Institute -- September 7, 2018

companies img A transmission electron micrograph of a cancerous B cell that has secreted exosomes.

Credit: BMC Biology 2016. https://doi.org/10.1186/s12915-016-0268-z. CC BY 4.0.

A new study has identified what may be an important and previously unknown route by which tumors evade the immune system: They secrete small membrane-encased sacs, called exosomes, that are studded with a protein that dials down the immune response.

The study, led by researchers at the University of Pennsylvania, found that in lab models of the skin cancer melanoma and in humans with the disease, tumor cells release exosomes coated with proteins called PD-L1. These proteins are part of a family of immune checkpoint proteins that bind to partner molecules on immune cells, effectively deactivating them.

The researchers likened the PD-L1-studded exosomes to a fleet of drones engaged in preemptive strikes, moving throughout the body to thwart an antitumor attack before immune cells-namely those known as cytotoxic T cells-ever have a chance to reach the tumor.

Findings from the study, published August 8 in Nature, also raise the possibility that measuring levels of PD-L1 on exosomes in patient blood samples could help to guide treatment decisions, said study co-leader Xiaowei Xu, M.D., Ph.D.

Although the study's findings are provocative, it's still too early to know to what extent exosomes carrying PD-L1 influence the immune response against tumors in people with melanoma, said Suzanne Topalian, M.D., associate director of the Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins University.

"There are still many, many questions" to address before reaching that conclusion, said Dr. Topalian, who was not involved in the study. And the study also raises other questions, she added.

Among them, she said: "What other types of immune-modulating molecules might be on the surface of these exosomes?"

Following the Evidence Trail

For many years, scientists thought exosomes served strictly as molecular garbage trucks, transporting waste out of cells. But it's become clear that extracellular vesicles like exosomes influence a variety of biological processes, said Jennifer Jones, M.D., Ph.D., of NCI's Center for Cancer Research.

Researchers have known for some time that "exosomes have important roles in cancer and in the immune system," Dr. Jones said. "But it has been difficult to know which exosomes do what."

The volume of each exosome is one million times smaller than the volume of a typical cell, she continued, and "most of the tools of modern biomedical research are not suitable for precise and functional analyses of the cargo within individual exosomes."

Based on some earlier studies that found PD-L1 in blood samples and different types of vesicles released by cancer and other cells, the Penn team used a broad approach to look more closely at PD-L1 in these cellular outcasts to see if they influence the immune system's interaction with tumors.

On the Surface of Tumor Cells and Exosomes

Melanoma is known for eliciting a particularly strong immune response, and several immune checkpoint inhibitors have been approved by the Food and Drug Administration to treat melanoma. So the researchers began by evaluating different melanoma cell lines.

Right away they were surprised by what they found, Dr. Xu said.

Exosomes released from melanoma cells did contain PD-L1, they confirmed. Moreover, the exosomes from metastatic melanoma cells contained far more PD-L1 than cells from an initial, or primary, melanoma tumor.

The surprise came when they used electron microscopy to get a detailed view of the exosomes. The PD-L1 proteins were not inside the exosomes. Rather, the proteins were carried on their surface, with the binding portion of the protein protruding outside the surface-just as it does on tumor cells.

"That got us really excited, because if that's the case, that means the exosomal PD-L1 can directly interact with T cells," said Dr. Xu.

Further experiments confirmed that possibility. The team showed that the exosomes could bind to cytotoxic T cells-the immune cells most involved in directly killing cancer cells-and prevent them from proliferating and killing cancer cells.

When they moved their work to mouse models of melanoma, the research team also found exosomes studded with PD-L1 on their surface. Using a mouse model of melanoma that more closely mimics human cancer, injecting the mice with exosomes with PD-L1 on their surface made the tumors grow faster and reduced the accumulation of T cells and other immune cells in and around tumors.

A Treatment Biomarker?

The research team next looked at blood samples collected from people who had been treated for melanoma, and again they saw exosomes coated with PD-L1. They also found extracellular vesicles, most commonly exosomes, carrying PD-L1 in blood samples collected from people who had been treated for breast and lung cancers.

Their work raised an interesting possibility: that levels of PD-L1 on exosomes could be used to potentially identify patients who are most likely to respond to checkpoint inhibitors or to track their response to these drugs, Dr. Xu said.

For example, they analyzed blood samples from people who had been treated for melanoma with the checkpoint inhibitor pembrolizumab (Keytruda), which blocks PD-1, the immune cell binding partner of PD-L1. Patients whose tumors responded best to the drug had much lower exosomal PD-L1 levels before treatment than those who did not respond. And patients with the highest pretreatment levels of exosomal PD-L1 had worse outcomes than those with lower levels.

Exosomal PD-L1 levels measured after treatment began, however, told a different story. Patients who had large increases anywhere from 3-6 weeks after beginning treatment were much more likely to have reductions in the size of their tumors than those who had smaller increases.

Although the findings appear to be contradictory, they make biological sense, Dr. Xu said.

"It means there are two different processes going on," he explained.

Before treatment, the exosomal PD-L1 levels likely reflect the size of the tumor or extent of the disease. Meaning, if the circulating PD-L1 is high, there's a lot of tumor, which is associated with a poor prognosis.

After treatment with pembrolizumab, he said, "the rapid increase of exosomal PD-L1 [in treatment responders] means that the T cells are being activated, so they secrete more cytokines like IFN-gamma," he said. Cytokines are signaling molecules that can stimulate the immune system.

In melanoma cell lines, in fact, the researchers showed that treating the cells with IFN-gamma increased exosomal PD-L1. And in their analysis of patient samples, they found that exosomal PD-L1 levels tended to rise and fall with IFN-gamma levels.

More Work to Do

The Penn team has "identified one important exosome population among a tremendously diverse repertoire of exosome populations that influence biological processes," Dr. Jones said. "New tools and new approaches are needed to study these very small packages in more precise detail."

Dr. Topalian stressed that further studies are needed, including those that involve a much larger number of samples from patients with melanoma-and more cancer types-and those that closely compare PD-L1 in tumor biopsies and tumor-released exosomes.

For example, work by Dr. Topalian's lab and others has shown that only about 40% of human melanomas contain tumor cells expressing substantial levels of PD-L1 on their surface. Future studies, she said, should look to see if there is a correlation between the amount of PD-L1 in tumors and on exosomes from the same patient.

Also, the idea that there is a large amount of exosomal PD-L1 in the circulation of people with melanoma would imply that it's having "a global effect on suppressing immunity" in those patients, she said. "And there's no evidence that most patients with stage IV melanoma are globally immune suppressed."

© 2018 The National Cancer Institute

Two Drugs Work Together to Block 'Master Regulator' of Breast, Other Cancers

by NCI Staff

The National Cancer Institute -- September 4, 2018

companies img A computer model shows how arsenic (red and yellow spheres) interacts with and inhibits the activity of the Pin1 protein (red, white, and blue). Nature Communications Aug 2018 doi: 10.1038/s41467-018-05402-2. CC BY 4.0

A two-drug combination commonly used to treat a type of leukemia blocks an enzyme that has a central role in breast and many other cancers, a new study has found.

The drug combination, arsenic trioxide (Trisenox) and tretinoin (also known as retinoic acid), has essentially turned acute promyelocytic leukemia (APL) from a fatal disease into a curable one. But the mechanism by which it kills cancer cells has been a mystery.

In an earlier study, Kun Ping Lu, M.D., Ph.D., and Xiao Zhen Zhou, M.D., of Beth Israel Deaconess Medical Center, in Boston, and their colleagues found that retinoic acid inhibits the key enzyme, Pin1. Now, they've found that arsenic also blocks Pin1, and the combination of the two drugs inhibits the enzyme more effectively than either drug alone.

Pin1 is considered a cancer master regulator-a protein that regulates entire cellular networks that are critical to cancer progression. Some scientists consider master regulators ideal drug targets.

The findings are "an interesting launching pad for further investigation," said Joanna Watson, Ph.D., of NCI's Division of Cancer Biology, which helped fund the study.

The combination treatment slowed the growth of several different laboratory models of breast cancer, the researchers reported. Their findings, published August 9 in Nature Communications, provide the rationale to test the drug combination in a clinical trial of women with breast cancer, said Dr. Lu.

Pin1: An Ideal Drug Target

Pin1 switches the shape of the amino acid proline within proteins. This conformation change can activate 40 proteins that promote tumor growth and inactivate more than 20 proteins that suppress tumor growth.

Pin1 is overactive in many different types of cancer, including breast, lung, prostate, and colon cancer. It is also found at higher than normal levels in breast cancer stem cells-specialized cancer cells that are thought to be responsible for tumor initiation, growth, metastasis, and drug resistance.

On the other hand, mice that lack Pin1 are protected from developing cancer even in the presence of cancer-causing mutations in other genes.

Because arsenic is often combined with retinoic acid to treat APL, the researchers wanted to know if arsenic also targets Pin1. But rather than studying APL, they focused on triple-negative breast cancer because this aggressive disease has a poor prognosis and is not effectively treated with targeted therapies.

Arsenic and Retinoic Acid Work Together

First, the researchers found that arsenic inhibited Pin1 activity, which in turn slowed the growth of triple-negative breast cancer cells. They then showed that arsenic needed to bind to Pin1 to impede breast cancer cell growth. Interacting with arsenic makes Pin1 unstable, explained Dr. Lu, and as a result, the protein is destroyed.

Arsenic also lowered Pin1 levels and slowed the growth of breast cancer xenograft tumors in mice.

Next, the researchers examined the effects of combining arsenic and retinoic acid in cell and mouse models of triple-negative breast cancer.

Treating cells or mice with arsenic or retinoic acid alone lowered Pin1 levels and slowed cell growth. But the combination of the two drugs had an even greater effect. The combination also prevented Pin1 from altering the levels of certain proteins that control cancer growth, producing effects that are similar to those of inactivating the Pin1 gene in breast cancer cells.

The combination showed synergy, meaning that the resulting effect "is above and beyond what you would expect by just adding the two [drugs] together," explained Dr. Watson.

Synergy may reflect the fact that, in APL cells, retinoic acid treatment raises the level of a transporter that brings arsenic inside of cells. Levels of the transporter also increased when Dr. Lu and his colleagues treated triple-negative breast cancer cells with retinoic acid. By contrast, arsenic and retinoic acid did not act synergistically in triple-negative breast cancer cells engineered to lack this transporter.

These results suggest that, in addition to inhibiting Pin1 directly, retinoic acid increases the amount of arsenic in cells by boosting the level of this transporter, Dr. Lu explained. The arsenic then further inhibits Pin1.

He added, this also implies that when used in combination with retinoic acid, a lower concentration of arsenic could achieve the desired effect-potentially reducing the side effects of arsenic, which is extremely toxic at high doses.

Targeting Breast Cancer Stem Cells

Developing drugs that effectively target cancer stem cells has proven to be a challenge, and cancer stem cells that remain after treatment are thought to be a cause of cancer relapse and metastasis.

Dr. Lu's team found that, to a greater extent than either drug alone, the combination of arsenic and retinoic acid eliminated triple-negative breast cancer stem cells. The effects of the combination treatment were similar to those of inactivating the Pin1 gene in breast cancer cells, they found.

The researchers also found that the combination of arsenic and retinoic acid eliminated cancer stem cells that were resistant to chemotherapy, and it eliminated cancer stem cells in mouse models of triple negative breast cancer.

New Insights and Potential New Therapy

It had long been thought that arsenic's main target was a fusion protein that is found only in APL, and there were doubts that the drug would be effective against other types of cancer, despite some evidence of activity. In their earlier study, Drs. Lu and Zhou and their colleagues found that retinoic acid targets this fusion protein by inhibiting Pin1.

"Identifying Pin1 as the major target of arsenic will hopefully stimulate clinical trials for other [types of] cancer," Dr. Lu said.

The researchers hope to develop a clinical trial to combine arsenic with the standard therapy for women with triple-negative breast cancer. And because their findings show that arsenic's activity depends on the expression of Pin1 and its transporter, Dr. Lu said they want to select patients whose cancers express both proteins.

As for retinoic acid, it is normally broken down quickly inside the human body. To enhance its ability to reach solid tumors, the team is interested in developing a more stable form of retinoic acid. If such a form can be created, it could potentially be combined with arsenic in clinical trials, Dr. Lu said.

Another advantage of having learned one mechanism of arsenic's anticancer activity, said Dr. Watson, is being able to develop new drugs that potentially target Pin1 more efficiently and with fewer side effects than arsenic itself. The research team is also working to develop a targeted drug that blocks Pin1 activity.

Dr. Lu noted that because Pin1 controls multiple pathways that contribute to cancer development, cancer cells might be less able to develop resistance to drugs that block Pin1's activity-something that often occurs with targeted therapies that attack a single pathway.

© 2018 The National Cancer Institute

Melody Management

Cancer Research & APP Development

MD Anderson slates third annual Boot Walk to End Cancer

Cancer survivors, MD Anderson supporters prepare to give cancer the boot on Saturday, Nov. 10

MD Anderson Cancer Center -- October 25, 2018

companies img

HOUSTON -- Thanks to a grassroots campaign at Houston-area Walmart stores and generous support from individuals, teams and other corporate sponsors, fundraising already has generated more than $1.6 million as The University of Texas MD Anderson Cancer Center makes final preparations for the Boot Walk to End Cancer. Check-in for the third annual noncompetitive walk will open at 11 a.m. Saturday, Nov. 10. The 1.2-mile walk starts at 1 p.m., beginning and ending at Bertner Avenue and East Road. Free parking will be available at MD Anderson's Mid Campus Garage, 7007 Bertner Ave. Free ADA parking will be available in the Armory Lot at 1902 Old Spanish Trail.

There's still time to start or join a team and be a part of the festivities with co-chairs Ashley and Lance Loeffler.

"MD Anderson holds a special place in our hearts," said Ashley Loeffler. "We're grateful to give back to a place that gives so much to so many."

Participants are encouraged, but not required, to wear their favorite boots to symbolize giving cancer "the boot." Registration (www.mdanderson.org/bootwalk) is free and open to all ages. Participants who raise at least $100 will earn a commemorative T-shirt, available for pick-up on event day or the week before the event. Strollers and baby joggers are allowed on the route. Participants are asked to leave pets at home, though service animals are welcome.

Event day will feature a festive finish line party, with live music, food trucks, face painting, balloon artists, lawn games, a Topgolf simulation booth, photo ops and more. Justin Stapleton, KPRC-TV meteorologist, will emcee the event, and Sarah Pepper of Mix 96.5 and George Lindsey of 100.3 The Bull will be on hand to cheer participants across the finish line.

"The Boot Walk is a wonderful opportunity to bring together all of us who have been touched by cancer," said Peter WT Pisters, M.D., president of MD Anderson. "It's incredible to see the community coming together to support our efforts in Making Cancer History."

