A Peer-Reviewed Journal
PM O
BIOMARKERS • TARGETED THERAPIES • DIAGNOSTICS
Personalized Medicine in Oncology TM
INTERVIEW WITH THE INNOVATORS Early Recurrence Detection: Analyzing DNA from Circulating Tumor Cells and Circulating Cell-Free DNA. An Interview with Paul W. Dempsey, PhD, and Paul Y. Song, MD, of Cynvenio ......................................Page 195
BRAF MUTATIONS Implications of BRAF Mutations in Cancer........Page 200
GENETIC COUNSELING Inherited Ovarian Cancer: What Have We Learned?.............................................................Page 210
AMERICAN ASSOCIATION FOR CANCER RESEARCH Nivolumab Represents New Standard in Recurrent Head and Neck Cancer...............................214 Novel Regimen Outperforms Standard Therapy in HER2 Breast Cancer.................................. 217
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TABLE OF CONTENTS INTERVIEW WITH THE INNOVATORS
195
PMO speaks with Drs Dempsey and Song about their multiple-template strategy that analyzes DNA from circulating tumor cells and circulating cell-free DNA in blood as well as the initiation of their clinical trial in triple-negative breast cancer. BRAF MUTATIONS
200
Director, Creative & Design Robyn Jacobs
Implications of BRAF Mutations in Cancer Christos Fountzilas, MD; Virginia G. Kaklamani, MD, DSc The authors discuss inhibition of BRAF as an attractive treatment strategy for melanoma and lung cancer harboring activating mutations.
CLINICAL TRIALS TRACKER
206 Select Ongoing Trials Currently Enrolling Patients with Colorectal Cancer
Quality Control Assistant Theresa Salerno Director, Production & Manufacturing Alaina Pede
Early Recurrence Detection: Analyzing DNA from Circulating Tumor Cells and Circulating Cell-Free DNA. An Interview with Paul W. Dempsey, PhD, and Paul Y. Song, MD, of Cynvenio
GENETIC COUNSELING
210
Inherited Ovarian Cancer: What Have We Learned?
Cristi Radford, MS, CGC
Design Managers Chris Alpino Lora LaRocca Director, Digital Marketing Samantha Weissman Digital Content Manager Anthony Trevean Digital Editor John Parkinson Digital Media Specialist Charles Easton IV Jr Digital Content Manager Walford