Sponsors include LyondellBasell (Presenting); PepsiCo (Diamond); Walmart (Gold); Boot Barn, IBC Bank and MustangCAT (Silver); and The Houston Livestock Show and Rodeo, Regina Rogers and Topgolf (Bronze). In-kind media sponsors are Outfront Media, Univision, Modern Luxury, Texas Monthly, Lifestyles & Homes Magazines, Texas Tribune and Pandora. Media partners are Houstonia, KPRC, 100.3 The Bull and Mix 96.5.

Since the Boot Walk's inception in 2016, more than 1,000 teams and 11,000 cancer survivors, caregivers, MD Anderson staff and supporters have raised approximately $2 million to support critical patient care and research programs.

To learn more or to volunteer to help out on event day, visit www.mdanderson.org/bootwalk.

© 2018 The University of Texas MD Anderson Cancer Center

Studying "Total Diet" and Its Impact on Health, Including Cancer Risk

by Jill Reedy, Ph.D., M.P.H., R.D.

The National Cancer Institute -- October 25, 2018

companies img Credit: iStock

Does what we eat and drink affect our risk of developing cancer?

Many studies have asked this question, but answering it is challenging. Foods and beverages, as well as the nutrients and dietary constituents they contain, are consumed together, never in isolation of one another.

To account for this, and to improve the quality of research related to the connection between diet and disease, the research community is shifting how we look at the health impact of diet, and how we assess diet and cancer risk. We're taking a more holistic approach and looking at dietary patterns versus individual foods or nutrients across the lifespan, and we are developing tools that can incorporate dietary patterns to reflect this shift.

In other words, we're interested in assessing what eating broccoli or a cheeseburger means for your health-but in the context of a larger dietary pattern and overall diet quality that includes the what, where, when, why, and how we eat.

Expanding the Approach to Diet Research

Research on diet and cancer risk has often taken a reductionist approach, focusing on specific dietary components. That approach, however, assumes that a food or nutrient alone, without consideration of other accompanying foods or nutrients, can induce a specific biological effect that can fuel the formation and growth of cancer cells.

But there are limitations-and unanticipated findings-when only using this approach. For example, in the late 1980s, the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study was initiated after some studies found that diets high in certain vitamins were associated with a reduced risk of lung cancer. However, taking these vitamins as pills (and not packaged in foods) did not reduce the incidence of lung cancer among smokers, and may actually have caused some harm.

These apparently paradoxical findings might be explained by recognizing that nutrient and food consumption is closely connected, making it difficult to examine associations between any one dietary factor and chronic disease. Dramatically increasing intake of one nutrient by taking a supplement could have unanticipated effects, such as decreasing the absorption or circulating concentrations of other beneficial nutrients.

There are also likely interactive or synergistic effects among foods and nutrients, such that the totality of diet may have cumulative effects. This may be one of the reasons the NIH-funded Dietary Approaches to Stop Hypertension study, a clinical trial that examined the effect of changing an overall dietary pattern rather than a single food or nutrient, showed positive health outcomes.

By looking at total diet quality, we can try to fit the different puzzle pieces together. We can look beyond a certain food or nutrient and learn how that food was consumed and what other issues might be at play, such as the timing of meals and circadian rhythms. NCI is already funding research investigating these and other factors that can define a total diet.

How NCI is Working to Improve Dietary Patterns Research

companies img Jill Reedy, Ph.D., M.P.H., R.D., Program Director, Risk Factor Assessment Branch, NCI Division of Cancer Control & Population Sciences.

Every 5 years, the US Department of Agriculture (USDA) and NCI collaborate to update a dietary tool called the Healthy Eating Index (HEI). This tool is used to assess how closely an eating pattern, or any set of foods in the food supply chain, aligns with the most recent Dietary Guidelines for Americans.

The HEI has been applied by researchers to describe diet quality among the US population. It has also been used to evaluate the quality of foods you'd find in different environments: for example, in a fast food restaurant, a federal food distribution program, a food bank, or a school cafeteria.

The most recent Dietary Guidelines (for 2015-2020) reflect this shift toward focusing on total diet. For example, the guidelines now stress an overarching approach to diet, such as following a healthy eating pattern across the lifespan; eating a variety of foods, with a focus on nutrient density and amount; and limiting calories from added sugars and saturated fats and reducing sodium intake.

Our most recent updates to the HEI, described in three articles in the Journal of the Academy of Nutrition and Dietetics, also reflect this emphasis on total diet.

The fact that tools like the HEI can now be applied to any set of foods in the food supply chain is important because large segments of the population don't have access to, or can't afford, healthy food. If we assess how well a set of foods-for example, those provided by a food bank-align with dietary guidance focused on total diet, we can then work toward improving that set of foods to minimize the risk of cancer and other health conditions.

In an editorial accompanying our articles on the HEI, Barbara Millen, Dr.P.H., R.D., chair of the 2015 Dietary Guidelines Advisory Committee, wrote that "the evidence base is stronger than ever before linking the total diet-its dietary patterns, nutrient density, and overall quality-to health promotion and disease prevention across the human life span."

We agree with Dr. Millen that the updated HEI is a "powerful tool to assess total diet quality" and hope other researchers will use the HEI and other evidence-based tools that fully embrace this total diet approach.

And the time is ripe for this shift. There is a growing interest in online platforms and apps for diet and physical activity monitoring that may be integrated with assessment tools like the HEI, providing opportunities for new research, tools, and technologies that eventually will help in the design of tailored nutrition interventions at the individual and community levels.

To assist in measuring dietary patterns, for example, NCI has supported the development of a freely available dietary assessment tool, the Automated Self-Administered 24-Hour Dietary Assessment Tool (ASA24), which enables research participants to report what they've consumed within the last 24 hours or in real time as a food record. This tool provides information that previous tools don't, such as when food was eaten, where, and with what other foods and beverages.

It's been exciting to see the field of diet and cancer research expand, and we'll continue to improve methods to incorporate this new approach of looking at the total diet. Our biggest hope is that research like this can better guide efforts to understand how and what we eat affects health, and in turn inform policies and practices that reduce risk and improve health for everyone.

© 2018 The National Cancer Institute

Suppression of DKK3 protein thwarts pancreatic tumor progression and prolongs survival

Antibody that blocks DKK3 developed by MD Anderson researchers in mouse study

MD Anderson Cancer Center -- October 24, 2018

companies img Rosa Hwang, M.D.

HOUSTON -- Researchers at The University of Texas MD Anderson Cancer Center have shed new light on why pancreatic tumors are so resistant to therapy. The answer may lie in treating a protein found in the scar-type tissue called stroma which often surrounds the tumors.

The tumor-associated stroma is comprised mostly of pancreatic stellate cells (PSCs) and its density and possibly the cells themselves are thought to prevent current treatments from effectively killing the tumor. Dickkopf-3 (DKK3), is produced by the stromal cells but acts on the neighboring cancer cells to increase their growth, metastasis and resistance to therapy. DKK3 has been identified as a potential target for treatment with a newly developed DKK3-blocking antibody, according to results from a study led by Rosa Hwang, M.D., professor in Surgical Oncology and Breast Surgical Oncology. Findings are published in the Oct. 24 online issue of Science Translational Medicine.

Hwang's lab found DKK3 to be highly expressed in pancreatic ductal adenocarcinoma (PDAC), the most common type of pancreatic cancer, and specifically by PSCs rather than cancer cells, and her team discovered different ways to silence DKK3 from acting on cancer cells as well as immune cells in the tumor microenvironment. The researchers developed an antibody to block the DKK3 molecule in mice, which not only inhibited tumor growth but also significantly prolonged life.

"Pancreatic cancer has a dismal prognosis and it is unclear if its stromal infiltrate contributes to its aggressiveness. We demonstrated that DKK3 is produced by PSCs and is present in the majority of human pancreatic cancer," said Hwang. "DKK3 stimulates cancer growth, metastasis, and resistance to chemotherapy and immunotherapy. Targeting DKK3 in a pancreatic cancer mouse model boosted immune cell infiltration and more than doubled survival."

DKK3 expression and effects on pancreatic cancer

Hwang's team examined DKK3 expression in human pancreatic tumors and found that at least two-thirds of patients had moderate-to-very strong levels of DKK3. Compared to normal controls, DKK3 levels were 4.5 times higher in PDAC.

Due to DKK3's dual effects in promotion of tumor growth and in resistance to therapy, Hwang's results indicate that DKK3 is a therapeutic target as either monotherapy or in combination with immunotherapy or chemotherapy.

"Previous efforts to target pancreatic cancer stroma were directed at broadly eliminating stromal elements," she said. "Our study shows that a more effective strategy may be to inhibit specific tumor-promoting mechanisms attributed to PSCs, such as DKK3."

MD Anderson research team members included Liran Zhou, Ph.D.; Hongmei Husted, Ph.D.; Todd Moore, B.S.; Mason Lu, M.D., Ph.D.; and Jeffrey Lee, M.D., all of the Department of Surgical Oncology; Defeng Deng, Ph.D.; Yan Liu, M.D.; Vijaya Ramachandran, Ph.D.; Thirudvengadam Arumugam, Ph.D.; and Craig Logsdon, Ph.D., of the Department of Cancer Biology; Huamin Wang, M.D. and Anirban Maitra, M.B.B.S., of the Department of Pathology; Paul Chiao, Ph.D.; Jianhua Ling, Ph.D.; and Mien-Chie Hung, Ph.D., of the Department of Molecular and Cellular Oncology; and Michael Curran, Ph.D. of the Department of Immunology. The German Cancer Research Center, Heidelberg, Germany, also participated in the study.

The study was funded by the National Institutes of Health (5K08CA138912-5 and P30CA016672); an American Cancer Society Institutional Research grant; the Lustgarten Foundation; and MD Anderson Knowledge Gap Seed Funding.

© 2018 The University of Texas MD Anderson Cancer Center

Study Improves the Quality of Biopsy Specimens for Cancer Research

by NCI Staff

The National Cancer Institute -- October 23, 2018

companies img Tumor biopsies collected for research often don't have enough of the tumor tissue. These two biopsy samples from the same patient have very different amounts of tumor tissue (green boxes). Reprinted with permission J Oncol Pract. 2018 Oct 4:JOP1800092.

Credit: National Cancer Institute

Researchers have developed recommendations for improving the quality of biopsy specimens collected from patients participating in cancer clinical trials. Tumor biopsy samples can provide valuable information to researchers, such as insights into how cancer therapies behave in the human body.

The recommendations provide practical suggestions for the leaders of clinical trials, such as ensuring that the interventional radiologists who collect the study biopsy specimens are given clear information about the study's goals and tissue requirements. Interventional radiologists use ultrasound, CT scans, and MRI to identify locations in tumors from which they extract tissue.

Other recommendations include increasing the amount of biological material collected for research and ensuring that patients who are enrolled in a clinical trial that has a requirement for a research biopsy have tissue that is amenable to biopsy.

The recommendations, which appeared in the Journal of Oncology Practice on October 4, were based on an analysis of research biopsies conducted by a multidisciplinary team of experts.

    Main Recommendations to Improve the Quality of Research Biopsy Specimens in Cance Clinical Trials

  • Include interventional radiologists, who perform the research biopsies, on the research team.
  • Facilitate communication among all members of the biopsy team to establish the research needs and time points during the trial to assess and discuss success rates and research outcomes.
  • Obtain informed consent from patients to collect up to five cores per biopsy procedure if safe and feasible.
  • Create standard operating procedures for each clinical trial that detail research biopsy specimen quality requirements to guide the interventional radiologist and to help ensure that the requirements and expectations of the researcher, radiologist, and patient are met.
  • Review each patient with an interventional radiologist to ensure that patients who do not have tumors amenable to biopsy are not enrolled in clinical trials that have a research biopsy requirement.
  • Prepare evidence-based practice guidelines for research biopsies and other materials that convey the added value from collaborative efforts to collect better biopsy samples. This may help develop a reimbursement plan for research tissue sampling that reflects the extra time and imaging approaches the biopsy team needs to obtain better tumor biopsy samples.

"Our analysis suggests that clear communication by all parties involved in the collection, handling, processing, and storing of biopsies is critical for success," said Kate Ferry-Galow, Ph.D., of the Clinical Pharmacodynamic Biomarkers Program at NCI's Frederick National Laboratory for Cancer Research.

"We now hold regular meetings throughout a clinical trial, and the biopsy team-including the oncologists, interventional radiologists, pathologists, and assay scientists-communicate about the quality of the biopsies," Dr. Ferry-Galow continued. "That communication has helped tremendously."

When the researchers implemented the recommendations during clinical trials conducted by NCI's Developmental Therapeutics Clinic, the new strategy led to a better success rate in terms of obtaining suitable biopsy specimens for analysis, compared with previous studies.

Using Tumor Samples to Conduct Multiple Tests

Conducting biopsies for research purposes can be challenging, Dr. Ferry-Galow noted. One challenge is that such biopsies ideally involve the collection of more tissue from a patient than biopsies conducted during routine patient care.

As the team's analysis revealed, the need for additional tissue has not always been communicated clearly to interventional radiologists on clinical trials. The need for more tissue reflects the fact that research biopsy specimens may be used for a variety of genetic and molecular tests, such as next-generation DNA sequencing.

In some early-phase clinical trials of investigational therapies, for example, researchers may collect tissue from the same tumor before and after a patient receives a drug. Analyzing pairs of biopsy specimens can reveal whether drugs designed to block certain signaling pathways in tumors actually do so in the human body.

"Today, we can develop evidence that a drug is working at the molecular level-and in greater detail than ever before," said coauthor Alda Tam, M.D., the clinical medical director in the Department of Interventional Radiology at the University of Texas MD Anderson Cancer Center.

Despite the importance of research biopsies, these procedures often fail to produce the specimens needed to answer research questions about cancer clinical trials, Dr. Tam noted.

A retrospective analysis of four early-phase clinical trials conducted at NCI's Developmental Therapeutics Clinic, for example, found that only 83 of 112 (74%) needle biopsies collected to study the activity of drugs in the body produced specimens that met quality-control standards. The reasons included an insufficient amount of tumor collected and/or specimens of poor quality.

Bringing Together Experts on Research Biopsies

To address the need to improve research biopsies, Alice Chen, M.D., of NCI's Division of Cancer Treatment and Diagnosis (DCTD), and her colleagues convened several meetings with oncologists, pathologists, laboratory scientists, and interventional radiologists from around the country. The participants reviewed and discussed all aspects of the processes involved in collecting and analyzing research biopsies.

The discussions "represent the first time we've had a national conversation about research biopsies that included interventional radiologists and pathologists," said Dr. Tam. "And the conversation showed that we all could work better as a team."

Among other findings, the researchers learned that some radiologists weren't aware of the different requirements for research biopsies compared with the requirements for other types of biopsies, such as diagnostic biopsies, Dr. Ferry-Galow said.

Another finding was the need for greater recognition and financial support for the investment of time and scientific contributions made by interventional radiologists and pathologists.

"What interventional radiologists are asked to do in the research setting is different from what they do in the clinical setting, and they aren't always being recognized for their time," said Dr. Ferry-Galow.

The study authors suggested that the important contributions of interventional radiologists and pathologists could be recognized by making them coauthors of studies reporting the results of clinical trials they helped to conduct.

Sharing the Findings with the Research Community

As a next step, the study authors are working to communicate the need and the resources available for improving the quality of research biopsy specimens. For example, DCTD posts standard operating procedures for tissue collection for validated biomarker assays online.

In addition, the publicly available Biospecimen Research Database-which includes standard operating procedures in the field of human biospecimen science-is being revised as a resource to promote the dissemination of references, data, and best practices related to radiology and pathology, the study authors wrote.

They plan to conduct additional outreach at national scientific meetings and through professional societies.

"The findings of our study are incredibly positive," said Dr. Tam. "They show that just sitting down and talking through what each person brings to a clinical trial will improve the execution of the biopsy process and quality of the results."

© 2018 The National Cancer Institute

Trial Results Highlight Changing Lung Cancer Treatment Landscape

by NCI Staff

The National Cancer Institute -- October 15, 2018

companies img In patients with non-small cell lung cancer whose tumors have alterations in the ALK gene, ALK-inhibitors like brigatinib and crizotinib can dramatically shrink tumors.

Credit: J Pers Med April 2012. CC BY 3.0.

New results from two large clinical trials are expected to have an immediate impact on the care of patients with the most common form of lung cancer.

The drugs tested in the trials, brigatinib (Alunbrig) and durvalumab (Imfinzi), respectively, are already being used to treat some patients with the disease, non-small cell lung cancer (NSCLC). Lung cancer experts agreed that the trials' findings should further cement the value of these drugs in treating NSCLC, and continue an important trend.

"We're seeing a lot of changes in the treatment of non-small cell lung cancer," said Azam Ghafoor, M.D., of NCI's Thoracic and GI Malignancies Branch. "In particular there has been a paradigm shift in the expanded use of immunotherapy and targeted therapies."

Results from both trials were presented September 25 at the World Conference on Lung Cancer in Toronto and simultaneously published in the New England Journal of Medicine.

For NSCLC with ALK Alterations, Multiple Options

Brigatinib is an inhibitor of the ALK protein, the gene for which is altered (most commonly as a fusion, or translocation, with another gene) in 4%-7% of patients with NSCLC. It was initially approved by the Food and Drug Administration (FDA) last year to treat patients with NSCLC whose tumors have an ALK alteration and whose cancer has progressed despite treatment with crizotinib (Xalkori). In 2011, crizotinib became the first ALK-targeted drug to receive FDA approval.

The ALTA-1L trial compared the drug against crizotinib in people with advanced NSCLC. The trial was funded by Takeda Pharmaceutical Company, the manufacturer of brigatinib.

In the trial, patients who were treated with brigatinib lived longer without their disease worsening than those treated with crizotinib. At 12 months after initiating treatment, 67% of patients treated with brigatinib were still alive without any evidence of their cancer getting worse, compared with 43% of those treated with crizotinib.

Brigatinib was also more effective than crizotinib at shrinking brain lesions among trial participants whose cancer had spread to their brain: 78% of patients treated with brigatinib, compared with 29% of patients who received crizotinib.

The latter finding was not necessarily a surprise to researchers. As a second-generation ALK inhibitor, brigatinib was designed to address some of the shortcomings of the first-generation crizotinib. Among the improvements in the second-generation ALK-targeted drugs-which also includes alectinib (Alecensa) and ceritinib (Zykadia)-is an enhanced ability to cross the blood-brain barrier.

That particular improvement is critical because, in NSCLC with ALK alterations, "[disease] progression tends to occur in the brain," explained the trial's lead investigator, Ross Camidge, M.D., of the University of Colorado Cancer Center, during a conference press briefing.

Alectinib has already been approved by FDA as an initial treatment for patients with ALK-positive tumors, based on findings from a phase 3 clinical trial in which it extended progression-free survival longer than crizotinib and was more effective at preventing and shrinking brain metastases.

Both brigatinib and alectinib have side effects, but they are not entirely the same. In the ALTA-1L trial, for example, a small percentage of patients treated with brigatinib experienced inflammation in the lungs, a problem that has not been seen with alectinib.

Dr. Camidge noted that, overall, patients tolerated brigatinib very well. He also noted that the trial included patients who had already received chemotherapy-which the alectinib versus crizotinib trial did not-so ALTA-1L participants were more representative of a real-world population of patients.

Brigatinib is not yet approved by FDA as an initial treatment in patients with ALK-positive NSCLC. But if that happens, Ravi Salgia, M.D., Ph.D., associate director for clinical sciences at the City of Hope Cancer Center, said that either alectinib or brigatinib could be the preferred first choice in this group of patients.

"That's what medical oncology is. You use what you have the most experience with and then gain experience with other drugs," Dr. Salgia said.

Factors such as the side effect profile of each drug and insurance coverage could also affect the choice, Dr. Ghafoor said.

Lung cancers with ALK alterations "have unique patterns of metastasis," Dr. Salgia explained, including to the stomach, peritoneum, and other sites in the body "that other lung cancers don't tend to metastasize to."

Moving forward, he continued, studies can hopefully provide more information about issues such as how the respective ALK inhibitors work against tumors that spread to these sites and whether they work better when combined with radiation or other therapies.

But for now, he said, oncologists who regularly treat lung cancer "are just happy that we're developing these new drugs, that they're effective, and that the [tumor] responses are deep and durable."

For Stage III NSCLC, A New Standard of Care?

The durvalumab trial, called PACIFIC, involved a very different group of patients. People in the trial-which was funded by the drug's manufacturer, AstraZeneca-had stage III NSCLC, which means the cancer has progressed in and around the lungs but has not spread widely in the body.

Although patients with stage III disease can sometimes be treated with surgery, the extent of the disease in patients in PACIFIC was such that surgery was not considered a viable treatment option. In addition, the patients in the trial had to have responded to treatment with the current standard, chemotherapy and radiation-that is, their tumors had already reduced in size following this treatment.

Participants in the trial were randomly assigned to receive durvalumab or a placebo once every 2 weeks for up to 12 months or until their cancer began to progress.

An earlier analysis of the PACIFIC trial showed that patients treated with durvalumab-an immune checkpoint inhibitor that targets the protein PD-L1-lived substantially longer without their disease progressing than patients treated with placebo. The FDA approved durvalumab earlier this year based on those initial results.

The results presented in Toronto come from a longer-term follow-up analysis of the trial. The analysis confirmed the improvement in progression-free survival and showed that patients treated with durvalumab also lived substantially longer overall, reported the study's lead investigator, Scott Antonia, M.D., Ph.D., of the Moffitt Cancer Center in Florida.

At 2 years after initiating treatment, 66% of patients who received durvalumab were still alive, compared with 55% of patients who received a placebo. More patients treated with durvalumab experienced serious side effects (30.5% versus 26.1%) and more had to stop treatment because of side effects (15.4% versus 9.8%).

A concern going into the trial was lung inflammation, a known and potentially deadly side effect of durvalumab, Dr. Antonia explained during a press briefing. But that concern was not borne out, he noted, with lung inflammation being no more common in patients treated with durvalumab than in those treated with chemotherapy and radiation.

"This is a new standard of care ... for patients with this disease," Dr. Antonia said.

The researchers analyzed survival outcomes in patients according to whether their tumors expressed PD-L1, which has been closely studied as a potential biomarker that can identify patients who are likely to respond to treatment with immune checkpoint inhibitors.

Patients whose tumors didn't express PD-L1 didn't seem to benefit from durvalumab, the analysis showed. Dr. Ghafoor cautioned, however, that the PD-L1 analysis was not a planned part of the trial and that the drug can be used to treat all patients, regardless of PD-L1 status.

One group in which some caution in using durvalumab might be warranted is patients whose tumors have mutations in the EGFR gene, said Joshua Bauml, M.D., who specializes in lung cancer at the University of Pennsylvania Abramson Cancer Center and was not involved with the study.

It's not clear from the trial results whether patients with EGFR mutations who were treated with durvalumab had improved survival, Dr. Bauml noted.

In clinical practice, patients with EGFR mutations whose cancer progresses despite durvalumab treatment might go on to receive an EGFR-targeted therapy, of which several are approved by FDA. But in several small studies, Dr. Bauml noted, use of an EGFR-targeted drug in combination with PD-L1 targeted agent greatly increased the risk of serious side effects in the lungs.

"So we need to talk with our patients with EGFR [mutations] who have completed chemoradiation, walk through these issues, and come to a conclusion about what the best option is for them," he said.

© 2018 The National Cancer Institute

For HPV-Positive Women, Test Can Guide Cervical Cancer Screening Follow-Up

by NCI Staff

The National Cancer Institute -- October 11, 2018

companies img Dual stain testing on Pap test samples identifies the presence of two proteins: p16 (brown) and Ki-67 (red).

Credit: National Cancer Institute

A new test can help to improve the clinical management of women who screen positive for human papillomavirus (HPV) infection in routine cervical cancer screening, an NCI-led study has shown.

The test, called p16/Ki-67 dual stain, more accurately predicted whether an HPV-positive woman would go on to develop cervical precancer within 5 years, compared to a Pap test-the current standard for managing HPV-positive women.

As HPV testing becomes more central to cervical cancer screening, "the challenge is how to best manage, or triage, HPV-positive women," said senior investigator Nicolas Wentzensen, M.D., Ph.D., of NCI's Division of Cancer Epidemiology and Genetics (DCEG).

Dual stain testing measures the presence of two specific proteins, p16 and Ki-67, in Pap test samples. Previous studies have suggested that the combination of these two markers is better at identifying HPV-positive women who have precancers than Pap testing.

The study's lead investigator, Megan Clarke, Ph.D., M.H.S., also of DCEG, said that it addresses a critical question: "how often and at what time interval should HPV-positive women who test negative with dual stain come back for repeat screening?"

In the prospective study, HPV-positive women who had a negative result on the dual-stain test had a low risk of developing cervical precancer over the ensuing 5 years, the researchers reported October 11 in JAMA Oncology. These women, they concluded, can safely wait 3 years before undergoing their next round of screening.

"This is a very important study," said Mark Stoler, M.D., associate director of Surgical Pathology and Cytopathology at the University of Virginia School of Medicine. It's the first study performed in the United States, Dr. Stoler continued, "that really provides the assurance that [dual stain] is a better triage test" than the Pap test.

Cervical Cancer Screening in the US

There are many sexually transmitted HPV types, approximately 12 of which are known to cause cervical and several other cancers. HPV infections are very common, but most are controlled by the immune system and do not lead to cancer. When an infection persists for many years, however, it can cause cells to undergo changes and may ultimately become cancer.

Testing cervical cells for HPV infections is now recommended as a standard way to screen for those early changes, so researchers are searching for ways to distinguish between HPV infections that are likely to cause cancer-and therefore require follow-up procedures-and infections that can be safely monitored. Follow-up procedures include colposcopy, during which biopsies of abnormal areas in the cervix are taken. Biopsy-confirmed precancers can then be removed by one of several different methods.

Current guidelines for cervical cancer screening recommend one of three approaches: the Pap test alone, the HPV test alone, or a combination of the two-known as an HPV/Pap cotest. According to the US Preventive Services Task Force (USPSTF), women age 30 to 65 years at average risk of cervical cancer can be safely screened with an HPV test or HPV/Pap cotest every 5 years.

Historically, the Pap test greatly reduced the incidence of cervical cancer in all countries where screening was implemented. The addition of the HPV test further improved the accuracy of screening. But this approach has some limitations.

For example, women who test positive for HPV and who have minor abnormalities on a Pap test are usually referred for immediate colposcopy. But only a small percentage of abnormalities turn out to be cervical precancer or cancer, meaning that most of these women may have received a colposcopy that was unnecessary, Dr. Wentzensen explained.

Because of these limitations, "there is a big effort to find better markers that allow us to triage HPV-positive women more efficiently," said Dr. Wentzensen.

The dual-stain approach has been under study for more than a decade, Dr. Stoler said. The expression of p16 is strongly linked with HPV infection, and Ki-67 is used as a biomarker for the rapid cell division seen in precancers and cancer.

In terms of potential triage approaches for HPV-positive women, dual-stain testing "is probably the most advanced method available," added Dr. Clarke. This new study adds to that body of evidence, she said.

Searching for a Better Triage Test for HPV-Positive Women

To conduct the study, the investigators followed 1,549 women aged 30 or older who had tested positive for HPV while undergoing routine HPV/Pap cotesting at Kaiser Permanente Northern California between January and May 2012.

Women with a normal, or negative, Pap test result were recommended to repeat the cotest in 1 year, while women with an abnormal, or positive, Pap test result were referred for immediate colposcopy. Colposcopy results can reveal a range of disease states, including normal, low-grade to high-grade precancer, and cancer.

Dual-stain testing was performed on participants' Pap test samples at the time of enrollment, and the women were then followed for 5 years.

Overall, 46% of women in the study had a positive dual-stain test and 51% had a positive Pap test. Compared with women with normal Pap results, more women with severely abnormal Pap test results had a positive dual-stain test, the researchers found.

The same was true for the biopsy results: Over the 5-year study period, 77% of women found to have a high-grade precancer and 91% found to have cancer had a positive dual-stain test.

The team also found that, compared with Pap test results, dual-stain test results were far more indicative of the 5-year risk of cervical precancer.

For example, women with a negative dual-stain test result had a lower risk of developing cervical precancer within 5 years, compared to women with a negative Pap test. This means that a negative dual-stain test result gives greater reassurance than a negative Pap test result that precancer won't develop during the ensuing 5 years, Dr. Wentzensen explained.

Conversely, women with a positive dual-stain test result had a higher risk of developing cervical precancer over the next 5 years than women with a positive Pap test result. That finding, together with the lower positivity of dual stain, suggests that using the dual stain test to triage HPV-positive women might lead to fewer unnecessary colposcopies, Dr. Clarke noted.

Based on the 5-year risks of cervical precancer, the researchers determined that women with a negative dual-stain result can wait 3 years before being screened again.

The ability of the dual stain test to improve on the sensitivity of the Pap test (i.e., better identifying women with a higher risk of having precancer) and its specificity (i.e., better at identifying those with a low risk) is impressive, Dr. Stoler said.

"It's very hard to have a test that improves sensitivity and specificity, but dual stain does it because of the biology behind the development of the test," he said.

Learning More About Dual Stain

The dual stain test is already being marketed and used in several countries, including Canada, Europe, and Australia, Dr. Stoler said. The clinical trial that would form the basis of clearance of the dual stain test by the Food and Drug Administration for its use in the United States is currently ongoing, he added.

In the future, HPV testing followed by dual stain for primary cervical cancer screening may be a more efficient alternative to HPV/Pap cotesting, Drs. Wentzensen and Clarke said.

The manufacturer of the dual stain test is analyzing the development of cervical precancer in HPV-positive women who have a positive test result from either dual stain or Pap in an ongoing study. In addition, Dr. Wentzensen and his colleagues are investigating the results of dual stain testing in a large population of women, including many who are HPV-negative.

"I think there will be sufficient data to change practice based on these observational studies," said Dr. Wentzensen.

And the test may soon have other attractive qualities, the investigators noted. A major advantage of the dual stain test, said Dr. Wentzensen, is that abnormal cells are highlighted with a colored stain and are therefore easier to detect and quantify.

"Currently, the dual stain test is evaluated manually, but we are working on an automated evaluation of this assay and we have exciting results," he added. Automation of the dual-stain test would enhance its reliability and make it easier to use, he said.

© 2018 The National Cancer Institute

Using Artificial Intelligence to Classify Lung Cancer Types, Predict Mutations

by NCI Staff

The National Cancer Institute -- October 10, 2018

companies img The AI-driven computer program analyzes tissue by creating a map of thousands of tiles. The map on the right shows squamous cell carcinoma (red), lung squamous cell carcinoma (blue), and normal lung tissue (gray).

Credit: NYU School of Medicine

Researchers have trained a computer program to read slides of tissue samples to diagnose two of the most common types of lung cancer with 97% accuracy. The program also learned to detect cancer-related genetic mutations in the samples just by analyzing the images of cancer tissue.

In a process known as machine learning, the computer program scanned images of tissue slices and developed the ability to differentiate normal lung tissue from the two most common forms of lung cancer, adenocarcinomas, which make up about 40% of lung cancers, and squamous cell carcinomas, which make up about 25% to 30% of lung cancers. Even experienced pathologists can struggle to distinguish these two types of lung cancer, which arise from different types of cells and require very different treatment regimens.

To train the computer program, researchers specializing in machine learning used a deep learning method originally developed and published by Google. The program uses artificial intelligence (AI) to teach itself to get better at a task-in this case, classifying lung cancer specimens-without being told exactly how.

The program was trained using more than 1,600 histopathology slides of lung specimens made publicly available by The Cancer Genome Atlas (TCGA). The study, led by researchers at New York University's Langone Medical Center and published September 17 in Nature Medicine, represents a large improvement in the accuracy of computational methods to diagnose lung cancer; the second most accurate computational method has an accuracy rate of 83%.

Images as Data and a Public Resource

TCGA made histopathology images of tumor specimens available as a quality control measure for researchers studying the genetic sequence data collected in the project. The images "were required to make sure that the quality and identity of the tissue were correct," said Jean C. Zenklusen, Ph.D., the director of TCGA at NCI. As an incidental benefit, Dr. Zenklusen said, the images themselves now serve as a resource for analysis.

The images made available by TCGA are large and high resolution, so the researchers at NYU divided each image into thousands of tiles, or "patches," in a grid for the computer program to analyze individually for visual cues that could be linked to the sample's classification. "We had about 500 patients per [lung cancer] subtype, but thousands of patches per image, so we had nearly one million patches in the end to train the model," said Narges Razavian, Ph.D., a machine learning and AI researcher at NYU Langone, who helped lead the study.

The accuracy with which the program learned to distinguish adenocarcinoma from squamous cell carcinoma and normal lung cells was about equal to that of experienced pathologists, but the analysis can be done much faster; the program was able to reach a conclusion in a matter of seconds rather than the minutes a pathologist would need.

The program also correctly classified 45 of 54 images that at least one of three pathologists participating in the study misclassified, suggesting that AI could offer a useful second opinion, the researchers wrote.

The program was tested on an independent set of lung cancer specimens-both frozen and freshly collected-from NYU to verify that it worked on a completely separate collection of samples.

The samples from TCGA were almost entirely tumor tissue. In this validation set, however, the samples often included other components, such as blood clots and dead tissue, "making the classification task more challenging" for the program, the researchers reported.

In response, they reworked the program to have it focus on the parts of the tissue samples that were largely tumor (as identified by a pathologist). With that change, the method's accuracy averaged more than 90%, which they described as "very encouraging."

AI's Role in Treatment and Research

In addition to showing that AI can be used to make a quick and accurate diagnosis, the research project showed that AI could be trained to predict the presence of six of the most common genetic mutations in lung cancer adenocarcinoma, with an accuracy ranging from 64% to 86%, depending on the gene.

"That is very exciting scientifically," Dr. Razavian said.

Currently, the only way humans can detect genetic mutations is by DNA sequencing, which can take up to 2 weeks.

"Lung cancer is usually detected late in the progression of the disease, so waiting 2 weeks to start any treatment is bad for the patient," Dr. Razavian noted.

Many medical teams will start treatment and then adjust the medication used based on genetic test results. "What we show is that, with this program, you could start a treatment that is more likely to be the right one immediately," Dr. Razavian said.

The program is a "black box," in that its decisions are the result of thousands of interconnected small steps, not easy to summarize. The researchers can't visualize exactly what the program detects in an image to predict the presence of genetic mutations, but the program can serve as "a lens that shows patterns that are hard to notice with the eye," Dr. Razavian said.

She and her colleagues are using the program to research how genetic mutations affect the structures of cells and tissues. To approach this problem, they are using automated methods that modify the images to figure out what visual elements most influence the program's ability to perceive mutations.

"The strengths of the study," said Paula Jacobs, Ph.D., the associate director of NCI's Cancer Imaging Program, "are the careful selection of the clinical problem to be addressed," how the program was trained, and the fact that the results were verified using an independent set of lung cancer specimens.

Michael Snyder, Ph.D., chair of genetics at Stanford University, sees AI as the future of diagnosis. "I think we need to shift to using machine learning rather than rely on pathologists alone to do all the work," he said. "Algorithms won't replace pathologists, but they will assist them in making classifications. They will reduce the errors that pathologists would otherwise make."

The code developed for the project is available for other researchers to use for other diagnostic applications. The NYU team has already started applying the code to learn to diagnose kidney, breast, and other cancers.

© 2018 The National Cancer Institute

Cancer patients with rare deadly brain infection treated successfully with off-the-shelf adoptive T-cell therapy in clinical trial

Treatment may have implications for leukemia, lymphoma and some other immunodeficiency disorders

MD Anderson Cancer Center -- October 10, 2018

companies img Katy Rezvani, M.D., Ph.D.

HOUSTON -- An emerging treatment known as adoptive T-cell therapy has proven effective in a Phase II clinical trial for treating progressive multifocal leukoencephalopathy (PML), a rare and often fatal brain infection sometimes observed in patients with cancer and other diseases in which the immune system is compromised.

The study, led by Katy Rezvani, M.D., Ph.D., professor, Department of Stem Cell Transplantation and Cellular Therapy at The University of Texas MD Anderson Cancer Center, showed marked improvement in three PML patients infused with donor T cells targeting the BK virus. Findings were published in the Oct. 11 online issue of the New England Journal of Medicine.

Results from the proof-of-principle study demonstrated BK, a virus similar to the JC virus which causes PML, as the basis for a potentially viable therapy. Both viruses are named for the initials of the patients in which they were first identified.

"The JC and BK viruses are genetically similar and share proteins that can be targeted by the immune system," said Rezvani. "Because of these similarities, we hypothesized that T cells developed against BK virus may also be effective against JC virus infection."

Rezvani's team developed a novel approach for the generation of BKV-specific T cells from healthy donors and established a bank of viral-specific T cells in MD Anderson's Good Manufacturing Practice (GMP) laboratory for immediate clinical use. The study treated three patients with third-party, partially human leukocyte antigen-matched (HLA) BK virus-specific T cells, taken from the GMP. HLAs are proteins found on the cell's surface vital to immune system recognition.

"As these products have become more popular, there's been a widespread recognition of the potential dangers," said Dr. Grana. "This study really highlights some of the reasons for these concerns."

PML in patients with leukemia, lymphoma and other diseases

PML is a member of the polyomavirus family and is caused by the JC virus, which, although commonly found in the general population, can be deadly or cause serious health issues in some blood cancer patients, including those with leukemia and lymphoma, people with AIDS, and patients with multiple sclerosis, rheumatoid arthritis, lupus and other autoimmune diseases treated with biologic therapies.

PML attacks white matter in the brain called the myelin sheath, which protects nerve cells. There is no current effective treatment for PML, which is fatal in the majority of patients. Symptoms can include clumsiness or loss of coordination, difficulty walking, facial drooping, vision loss, personality changes, trouble speaking and weak muscles.

Clinical trial treatment included patients with acute myeloid leukemia (AML)

PML patients infused with BK-specific virus T cells included:

  • Patient 1: 32-year-old female with AML who previously received a cord blood transplantation
  • Patient 2: 73-year-old female with JAK2-positive polycythemia rubra vera, a blood disorder causing over-production of red blood cells, who had been treated with the targeted therapy agent ruxolitinib
  • Patient 3: 35-year-old man with AIDS who had discontinued an aggressive form of multi-drug therapy known as highly active antiretroviral therapy (HAART) due to side effects and who was no longer able to walk.

Following the first infusion, all three patients had a reduction in JC viral load in their cerebrospinal fluid (CSF). Viral loads dropped from 700 to 78 copies in the first patient, 230,000 to 5,200 in the second, and 4,300 to 1,300 in the third patient.

"After infusion of viral-specific T cells, patients 1 and 3 had clinical improvement with significant reduction in JC virus in their cerebrospinal fluid," said Rezvani. "Both patients responded despite persistent T-cell immunodeficiency, supporting the concept that the response was mediated by the adoptively infused viral-specific T cells, and there were no infusion-related reactions."

Patient 1 received two additional infusions, which resulted in clearance of the virus in the CSF and no signs of PML 27 months after the first infusion. Patient 2 received a second infusion that further reduced JC viral load, but no further improvement was seen. The patient died eight months following the first infusion. Patient 3 received additional infusions resulting in complete clearance of the JC virus. The patient has regained mobility, and nine months after the first infusion, he is able to walk with a cane.

"We are encouraged that off-the-shelf, third-party partially HLA-matched BK viral-specific T cells may provide a therapy for PML," said Rezvani. "Further study in a larger group of patients is required to determine the success rate, durability and longer-term adverse events with this treatment."

The study was supported with funding from the Myelodysplastic Syndromes and Acute Myeloid Leukemia Moon Shot, part of MD Anderson's Moon Shots Program, a collaborative effort to accelerate the development of scientific discoveries into clinical advances that save patients' lives. The research also was supported by the National Institutes of Health (CA016672).

Other MD Anderson study team members include: Muharrem Muftuoglu, M.D., Amanda Olson, M.D., David Marin, M.D., Indreshpal Kaur, Ph.D., Li Li, M.D., Richard Champlin, M.D. and Elizabeth Shpall, M.D., all of the Department of Stem Cell Transplantation and Cellular Therapy; Victor Mulanovich, M.D., of the Department of Infectious Diseases; Sudhakar Tummala, M.D., of the Department of Neuro-Oncology; Linda Chi, M.D., of the Department of Diagnostic Radiology; and Alessandra Ferrajoli, M.D., of the Department of Leukemia.

© 2018 The University of Texas MD Anderson Cancer Center

Neoadjuvant combination checkpoint blockade trial yields high response rates for patients with high-risk stage 3 melanoma

First-of-its-kind study indicates that neoadjuvant approach is feasible but also cautions need to optimize current regimens

MD Anderson Cancer Center -- October 8, 2018

companies img

HOUSTON -- Combination checkpoint blockade before surgery (neoadjuvant therapy) produced a high response rate among patients with high-risk stage 3 melanoma, with nearly half having no sign of disease at surgery, but a high incidence of side effects caused the trial to be closed early.

The phase II study was led by researchers at The University of Texas MD Anderson Cancer Center. Results of the study, the first randomized neoadjuvant clinical trial of immune checkpoint blockade for melanoma patients, are reported in Nature Medicine.

Patients received either the PD-1 inhibitor nivolumab or the combination of nivolumab and the CTLA-4 checkpoint inhibitor ipilimumab. Each drug blocks a separate off-switch on T cells, freeing the immune system to attack cancer. All patients received nivolumab after surgery.

On the combination arm, 8 of 11 (73 percent) patients had their tumors shrink, 5 (45 percent) had no evidence of disease at surgery (pathological complete response), and 73 percent had grade 3 side effects, causing dose delays in 64 percent and delaying surgery for some. There were no grade 4 side effects.

In the nivolumab arm, 3 of 12 (25 percent) had their tumors shrink and had pathological complete response, only 8 percent had grade 3 side effects. Two patients progressed to stage 4 metastatic disease before they could get to surgery.

"In this trial, treatment with single-agent anti-PD-1 was associated with modest response rates, and we were concerned that two patients on that arm progressed and could not go to surgery," said co-first author Rodabe Amaria, M.D., assistant professor of Melanoma Medical Oncology. "Treatment with combined checkpoint blockade was much more effective, but at the expense of significant toxicity. It is clear from this trial that we need to further optimize this treatment approach."

All of those who achieved pathological complete response in either arm remain without evidence of disease recurrence. Overall survival was 100 percent at 24 months in the combination arm and 75 percent in the nivolumab arm.

"The advantage of a neoadjuvant approach in this setting is that it enables an interval evaluation of the tumor cells after therapy to determine the extent to which those tumor cells responded to the therapy in real time and predict which patients are likely to experience durable responses going forward. It also provides us the tissue resources to determine why tumors may not respond to therapy and thus tailor therapies going forward as we learn more about resistance," said co-senior author on the study, Michael Tetzlaff, M.D. Ph.D., associate professor of Pathology and Translational and Molecular Pathology.

Checkpoint blockade has been effective against metastatic melanoma and in reducing the risk of relapse after surgery for high-risk stage 3 disease. However, there is evidence in preclinical models that treatment before surgery may be superior to giving these agents in the adjuvant setting (after surgery).

Amaria and senior author Jennifer Wargo, M.D., associate professor of Surgical Oncology and Genomic Medicine, launched the investigator-initiated trial through MD Anderson's Moon Shots Program, a collaborative effort to accelerate the development of scientific discoveries into clinical advances that save patients' lives.

Due to the results of this study, the team re-designed the study to explore the safety and efficacy of nivolumab plus relatlimab, an inhibitor of the LAG3 immune checkpoint, a combination that Amaria notes thinks may be more effective than nivolumab alone with a better side effect profile than treatment with combined CTLA-4 and PD-1 blockade.

Identifying biomarkers of response and resistance

"This presurgical platform provides an ideal setting to study biomarkers of response, mechanisms of resistance, and differential effects of these two commonly used treatment regimens," said co-first author Sangeetha Reddy, M.D., instructor in Cancer Medicine. "In this study we confirmed known biomarkers of response and observed novel biomarkers of therapeutic response that we are now studying further"

Analysis of biopsies and blood samples taken at multiple time points during the trial revealed:

  • Baseline infiltration of tumors by lymphoid cells and total mutational burden were associated with response to therapy.
  • Early on-treatment biopsies were better predictive of who would respond to both therapies compared to baseline biopsies.
  • Molecular analyses using a novel spatial profiling technology identified differential abundance of multiple immune markers that correlated with response and/or resistance to neoadjuvant immune checkpoint blockade.
  • T cell receptor sequencing identified differential patterns in responders versus non-responders to anti-PD-1 therapy versus combined CTLA-4 and PD-1 blockade. Responders to PD-1 monotherapy showed evidence of a pre-existing but inhibited T cell repertoire that further expanded during treatment, while treatment with combination therapy was associated with more variable changes in the T cell repertoire.

This trial was performed in parallel to a trial co-led by Christian Blank, M.D., Ph.D., and Ton Schumacher, Ph.D. of the Netherlands Cancer Institute - who tested the use of neoadjuvant versus adjuvant (post-surgical) treatment with combined CTLA-4 and PD-1 blockade in a similar patient population.

"The findings in their trial are provocative, demonstrating that a higher number of tumor-resident TCRs expanded in the peripheral blood of patients receiving neoadjuvant as opposed to adjuvant checkpoint blockade - supportive of what was seen in preclinical models - and suggests that the neoadjuvant approach may be superior." Wargo said.

This MD Anderson-led team is now working with others worldwide in an international neoadjuvant melanoma consortium to harmonize these efforts.

Bristol Myers Squibb provided drugs and funded the clinical aspects of the study, but played no role in study design, execution, data collection, analysis or interpretation. Correlative studies of tumors and blood samples were funded by MD Anderson's Melanoma Moon Shot and the Parker Institute for Cancer Immunotherapy.

Co-authors with Amaria, Reddy, Tetzlaff and Wargo are: Hussein Tawbi M.D., Ph.D., Michael Davies M..D., Ph.D., Isabella Glitza M.D., Ph.D., Wen-Jen Hwu, M.D.,., Adi Diab M.D., Michael K. Wong M.D., Scott Woodman M.D. PhD, Patrick Hwu M.D., Sapna Patel M.D., Lauren Simpson, R.N., Liberty Posada, all of Melanoma Medical Oncology; Merrick Ross M.D., Janice Cormier M.D., Richard Royal M.D., Richard Ehlers M.D., Anthony Lucci M.D., Jeffrey Lee M.D., Jeffrey Gershenwald M.D., Elizabeth Burton, Lauren Haydu Ph.D., Vancheswaran Gopalakrishnan Ph.D., Alexandre Reuben, Ph.D., Miles Andrews, Ph.D.,all of Surgical Oncology; Carol Lewis M.D., Ehab Hanna M.D., Neil Gross M.D., Randal Weber M.D., Stephen Lai M.D., Amy Hessel M.D., all of Head and Neck Surgery; Jorge Blando, D.M.V., Padmanee Sharma M.D., Ph.D., and Jim Allison, Ph.D., all of Immunology, Denai Milton of Biostatistics; Robin Kageyama Ph.D. and Danny Wells Ph.D. of the Parker Institute for Cancer Immunotherapy; Linghua Wang Ph.D., Shaojun Zhang Ph.D., Christine N. Spencer Ph.D. of Genomic Medicine, Alexander Lazar M.D., Courtney Hudgens., and Victor Prieto M.D. of Pathology.

© 2018 The University of Texas MD Anderson Cancer Center

Vaping Pods Produce High Nicotine Levels in Young Users

by NCI Staff

The National Cancer Institute -- October 5, 2018

companies img Addiction at a young age is linked to continued use of nicotine products.

Credit: iStock

The most commonly used types of e-cigarettes among teens may deliver very high levels of nicotine, a new study has found.

In the study of adolescents who regularly used pod-style e-cigarettes, such as the brand Juul, researchers found that recent users had higher levels of nicotine in their bodies than have previously been found in adolescents who regularly smoked conventional cigarettes.

The study's findings are concerning for several reasons, explained Rachel Grana, Ph.D., M.P.H., of NCI's Tobacco Control Research Branch (TCRB), who was not involved with the study. One is the high potential for youth exposed to nicotine to become addicted.

"Early addiction has been linked to the continued use of nicotine-containing products, so it may be a lifetime problem if they start during adolescence," Dr. Grana said. The potential for these products to deliver high doses of nicotine is another concern for this age group, she added.

Nicotine is thought to have damaging effects on the developing brain, explained Maciej Goniewicz, Ph.D., Pharm.D., of Roswell Park Comprehensive Cancer Center, who led the study. These effects may include impairment of memory and attention. Other chemicals in e-cigarettes, such as the flavoring additives they can contain, may also be hazardous but have yet to be studied in depth, he added.

"As these products have become more popular, there's been a widespread recognition of the potential dangers," said Dr. Grana. "This study really highlights some of the reasons for these concerns."

The study results were published in Tobacco Control on September 7.

Measuring Nicotine Exposure

Pod-type e-cigarettes have skyrocketed in popularity over the last several years. Just one brand-Juul-now makes up about 70% of the e-cigarette market in the United States, according to recent consumer data, said Dr. Grana.

Pod systems differ substantially from earlier generations of e-cigarettes, Dr. Goniewicz explained. Earlier products used electricity to heat a cartridge of liquid, which usually contained nicotine in a so-called free-base form. This form of nicotine can cause a harsh sensation when inhaled, which may make it unappealing to young users, he added.

In contrast, pods work by vaporizing nicotine salts-a compact substance that allows the pods to be made small enough to fit in the palm of a hand. Nicotine salts are known to quickly deliver a high concentration of nicotine to the body without an unpleasant, harsh sensation. Dr. Goniewicz and his colleagues wanted to get an idea of how products incorporating these salts might be affecting young users.

They recruited 506 young people aged 12-21 who visited one of three outpatient clinics in Long Island, New York, in 2017 or 2018. All study participants completed an anonymous questionnaire about their use of e-cigarettes and other tobacco products. They also provided a urine sample.

Thirty-eight of the participants reported that they used pods daily or on some days and did not smoke conventional cigarettes. Their exclusive use of pods was confirmed by testing their urine samples for a biomarker of tobacco combustion.

The pod users had evidence of high levels of nicotine in their body. The median concentration of cotinine, a molecule that is formed during the breakdown of nicotine, in the participants' urine samples was more than 50% higher than the urinary cotinine levels reported in a previous study of youth tobacco smoking.

The researchers also performed lab tests to measure nicotine outputs from the pod products that were used by participants. They found that 10 puffs from each of the pod products contained considerably more nicotine than 10 puffs from earlier-generation e-cigarettes.

"These [pods] are highly effective nicotine delivery systems," said Dr. Goniewicz.

Reducing the Dangers

The study coincides with a growing national concern about e-cigarette use among adolescents and young adults. "Since 2011, use has increased dramatically among youth, with a spike in 2014 and 2015 to about 16% of high school students," said Dr. Grana.

"[E-cigarettes are] by far the most commonly used class of tobacco product among youth," she added.

Selling e-cigarettes to people under the age of 18 is illegal. But until recently, many websites that sell these products have not performed rigorous age verification for online purchases. Some have recently implemented stricter verification, said Dr. Goniewicz, but others have not. Many brick-and-mortar stores are also lax about verifying the age of customers who purchase e-cigarettes. And some minors get the products from older peers who can buy them legally, he added.

Last month, the Food and Drug Administration (FDA) announced a crackdown on the sale of e-cigarettes to minors. The agency issued more than 1,300 warning letters and fines to retailers who illegally sold e-cigarette products, including pods, to minors.

FDA also issued warning letters to the manufacturers of the five top-selling brands of e-cigarettes, requiring them to explain to the agency within 60 days how they plan to limit youth access to their products.

The letters explained that failure to submit a plan or submission of a plan that the agency considers to be inadequate may force FDA to revisit whether a company can legally sell their products in the United States.

An Unacceptable Tradeoff

Although some believe that e-cigarettes may help adult smokers quit using conventional cigarettes-products that contribute to almost half a million deaths every year-the evidence to support this view is limited, explained Michele Bloch, M.D., Ph.D., chief of TCRB.

"I still believe ... that there are opportunities to move adult smokers down that ladder of harm" using e-cigarettes, said FDA Commissioner Scott Gottlieb, in a statement that accompanied the enforcement actions. But "FDA won't tolerate a whole generation of young people becoming addicted to nicotine as a tradeoff for enabling adults to have unfettered access to these same products," he added.

The new enforcement actions are being accompanied by an expansion of an educational campaign called The Real Cost, which aims to explain the dangers of e-cigarettes to youth nationwide.

"Research shows that kids don't understand addiction very well," said Dr. Grana. The new campaign, she added, "focuses on getting rid of the 'cost free' mentality; focusing on the fact that e-cigarettes are not harmless and that there are real costs [to youth] to using the product."

    Studying the Impact of E-Cigarettes

    Tobacco control researchers are increasingly studying the impact of e-cigarettes. NCI currently funds 36 grants related to e-cigarette use, about half of which are funded through an NIH-FDA partnership to inform FDA's tobacco regulatory activities. These grants investigate a broad spectrum of topics, including examining perceptions of e-cigarettes' risks and harms, use by adolescents and young adults, and the impact of e-cigarettes on smoking cessation.

© 2018 The National Cancer Institute

For Small Cell Lung Cancer, Immunotherapy Drug Finally Brings Improved Survival

by NCI Staff

The National Cancer Institute -- October 3, 2018

companies img Small cell lung cancer cells

Credit: Clin Pract. 2012 May 29; 2(3): e62. CC BY-NC 3.0.

For the first time in more than two decades, a treatment has been shown to improve how long patients with advanced small cell lung cancer (SCLC) live.

In a large clinical trial, treatment with the immunotherapy drug atezolizumab (Tecentriq), combined with a standard chemotherapy regimen, increased survival in patients with this highly aggressive form of lung cancer. Although the survival improvement was modest, the researchers hailed the positive survival findings as an important advance for the treatment of this intractable cancer.

"We're really hoping that [these results are] just the beginning; that this is something we can build on further," said the trial's lead investigator, Stephen V. Liu, M.D., of Georgetown University's Lombardi Comprehensive Cancer Center.

The results were presented on September 25 at the World Conference on Lung Cancer and published simultaneously in the New England Journal of Medicine.

Better Survival in SCLC: A Long Time Coming

Even compared with the more common form of lung cancer, non-small cell lung cancer, SCLC is particularly aggressive.

SCLC spreads very rapidly, often doubling the amount of tumor in the patient's body in a matter of weeks, explained Frances Shepherd, M.D., a lung cancer researcher at Princess Margaret Cancer Centre in Toronto, during a conference press briefing. In fact, at the time of their diagnosis, most patients have what is called extensive-stage disease, Dr. Shepherd said, and surgery is not a treatment option.

All 400 patients in the trial-called IMpower133 and funded by the drug's manufacturer, Genentech-had extensive-stage disease. Patients in the study were randomly assigned to either atezolizumab, an immune checkpoint inhibitor, in combination with standard chemotherapy (the drugs carboplatin and etoposide) or chemotherapy and a placebo.

The standard treatment actually shrinks tumors in most patients, Dr. Liu said. "But the response is transient," he said. "We expect a response, we expect a relapse."

Patients in the trial initially received atezolizumab and chemotherapy for four treatment cycles, called induction therapy, and then continued to receive atezolizumab or placebo alone after that, known as maintenance therapy.

Patients in the atezolizumab group lived longer overall: a median of 12.3 months, versus 10.3 months. The time it took for patients' disease to begin progressing was also improved by approximately one month: a median of 5.2 months, versus 4.3 months.

Side effects related to treatment were seen in both patient groups, Dr. Liu said, with more immune-related side effects in patients treated with the checkpoint inhibitor. The most common serious side effects in patients treated with atezolizumab included anemia and reduced levels of white blood cells called neutropenia, which increases the risk of infection.

Importantly, Dr. Liu noted, treatment-related side effects did not prevent any patients from completing the induction therapy portion of the treatment.

A Small but Important Improvement

Although the overall survival increase in the trial was small, the fact that it was improved at all is a major achievement, Dr. Liu said.

Carboplatin and etoposide have been used to treat SCLC for more than 20 years, he said, because no other treatments have been able to help patients live longer.

"And it's not for lack of trying," Dr. Liu continued. More than 40 phase 3 clinical trials have been conducted during this time using more than 60 different drugs, he said, with none increasing survival.

Few patients diagnosed with SCLC survive for even a year despite treatment, said Joshua Bauml, M.D., of the University of Pennsylvania Abramson Cancer Center, who specializes in treating lung cancer but was not involved in the study. "So any advance in survival is really important."

Some, however, were hoping for more from adding the immunotherapy drug to the standard treatment.

On Twitter, for example, Paul Wheatley-Price, M.D., of the University of Ottawa, called the finding "good news." Even so, he added, "Greedily I want more benefit, but it's a start."

In addition to new therapies like atezolizumab, Dr. Bauml said, another potential avenue of further survival improvements in SCLC, which is strongly linked to smoking, may come from the increased uptake of lung cancer screening with chest CT. He pointed to the findings from another trial presented at the meeting, called NELSON, of screening of men and women at high risk of developing lung cancer because of their smoking history.

Using an approach of four screenings over more than 6 years or no invitation to screening, the trial-conducted in the Netherlands-showed an even larger decrease in lung cancer deaths than the NCI-funded National Lung Screening Trial.

The screening, noted Dr. Bauml, led to far more people being diagnosed with lung cancer at an earlier stage than they otherwise would have been without screening, meaning the cancers should be "potentially curable." In one analysis from the trial, in fact, participants who underwent screening were far more likely to have surgery as a treatment for lung cancer than those were not invited for screening.

With "more robust screening programs," Dr. Bauml continued, "we will see even more patients diagnosed with SCLC at an earlier stage."

© 2018 The National Cancer Institute

MD Anderson immunologist Jim Allison awarded Nobel Prize

T cell discoveries led to game-changing treatment revolutionizing cancer care

MD Anderson Cancer Center -- October 1, 2018

companies img Meet Dr. Jim Allison, winner of 2018 Nobel Prize in Physiology or Medicine

HOUSTON -- Jim Allison, Ph.D., chair of Immunology and executive director of the Immunotherapy Platform at The University of Texas MD Anderson Cancer Center, today was awarded the 2018 Nobel Prize in Physiology or Medicine for launching an effective new way to attack cancer by treating the immune system rather than the tumor. Allison is the first MD Anderson scientist to receive the world's most preeminent award for outstanding discoveries in the fields of life sciences and medicine.

"By stimulating the ability of our immune system to attack tumor cells, this year's Nobel Prize laureates have established an entirely new principle for cancer therapy," the Nobel Assembly of Karolinska Institute in Stockholm noted in announcing the award to Allison and Tasuku Honjo, M.D., Ph.D., of Kyoto University in Japan.

"I'm honored and humbled to receive this prestigious recognition," Allison said. "A driving motivation for scientists is simply to push the frontiers of knowledge. I didn't set out to study cancer, but to understand the biology of T cells, these incredible cells that travel our bodies and work to protect us."

Allison started his career at MD Anderson in 1977, arriving as one of the first employees of a new basic science research center located in Smithville, Texas. He was recruited back to MD Anderson in November 2012 to lead the Immunology Department and to establish an immunotherapy research platform for MD Anderson's Moon Shots Program.

"Jim Allison's accomplishments on behalf of patients cannot be overstated," said MD Anderson President Peter WT Pisters, M.D. "His research has led to life-saving treatments for people who otherwise would have little hope. The significance of immunotherapy as a form of cancer treatment will be felt for generations to come."

The prize recognizes Allison's basic science discoveries on the biology of T cells, the adaptive immune system's soldiers, and his invention of immune checkpoint blockade to treat cancer.

Allison's crucial insight was to block a protein on T cells that acts as a brake on their activation, freeing the T cells to attack cancer. He developed an antibody to block the checkpoint protein CTLA-4 and demonstrated the success of the approach in experimental models. His work led to development of the first immune checkpoint inhibitor drug. Ipilimumab was approved for late-stage melanoma by the U.S. Food and Drug Administration in 2011.

His drug, known commercially as Yervoy, became the first to extend the survival of patients with late-stage melanoma. Follow-up studies show 20 percent of those treated live for at least three years with many living for 10 years and beyond, unprecedented results. Subsequent research has extended this approach to new immune regulatory targets, most prominently PD-1 and PD-L1, with drugs approved to treat certain types and stages of melanoma, lung, kidney, bladder, gastric, liver, cervical, colorectal, and head and neck cancers and Hodgkin's lymphoma. Clinical trials are underway in many other cancer types.

"I never dreamed my research would take the direction it has," Allison said. "It's a great, emotional privilege to meet cancer patients who've been successfully treated with immune checkpoint blockade. They are living proof of the power of basic science, of following our urge to learn and to understand how things work."

"Science advances on the efforts of many," Allison said. "A succession of graduate students, postdoctoral fellows and colleagues at MD Anderson, the University of California, Berkeley, and Memorial Sloan Kettering Cancer Center played important roles in this research."

Allison's ongoing leadership at MD Anderson focuses on improving knowledge of how these drugs work to extend the benefits of immunotherapy to more patients with more types of cancer. He continues his own research, focusing on the details of immune response to cancer and identifying new targets for potential treatment.

He also leads the immunotherapy platform for MD Anderson's Moon Shots Program, which conducts immune monitoring by analyzing tumor samples before, during and after treatment, aiming to understand why these drugs work for some patients but not for others. The platform works with more than 100 immunotherapy clinical trials at MD Anderson addressing a variety of cancers. The platform also collaborates with pharmaceutical companies to help them develop new drugs and combinations to better treat cancer.

"We need these drugs to work for more people," Allison said. "One challenge is that the clinical success has outrun our scientific knowledge of how these drugs work and how they might best be combined with other therapies to improve treatment and reduce unwanted side effects. We need more basic science research to do that."

Allison has collaboratively worked with scientists around the globe to expand the field of immunotherapy. Some of his leadership positions include serving as a co-leader of the Stand Up To Cancer-Cancer Research Institute Cancer Immunology Dream Team and as a director of the Parker Institute for Cancer Immunotherapy (PICI). Allison also is deputy director of the David H Koch Center for Applied Research of Genitourinary Cancers at MD Anderson and holds the Vivian L. Smith Distinguished Chair in Immunology.

Crucial funding for his research over the years has come from the National Institutes of Health, particularly the National Cancer Institute, Howard Hughes Medical Institute, the Cancer Research Institute, Prostate Cancer Foundation, Stand Up to Cancer and PICI.

Allison will be honored at Nobel ceremonies in Stockholm in December. The Nobel Prize in Physiology or Medicine 108 times to 214 Nobel Laureates between 1901 and 2017.

For more information about Allison, his work and the Moon Shots Program, please visit www.mdanderson.org/nobelprize.

© 2018 The University of Texas MD Anderson Cancer Center

Melody Management

Cancer Research & APP Development

Tailored Radiation to Treat Brain Metastases Reduces Impact on Cognitive Function

by NCI Staff

The National Cancer Institute -- November 26, 2018

companies img Whole brain radiation therapy that avoids the hippocampus (top 3 panels, green shaded area) compared with standard whole brain radiation therapy (bottom 3 panels).

Credit: Radiat Oncol Nov. 2015. doi: 10.1186/s13014-015-0555-9 CC BY 4.0

Radiation therapy, a widely used treatment for brain metastases, can impair important brain functions like memory, processing speed, and attention span, often greatly affecting patients' quality of life. Initial results from a large clinical trial now suggest that an advanced radiotherapy technique can limit the harm to patients' cognitive function compared to standard radiation therapy without affecting the treatment's ability to shrink or control brain tumors.

In the NCI-funded trial, patients with brain metastases were treated with the drug memantine (Namenda), which has been shown to help protect cognitive function, and whole-brain radiation therapy (WBRT). Half of the patients, however, received a technically advanced form of WBRT that specifically avoided the hippocampus, an area in the lower-middle portion of the brain.

Compared with patients who received standard WBRT, those who underwent hippocampal-avoidance WBRT were less likely to experience declines in cognitive function, said the trial's co-lead investigator, Vinai Gondi, M.D., director of research at the Northwestern Medicine Proton Center and the Northwestern Medicine Cancer Center Warrenville. Dr. Gondi recently reported the trial's findings at the annual meetings of the American Society for Radiation Oncology (ASTRO) and the Society for Neuro-Oncology (SNO).

The results confirm earlier studies that had suggested the hippocampus is highly sensitive to radiation, he said. They also verify that, by sparing the hippocampus, "we can achieve the objectives of protecting patients' cognitive function, effectively managing their brain metastases, and improving neurological symptoms."

Christina Tsien, M.D., of the Washington University School of Medicine in St. Louis, speaking at the ASTRO meeting, said that hippocampal-avoidance WBRT now represents a standard of care for patients with brain metastases.

But, Dr. Tsien cautioned, "it's a complex era" when it comes to treating cancer that has spread to the brain. With multiple approaches and therapies, she continued, treating brain metastases is now "much more nuanced" than it once was.

Protecting the Hippocampus

The goals of and approaches to treating brain metastases can vary, depending on factors like how many tumors are in the brain and the patient's health status, said Stuart Burri, M.D., chair of Radiation Oncology at the Levine Cancer Institute in Charlotte, NC.

Once cancer has spread to the brain, treatment is largely focused on "improving the patient's quality of life" by alleviating the neurologic problems that metastatic tumors often cause, Dr. Burri said.

Some targeted and immune-based therapies that attack cancer cells everywhere in the body (systemic treatments) have been shown to shrink brain metastases in some patients. But this is still a small group of patients, he cautioned.

Patients with three or fewer brain metastases typically receive stereotactic radiosurgery, in which high-dose radiation is specifically targeted to individual tumors. This approach can shrink tumors and help control symptoms with less risk of harming cognitive function than WBRT. The trade off, Dr. Gondi said, is that there is a higher risk of tumors developing elsewhere in the brain with stereotactic radiosurgery than with WBRT.

Stereotactic radiosurgery is increasingly being used to treat patients with more than three brain metastases, Dr. Burri said. But many patients still receive WBRT at some point, and nearly half of patients who receive traditional WBRT experience some cognitive decline, Dr. Tsien said. While some of these problems can resolve, others that are sustained and progressive "can be life changing" for patients and their caregivers, she added.

Based on these studies, researchers with the NCI-sponsored NRG Oncology clinical trials group decided to test whether tailored WBRT that avoids the hippocampus could help limit treatment-related cognitive decline.

The approach initially showed promise in a small phase 2 clinical trial. And those findings came not long after results from a large NCI-funded clinical trial showed that memantine could slow the development of WBRT-related cognitive problems, explained Ann O'Mara, Ph.D., R.N., head of palliative research in NCI's Division of Cancer Prevention.

The next logical question, Dr. O'Mara continued, was: "If we add memantine to hippocampal avoidance, might it reduce the effect [of WBRT] on cognitive function even more?"

Protecting Cognitive Function without Reducing Efficacy

The trial, called NRG-CC001, enrolled more than 500 patients with brain metastases. Participants could have any number of brain metastases, but none within 5 millimeters of the hippocampus. Most patients in the trial had lung cancer and approximately 40% of patients had brain metastases as their only site of metastatic cancer.

Participants in the trial completed several different tests commonly used to assess cognitive function when they entered the trial and again at several time points over the ensuing year.

There was no difference in how long participants treated with hippocampal-avoidance WBRT lived overall and without further spread or growth of tumors in their brains compared with those treated with standard WBRT. Illustrating the poor prognosis associated with brain metastases, nearly one-third of the patients died within 4 months of entering the trial.

At the ASTRO meeting, Dr. Gondi reported that, at each testing point in the trial, participants who had undergone hippocampal-avoidance WBRT were less likely to experience cognitive decline-which the researchers defined as a meaningful decrease in scores on any of the cognitive function tests-than those who received standard WBRT.

Overall, patients who underwent hippocampal avoidance had a 26% reduced risk of experiencing cognitive decline. Patients in this group who were age 61 or younger were less likely to experience cognitive decline than those who were older, but patients benefited from the approach regardless of age.

At the SNO meeting, the researchers presented a more detailed breakdown of the cognitive function testing results. The benefits of hippocampal avoidance, they reported, came largely in the areas of executive function-the ability to perform common daily tasks-and learning and memory. Patients also reported significant improvements in neurologic symptoms.

"We found that patients who received hippocampal avoidance reported improved cognition, less fatigue, improved ability to speak, and better preservation of their ability to remember things," said the trial's other co-lead investigator, Paul Brown, M.D., of the Mayo Clinic.

Overall, the trial's finding should be viewed in the context of the use of WBRT prior to the earlier trial of memantine, he said. When the findings from the memantine trial and this recent trial are combined, he continued, the combination of hippocampal avoidance WBRT and memantine may be able to reduce the risk of radiation-related cognitive decline by more than 40% compared with WBRT used alone.

Expanding Use of Hippocampal Avoidance?

Dr. Burri agreed that the findings are very important and should change practice. Smaller studies provided convincing evidence "that you're not doing any harm [to survival] with hippocampal avoidance," he said. But "it wasn't clear until these new data that it was actually superior" to standard WBRT in terms of protecting cognitive function.

Although it takes some training to be able to perform hippocampal-avoidance WBRT, Dr. Burri said, most hospitals and centers that perform radiation therapy should be able to offer it.

In the meantime, further studies are under way to better understand the role of this approach. NRG Oncology, for example, is conducting an NCI-funded trial to test hippocampal avoidance during prophylactic cranial radiation therapy in people with small cell lung cancer, in whom brain metastases are particularly common.

And studies are just beginning to look at how hippocampal avoidance WBRT performs in patients who have received prior immunotherapy or targeted therapies.

"That's an exciting and important area of ongoing investigation," Dr. Gondi said.

Radiation Therapy to Treat Cancer

© 2018 The National Cancer Institute

Stand Up to Cancer funds innovative approach to pancreatic cancer

MD Anderson, Baylor College of Medicine project pursues new angle on immunotherapy

MD Anderson Cancer Center -- November 20, 2018

companies img Credit: standuptocancer.org

HOUSTON -- Research on a new way of deploying the immune system against pancreatic cancer, an exceptionally lethal cancer that has so far resisted new immunotherapies, will receive $1 million in initial funding from Stand Up to Cancer.

The project led by researchers from The University of Texas MD Anderson Cancer Center and Baylor College of Medicine will collect T cells - the immune system's targeted warriors -- from tumors, expand their number by the billions and then customize them to resist being shut down by a common substance that's abundantly produced in tumor tissue.

Stand Up to Cancer, a program of the Entertainment Industry Foundation to encourage cancer research collaboration, and the American Association for Cancer Research on Tuesday announced funding of seven projects, the first under its Pancreatic Cancer Collective, a collaboration with the Lustgarten Foundation to accelerate research and improve patient outcomes for pancreatic cancer. Only about 8 percent of pancreatic cancer patients survive to five years, according to the National Cancer Institute.

"We're encouraged by Stand Up to Cancer's support for this potential approach to more efficiently target and overwhelm solid tumors with an immune response," said project leader Patrick Hwu, M.D., head of MD Anderson's Division of Cancer Medicine and chair of Melanoma Medical Oncology.

Immune checkpoint blockade drugs that unleash T cells to attack cancer have demonstrated some success in more than a dozen cancers, but have not worked against pancreatic cancer. Hwu is a pioneer in the field of adoptive cell therapy using tumor-infiltrating lymphocytes (TILs) - a process of capturing T cells that have attacked a patient's tumor, expanding them in the lab, and then re-infusing them in the patient by the billions.

Billions of T cells, genetically fortified

"We know pancreatic cancer is immunosuppressive and that very few T cells penetrate the tumor, so we hypothesize that checkpoint blockade doesn't work because there are too few T cells," said team co-leader Chantale Bernatchez, Ph.D., assistant professor of Melanoma Medical Oncology at MD Anderson.

The team's answer to this problem combines MD Anderson capabilities to massively expand the relatively few T cells found in pancreatic tumors with Baylor College of Medicine technology to insert a defective receptor for Transforming Growth Factor-Beta (TGF-Beta) on those T cells, allowing them to resist being deactivated by TGF-Beta secreted by the tumor and surrounding cells.

Co-leader Cliona M. Rooney, Ph.D., Baylor College of Medicine, professor of Hematology-Oncology and Cell and Gene Therapy, has developed the approach to insert a gene that expresses a truncated "decoy" receptor on the T cells that allows TGF-Beta to bind to the receptor, but not deactivate the T cell.

Rooney, Hwu and Bernatchez have collaborated for several years to optimize this gene modification on TILs used to treat melanoma. The anti-tumor efficacy of these genetically modified T cells is currently tested in a clinical trial to treat metastatic melanoma patients whose disease resists checkpoint blockade, a patient population with poor prognosis.

A durable response in a subset of these patients suggests that this strategy may work in tumor types not responsive to current immunotherapies, Bernatchez said.

The SU2C funding will support preclinical proof-of-concept studies testing this approach to treat human pancreatic cancer in mouse models. Stand Up to Cancer, 14 months from now, will select several of the original seven projects to fund clinical trials of the most promising approaches.

Bernatchez and her team demonstrated earlier this year that they could find enough T cells in human pancreatic tumors to cultivate them in a medium that includes interleukin-2 and two antibodies that stimulate T cell growth, creating the billions of T cells necessary to treat patients.

"We found we could grow enough T cells to infuse back into patients 90 percent of the time," Bernatchez said.

MD Anderson has joined with Iovance Biotherapeutics to open a clinical trial of these first-generation, unmodified TILs for patients with pancreatic cancer, ovarian cancer or osteosarcoma.

TILs have been used in a longstanding clinical trial for advanced melanoma, with MD Anderson reporting that 42 percent of 74 patients in the clinical trial had their tumors shrink, and 20 percent have durable responses. While checkpoint blockade drugs have superseded TILs in melanoma, researchers believe TILs might work in other tumor types, such as pancreatic cancer, that resist checkpoint blockade.

© 2018 The University of Texas MD Anderson Cancer Center

The Cancer Moonshot: Moving from Planning to Research

by NCI Staff

The National Cancer Institute -- November 19, 2018

companies img A research technician from the Advanced Technology Research Facility at NCI's Frederick National Laboratory for Cancer Research.

Credit: National Cancer Institute

The Cancer Moonshot was announced in 2016 with three overarching goals: accelerate progress in cancer research, encourage greater collaboration, and improve the sharing of data. More than 2 years later, the foundation has been laid for achieving those goals.

A critical component of that foundation was the Moonshot Blue Ribbon Panel, which engaged in a thoughtful and thorough process to develop a comprehensive report that laid out a series of recommendations to get us to those goals. In December 2016, Congress passed the 21st Century Cures Act, which allocated $1.8 billion over 7 years to transition the Moonshot from an ambitious idea to a reality.

NCI rapidly established a systematic process for implementing the report's recommendations. These efforts have resulted in the launching of a series of new scientific programs and the awarding of close to $600 million to research teams across the country. Each of the recommendations of the Blue Ribbon Panel are being addressed through these programs.

As the Moonshot moves forward, I want to provide an update to the cancer community about the science being supported by the Moonshot, because it is the science that will accelerate progress across the entire cancer continuum.

The Science Begins

The Blue Ribbon Panel's recommendations covered 10 areas that the panel of experts, based on their extensive deliberations and feedback solicited from across the cancer community, felt were poised for progress if additional funding could be made available.

NCI staff led the effort to operationalize those recommendations, forming working groups and using a variety of mechanisms to develop funding opportunities aligned with each recommendation. Currently, most of fiscal years' 2017 and 2018 funds have been awarded, and the next phase of the Moonshot-the research phase-is well underway.

    The Cancer Moonshot Initiatives

    From a cancer data ecosystem to improving cancer symptom management, learn more about all of the research initiatives being supported by the Cancer Moonshot.

Cancer immunotherapy is one example. Although progress in immunotherapy has been swift in recent years, the panel felt that, with an infusion of funds, even further advancement would be possible.

Under the Moonshot, NCI is funding two groups of research teams: one focused on immunotherapeutic approaches in adults and the other in children. The Immuno-Oncology Translational Network-which includes 31 principal investigators at 19 different institutions-is investigating the mechanisms by which tumors in adults interact with the immune system, developing new immune-based therapies, and creating approaches for minimizing the risk of treatment side effects.

Because most pediatric cancers are biologically quite different from adult cancers, a separate network of research teams has been established that will focus their efforts on identifying immune targets and treatments specific to pediatric cancers and developing laboratory models for testing immunotherapies against these cancers.

Also built into the immunotherapy component of the Moonshot is a data management center, which will allow researchers to share their work easily and facilitate collaboration. This is not unique to the immunotherapy recommendation. Data management centers are being established for other Moonshot-funded research networks as well.

The data management centers for these different networks will interact with each other, sharing data, information, and resources. They are central to public access and data sharing policy established for the Moonshot, which emphasizes the importance of investigators rapidly making available published studies that result from their Moonshot-funded research, including their primary data.

The panel also made recommendations for advancing progress in cancer prevention and early detection. Some of the research being funded in this area will make extensive use of implementation science-taking evidence-based interventions and testing ways to apply them in real-world settings. For example, several research teams will test ways to improve smoking cessation in economically disadvantaged populations where tobacco use remains stubbornly high.

Similarly, the uptake of colorectal cancer screening is low among certain populations, including several racial/ethnic minority groups. A Moonshot-funded initiative is tackling this issue directly, with research teams conducting pilot studies of approaches to improve both screening in underserved populations and the necessary clinical follow-up from that screening.

Supporting a Broad Spectrum of Investigation

The Moonshot is also focused on supporting fundamental research that will further improve our understanding of cancer.

One such example is the Human Tumor Atlas Network (HTAN), a collaborative network that includes investigators at 10 research centers and one data management center. Using a broad range of tools and technologies, these research teams will perform intensive analyses of tumor and tissue samples to construct 3-dimensional maps of human cancers. These maps will capture how cancers change over time-from a precancerous lesion to established tumor to resistant tumor to metastasis-and describe the composition of the types of cells within and around a tumor and the genetic makeup of those cells.

Research teams being funded will focus on highly aggressive pediatric cancers (e.g., neuroblastoma and glioblastoma), on cancer types that disproportionately affect minority and underserved populations (e.g., breast, lung), and on cancers that often have a hereditary component (e.g., colon).

The Blue Ribbon Panel also recognized that accelerating progress against a disease as complicated as cancer requires greater collaboration among researchers and a more efficient research process. One recommendation, for example, was the creation of a network for directly engaging patients. The network's aim will be to make it possible for any patient diagnosed with cancer to have their tumors molecularly profiled and be preregistered for any clinical trials for which they might become eligible.

An essential component of this patient network will be a biobank for storing tumor samples, other tissue specimens, and associated patient data. Special emphasis will be given to include rare tumors. In fact, under the Moonshot, an NCI research team has already launched a pilot project, called NCI-CONNECT, for people diagnosed with rare central nervous system tumors.

Moonshot research teams may be able to take advantage of core services, such as genomic analyses or the formulation of drug candidates for laboratory testing, available through NCI via contracts, including through the Frederick National Laboratory for Cancer Research.

A Foundation for Progress

companies img Dinah Singer, Ph.D. Co-Chair, Cancer Moonshot Blue Ribbon Panel NCI Acting Deputy Director

Credit: National Cancer Institute

As co-chair of the Moonshot Blue Ribbon Panel, I'm extremely pleased by what we've been able to accomplish in such a short period, with a process marked by a true spirit of collaboration and collegiality.

NCI leadership is committed to maintaining that collaborative spirit, and to managing the Moonshot in a way that will provide the stability and continuity necessary to allow research to continue at a swift pace and help to achieve the rapid gains envisioned for this effort. We're also committed to keeping the cancer research community fully informed as the Moonshot moves forward.

With these new research initiatives, the Moonshot is already well on its way to achieving its goals and having a lasting impact on cancer research.

© 2018 The National Cancer Institute

NCI-MATCH Update: More Labs, New Arms, and Initial Findings

by NCI Staff

The National Cancer Institute -- November 15, 2018

companies img Credit: National Cancer Institute

NCI-MATCH, the largest precision medicine trial of its kind, was launched in August 2015 by NCI and the ECOG-ACRIN Cancer Research Group. Initial findings from several of the trial's treatment arms-in effect, sub-studies of the larger trial that are testing specific therapies-have been released over the last year.

But, as is to be expected in a dynamic trial of this size and scope, much more is happening.

This includes the opening of new trial treatment arms that are testing additional drugs, and the addition of new laboratories to perform testing on tumor samples of potential trial participants.

Given the extent of the activity and the importance of this trial, we'd like to update the cancer community on the status of NCI-MATCH and share the plans for it going forward.

A New Referral Process

As a reminder, NCI-MATCH is a signal-finding trial with the goal of determining whether specific targeted therapies are safe and have activity in people with advanced cancer whose tumors have a "matching" gene mutation, regardless of their cancer type. When a strong signal is seen suggesting that a drug may shrink or stabilize tumors, it might then be further studied in a larger, more definitive clinical trial.

NCI-MATCH is enrolling patients at nearly 1,100 cancer centers and community hospitals represented across every state, the District of Columbia, and Puerto Rico, and it includes researchers from the National Clinical Trials Network and NCI Community Oncology Research Program. Pharmaceutical companies have provided the treatments being used in NCI-MATCH under an NCI Investigational New Drug application.

When the trial was first launched, doctors sent tumor tissue from new or recent patient biopsies to the NCI-MATCH Central Biorepository at the University of Texas MD Anderson Cancer Center. These tumor samples then underwent investigational genetic sequencing at one of four NCI-MATCH Network Laboratories.

In the next phase of the study, a lab referral process was developed to better capture advanced cancer patients with these rarer mutations who were having tumor testing performed as part of their routine care. Under this new approach, four additional laboratories were recruited to join the trial: two academic and two commercial labs. These labs do not specifically test samples for NCI-MATCH, but they have procedures in place to contact a patient's physician if they find a gene abnormality that allows a patient to be eligible for the trial.

That process was very successful, but due to the rarity of many of the tumor types and genetic mutations being tested for, it was apparent that many more laboratories were needed to join the network. What initially involved only four designated labs has since been expanded to a larger group of labs across the country, which should number around 30 by the beginning of 2019.

This process is now the only way for new patients to enroll in NCI-MATCH.

Because many of these facilities are large reference labs (they perform a large volume of different types of testing for many hospitals, clinicians, etc.) that are located across the country, we believe this approach will increase referrals to the trial arms and make NCI-MATCH more accessible to patients. At the moment, about 85% of people referred to the trial by one of these labs is enrolled on the study, with seven to eight new patients enrolling each week.

More Arms and Reporting Out Results

NCI-MATCH will soon have nearly 40 study arms testing different therapies that target specific gene abnormalities in tumors. Findings from four of those arms were released within the last year, and data from additional study arms will be reported over the next several months.

The arms that have announced results so far have found several promising signals, an observation that is particularly noteworthy given that the patients in these studies have typically received many prior treatments.

For example, findings from one arm showed that the drug nivolumab (Opdivo) has promising activity in tumors with defects in their ability to repair damaged DNA, called mismatch repair deficiency. Although this defect is most commonly seen in a subset of colorectal cancers and endometrial cancers, it was also present in many other cancers, including some very rare tumor types.

Findings from another NCI-MATCH arm suggested that an investigational targeted drug, AZD4547, may be effective against tumors with specific types of alterations, called FGFR gene fusions. This opens up the possibility of a new area of study and provides a potential novel treatment option for patients with few known effective treatments.

Most recently, researchers announced that in one arm, the AKT inhibitor capivasertib reduced tumor size in 23% of the 35 patients receiving the drug. Tumors stopped growing in another 46% of the patients on this arm. These are positive results that indicate further study of this drug is warranted in patients whose tumors have a specific mutation in the AKT1 gene.

NCI-MATCH is very much a dynamic, ongoing trial, and it is poised to generate additional results for months and years to come. Several treatment arms for rare molecular alterations continue to enroll patients. Five arms have recently been added, and another four arms will be added in the next six months.

Some of these new arms are being opened to address some of the promising results from initial trial arms. For example, one arm is testing a different drug in the same type of gene fusion that was used in the AZD4547 trial.

More Patients with Less Common & Rare Cancers

companies img Lyndsay Harris, M.D. Associate Director Cancer Diagnosis Program NCI Division of Cancer Treatment and Diagnosis

An important goal of the NCI-MATCH study was for about 25% of the enrolled patients to have rare or less common cancers, for which dedicated clinical trials may not be feasible. Surprisingly, 62.5% of the first 6,000 patients who entered the trial's initial screening phase had tumors other than the four most common cancers (breast, colorectal, non-small cell lung, and prostate cancer).

The inclusion of such a large proportion of patients with less common cancers is providing important opportunities to test new therapies against these rare tumor types and to determine the extent to which they share the same genetic abnormalities found in more common cancers. We are also learning what types of potentially targetable molecular alterations exist in these less common tumors. This is particularly important as these patients often have few treatment options.

In addition, the trial aims to study rarer gene abnormalities, and the change in the referral process has helped fill some of the arms studying those variants that hadn't accrued enough participants after the initial screening phase.

As the enrollment of patients with rare cancers and genetic mutations illustrates, the design and scale of NCI-MATCH is creating important opportunities that will allow oncologists to better understand how we can best use targeted therapies, incorporate genomic testing into patient care, and take advantage of innovative trials to advance our understanding of cancer and ability to treat it closer to where patients live.

Importantly, additional molecular studies are planned that will help us understand response and resistance to these targeted treatments.

Using these novel approaches, we are hopeful we can continue to make inroads against this devastating disease.

© 2018 The National Cancer Institute

FDA restrictions on e-cigarettes important step to protect the health of youth

MD Anderson supports efforts to lower nicotine use in teens and adolescents

MD Anderson Cancer Center -- November 15, 2018

companies img

Credit: iStock

HOUSTON -- The University of Texas MD Anderson Cancer Center applauds new actions announced today by the U.S. Food and Drug Administration (FDA) to limit the sale of most flavored electronic cigarettes (e-cigarettes) to age-restricted locations and require age-verification for online sales to lower the use of these products in children. In addition, the FDA plans to restrict the marketing of these products toward youth.

"Today's actions by the FDA represent a significant step toward protecting the health of our future generations," said Peter WT Pisters, M.D., president of MD Anderson. "These flavored products often are appealing to children and adolescents, and we support measures to prevent young people from developing a lifetime of addiction to nicotine, which can lead to a variety of health problems and potentially future tobacco use."

According to data today from the Centers for Disease Control and Prevention (CDC), more than 3.6 million middle and high school students were current e-cigarette users in 2018, up more than 1.5 million relative to 2017. Recognizing this as an epidemic among young people in this country, the FDA proposed actions to curb youth appeal in September 2018.

"While we have been encouraged by the progress made in lowering tobacco use, we remain troubled by the epidemic rates of e-cigarette use among our young people," said Ernest Hawk, M.D., division head and vice president of Cancer Prevention & Population Sciences. "It's especially concerning because of the wide variety of products available, each with different ingredients and nicotine concentrations. We can't really be sure what these products contain, what they deliver to users or what the corresponding health concerns may be."

According to the U.S. Surgeon General's report on e-cigarettes, the aerosol produced by these products is not a harmless vapor, but contains a number of volatile chemicals and known carcinogens. Further, the Surgeon General has affirmed a strong association between the use of e-cigarettes and conventional tobacco products. Nicotine itself is a highly addictive chemical that can disrupt adolescent brain development, impacting learning, mood and anxiety.

Recognizing the importance of educating youth about tobacco use and its harms, MD Anderson has a variety of programs designed to prevent tobacco initiation. Researchers led by Alex Prokhorov, M.D., Ph.D., professor of Behavioral Science, developed A Smoking Prevention Interactive Experience (ASPIRE), a youth-oriented tobacco prevention and cessation curriculum. The online program is designed to provide an engaging way for teens to learn about the dangers of tobacco products. Since its web-based launch in 2008, ASPIRE has reached 100,291 students in 8 countries. In 2018, the team launched an updated version of the curriculum, including new content focused on alternative tobacco products, such as e-cigarettes and hookah.

Further, as founding partners of the CATCH Global Foundation, MD Anderson and UTHealth School of Public Health support distribution of a youth e-cigarette prevention curriculum, CATCH My Breath, to middle schools across the country.

MD Anderson also has served as a resource for statewide tobacco control policies to protect the health of future generations. Through MD Anderson's EndTobacco© program, MD Anderson collaborated with The University of Texas System to launch the system-wide Eliminate Tobacco Use initiative in 2016, which supports a variety of collaborative actions designed to advance a tobacco-free culture on all UT System campuses. This effort led to all 14 institutions of the UT System becoming tobacco-free as of June 2017.

Additionally, EndTobacco has served as an educational resource to policy makers considering actions to limit youth tobacco exposure, such as raising the minimum legal sale age for tobacco products from 18 to 21 and a law adopted in 2017 to prohibit the sale of e-cigarettes to minors under 18. EndTobacco is an initiative of the cancer prevention and control platform, part of MD Anderson's Moon Shots Program, a collaborative effort to accelerate the development of scientific discoveries into clinical advances that save patients' lives.

"Tobacco use remains the leading cause of cancer in the United States and, unfortunately, the leading preventable cause of death," said Hawk. "We would encourage parents and educators to learn more about the health risks associated with e-cigarettes and talk to children about avoiding these products. Together, we remain committed to advancing evidence-based programs and policies that will lower current and future tobacco use, with the goal of saving lives and reducing current and future suffering from tobacco-related conditions."

© 2018 The University of Texas MD Anderson Cancer Center

Immunotherapy combination and chemotherapy show encouraging results in Phase II acute myeloid leukemia study

MD Anderson trial reveals 43 percent complete response rate for triple therapy

MD Anderson Cancer Center -- November 13, 2018

companies img Naval Daver, M.D.

HOUSTON -- A triple therapy combining two immune checkpoint inhibitors (ICPIs) with the standard-of-care chemotherapy, a hypomethylating agent called azacitidine, has shown promising results for treatment of relapsed or refractory acute myeloid leukemia (AML), according to findings from a Phase II study at The University of Texas MD Anderson Cancer Center.

Findings from the study, led by Naval Daver, M.D., associate professor of Leukemia, are being presented at the 60th American Society of Hematology Annual Meeting & Exposition in San Diego.

The study compared two patient cohorts - the first included 70 patients who received chemotherapy azacitidine (AZA) plus nivolumab. The second cohort with 20 patients was given a triple therapy employing the same two drugs with ipilimumab. Cohort 1 is now closed while cohort 2 continues to enroll patients.

The triple therapy showed promising results with a complete response rate of 43 percent and a projected one-year overall survival of 58 percent. The AZA plus nivolumab cohort reported a complete response rate of 22 percent with a projected one-year overall survival of 40 percent. Responses in both cohorts included best response within three months of therapy initiation.

"The response rate and survival in patients with relapsed AML treated with azacitidine with both nivolumab and ipilimumab, appears encouraging and potentially superior to azacitidine with nivolumab in a small cohort of patients," said Daver. "However, we need to study more patients with longer follow-up to make firm conclusions. Immune related toxicities are more common and may be more severe with this double checkpoint approach, and awareness and close monitoring, therapy interruption, and aggressive treatment of immune toxicities is critical if such approaches are to be successful."

Adverse side effects were reported in 11 percent of the AZA plus nivolumab group, with the most common events being pneumonitis and colitis. The triple therapy cohort reported grade 3 or 4 immune side effects in 35 percent of patients, including pneumonitis, skin rash, pituitary hormone and liver enzyme irregularities, and colitis.

"The current triple therapy cohort will enroll up to 30 patients, and after that we plan to open a new cohort that will evaluate a higher dose of ipilimumab and a lower dose of nivolumab in 30 patients," said Daver. "Once we analyze both cohorts and select the appropriate dosing approach, we hope to evaluate this approach in a larger multi-center study."

Detailed correlative analysis to identify biomarkers of response and resistance will be conducted on pre- and on-treatment bone marrow and blood samples for all patients in MD Anderson's Immunotherapy Platform under the supervision of Padmanee Sharma, M.D., Ph.D., professor of Genitourinary Medical Oncology.

MD Anderson study participants included Guillermo Garcia-Manero, M.D.; Jorge Cortes, M.D.; Farhad Ravandi, M.D.; Tapan Kadia, M.D.; Elias Jabbour, M.D.; Marina Konopleva, M.D., Ph.D.; Courtney DiNardo, M.D.; Rita Assi, M.D.; Sherry Pierce; Zeev Estrov, M.D.; Yesid Alvarado, M.D.; Koichi Takahashi, M.D.; Tauna Gordon; Naveen Pemmaraju, M.D.; Michael Andreeff, M.D., Ph.D.; Steven Kornblau, M.D.; Wilmer Flores; Mansour Alfayez, M.D.; Jairo Matthews; and Hagop Kantarjian, M.D., all of the Department of Leukemia; Jing Ning, Ph.D., and Graciela Nogueras Gonzalez of Biostatistics; Sreyashi Basu; Jorge Blando, D.V.M.; and James Allison, Ph.D., of Immunology; and Padmanee Sharma, M.D., Ph.D., of Genitourinary Medical Oncology.

The study was funded through a strategic collaboration with Bristol-Myers Squibb; and by the National Institutes of Health (CA016672 and CA100632); the Dick Clark Immunotherapy Fund; and the Myelodysplastic Syndromes and Acute Myeloid Leukemia Moon Shot, part of MD Anderson's Moon Shots Program, a collaborative effort to accelerate the development of scientific discoveries into clinical advances that save patients' lives.

© 2018 The University of Texas MD Anderson Cancer Center

Fecal transplant effective against immunotherapy-induced colitis

Common side effect successfully treated by microbiome manipulation

MD Anderson Cancer Center -- November 12, 2018

companies img Yinghong Wang, M.D., Ph.D.

HOUSTON -- For the first time, transplanting gut bacteria from healthy donors was used to successfully treat patients suffering from severe colitis caused by treatment with immune checkpoint inhibitors (ICIs). The study from The University of Texas MD Anderson Cancer Center, which includes two patients, suggests fecal microbiota transplantation (FMT) is worth investigating in clinical trials as a therapy for this common side effect of immunotherapy.

The research, led by Yinghong Wang, M.D., Ph.D., assistant professor of Gastroenterology, Hepatology & Nutrition and director of Medication Induced Colitis and Enteritis, was published today in Nature Medicine.

"The resolution of colitis in these patients can be confirmed clinically and endoscopically after FMT treatment," said Wang. "Based on these results, this should be evaluated even as a first-line therapy for ICI-associated colitis because it's safe, quick, and the effect is durable - from one treatment."

Immune checkpoint inhibitors, which release a block on the immune system to attack cancer, have been successful in providing durable responses for patients with several cancer types. However, these treatments are often associated with significant immune-related toxicities.

Colitis, inflammation of the colon, is the second most common side effect from ICIs, occurring in up to 40 percent of patients, explained Wang. When ICI-associated colitis is severe, guidelines require a patient to stop ICI treatment until the colitis is in remission.

"If the patient is a good responder to immunotherapy, that means you've taken their effective treatment away," said Wang. "We have a limited amount of time to fix the problem so they can resume ICI treatment, but I feel that we've made great progress in this area."

The researchers chose to investigate the potential for FMT as an alternative, compassionate-use therapy for patients suffering from refractory, or unresponsive, ICI-associated colitis. The two patients included in the study were treated at MD Anderson between June 2017 and January 2018.

FMT has shown promise in treating other types of gastrointestinal diseases, such as recurrent Clostridium difficile infection and inflammatory bowel disease (IBD), which shares many clinical and molecular characteristics with ICI-associated colitis. These conditions typically are treated with steroids and targeted immunosuppressive agents, which result in additional severe side effects and can counteract the effects of immunotherapy.

Both patients in the study had a complete resolution of their colitis following treatment with FMT. The first patient's colitis resolved within two weeks following a single FMT treatment; the second patient experienced a partial recovery after the first treatment, followed by complete recovery after a second FMT. With endoscopic evaluation before and after treatment, both patients displayed significant improvements in inflammation and ulcerations, including a reduction of inflammatory immune cells.

Pre- and post-treatment stool analyses revealed patients' gut microbiomes to be most similar to the donor immediately after treatment, with less resemblance to the donor over time. Still, post-treatment gut bacteria remained distinct from their own pre-treatment microbiome. Additionally, distinct new populations of bacterial species were evident in these patients following FMT compared to pre-treatment samples, including several species known to be protective or reduce inflammation.

The authors acknowledge significant limitations to this study based on the very small cohort, and they plan to pursue clinical trials to investigate the effectiveness of FMT in treating ICI-associated colitis as compared with standard immunosuppressive therapy. FMT continues to be offered to MD Anderson patients on a compassionate-use basis.

Previous MD Anderson research showed that bacteria in the gut influence patient response to ICI therapy, and other evidence suggests modifying the microbiome in mice can alter their response to immunotherapy. The current data further suggests there is the potential for many molecular studies to better understand the role of the microbiome in driving ICI-colitis and immunotherapy response more broadly.

The study was supported by the Andrew Sabin Family Fellowship Program; the American Association for Cancer Research - Stand Up to Cancer; the National Institutes of Health (CA219896-01A1, HL124112); the Cancer Prevention & Research Institute of Texas; and the Melanoma Moon Shot, part of MD Anderson's Moon Shots Program, a collaborative effort to accelerate the development of scientific discoveries into clinical advances that save patients' lives

In addition to Wang, other MD Anderson authors include: Diana Wiesnoski, Christopher Sanchez, and Chia-Chi Chang, Ph.D., all of Genomic Medicine; Beth Helmink, M.D., Ph.D., and Vancheswaran Gopalakrishnan, Ph.D., both of Surgical Oncology; Hamzah Abu-Sbeih, M.D., Gottumukkala Raju, M.D., and John Stroehlein, M.D., all of Gastroenterology, Hepatology & Nutrition; Edwin Parra, M.D., Ph.D., and Alejandro Francisco-Cruz, Ph.D., both of Translational Molecular Pathology; Matthew Campbell, M.D., Jianjun Gao, M.D., Ph.D., and Sumit Subudhi, M.D., Ph.D., all of Genitourinary Medical Oncology; Dipen Maru, M.D., of Pathology; Jorge Blando, DVM, and James Allison, Ph.D., both of Immunology; Padmanee Sharma, M.D., Ph.D., of Genitourinary Medical Oncology and Immunology; Michael Tetzlaff, M.D., Ph.D., of Translational Molecular Pathology and Pathology; Jennifer Wargo, M.D., of Genomic Medicine and Surgical Oncology; and Robert Jenq, M.D., of Genomic Medicine and Stem Cell Transplantation. Additional authors include Kati Choi, M.D., Baylor College of Medicine, Houston; Hebert DuPont, M.D., UTHealth School of Public Health and Kelsey Research Foundation, Houston; and Zhi-Dong Jiang, Dr.Ph., UTHealth School of Public Health, Houston.

© 2018 The University of Texas MD Anderson Cancer Center

Gene Tied to Alzheimer's May Be Associated with Cancer-Related Cognitive Problems

by NCI Staff

The National Cancer Institute -- November 9, 2018

companies img Two studies have identified a genetic factor that may be linked to cancer-related cognitive problems.

Credit: iStock

It's not unusual for cancer survivors to report problems with memory, attention, learning, and processing of information months or even years after completing treatment. Scientists are just beginning to understand why some people are particularly susceptible to these cognitive difficulties, which patients often call chemobrain or chemofog.

New findings from two related NCI-funded studies-a clinical study in older women and a mouse study-may help shed further light on genetic risk factors for developing cancer-related cognitive problems.

The clinical study results point to the role of the E4 version (or E4 allele) of the APOE gene, which is a risk factor for late-onset Alzheimer's disease. In the study, published October 3 in the Journal of Clinical Oncology, older women with breast cancer who were treated with chemotherapy and were carriers of the E4 allele were more likely to have cognitive problems than women without cancer who were also carriers of the E4 allele.

In the second study, researchers described the development of an APOE mouse model of cancer-related cognitive problems. The study showed that the mice developed chemotherapy-related changes in spatial learning and memory as well as physical changes in brain regions involved in those functions. Learning and memory problems are commonly reported in human studies of cancer-related cognitive decline and Alzheimer's disease. The mouse study was published October 4 in Neurotoxicity Research.

Although other studies have shown evidence of a link between the E4 allele of APOE and cognitive problems after chemotherapy in cancer survivors, "our study is the only large study to investigate this link in older cancer patients," said Jeanne Mandelblatt, M.D., M.P.H., a geriatrician at the Lombardi Comprehensive Cancer Center at Georgetown University Medical Center (GUMC) and lead author of the clinical study. William Rebeck, Ph.D., a neuroscientist at GUMC, led the mouse study, which he did in collaboration with Dr. Mandelblatt and other GUMC colleagues.

"These results are very exciting for furthering our understanding of who may be susceptible to cancer-related cognitive problems and may provide insight into some of the mechanisms involved," said Michelle Janelsins, Ph.D., M.P.H., of the University of Rochester's Wilmot Cancer Institute, who studies cancer-related cognitive difficulties but was not involved with the two new studies.

However, before these results can be used to inform clinical practice, the research findings from this genetic study need to be confirmed with additional studies with a larger number of patients who have the E4 allele and receive chemotherapy, Dr. Janelsins said.

The E4 allele of APOE is only present in about 25% of the US population, and fewer than 30% of older women receive chemotherapy for their breast cancers, explained Dr. Mandelblatt.

Focusing on Older Breast Cancer Survivors

Older cancer survivors may be more vulnerable to developing cognitive problems than younger survivors, due to normal aging processes and because they are more likely to have multiple chronic conditions. However, the risk of cognitive problems in older survivors has not been well studied, Dr. Mandelblatt said.

As part of the ongoing multicenter Thinking and Living With Cancer (TLC) study, Dr. Mandelblatt and her colleagues monitored cognitive function in 344 women ages 60-98 years old who were newly diagnosed with nonmetastatic breast cancer and a matched group of 347 women without cancer (controls). Recruitment of participants into the study is ongoing.

Using a battery of tests, the researchers assessed cognitive function in the women when they entered the study (before treatment, in the women with cancer) and after 12 and 24 months. They also tracked self-reported cognitive problems in the two groups.

The team found that older women who received chemotherapy, with or without hormonal therapy, experienced minor cognitive declines over time. Cognitive declines occurred in areas such as the ability to focus on and process information. Women who received only hormonal therapy or who did not have cancer did not show evidence of cognitive decline.

The researchers next tested whether the presence of the E4 allele of APOE was related to the way a woman's cognitive score changed over time. They found that older survivors who received chemotherapy and had one or two copies of the E4 allele tended to show greater cognitive decline in the first 2 years after diagnosis and treatment than women without cancer (controls) who had the allele.

In addition, when the team looked specifically at women who received chemotherapy, they found that older survivors exposed to chemotherapy showed a greater decline in cognitive scores than other groups in areas such as attention and processing speed, and this effect was largely confined to those with the E4 allele.

However, because the number of women who had the E4 allele and received chemotherapy was small, Dr. Mandelblatt noted that the link between the E4 allele, chemotherapy, and cognitive decline in this study is not definitive.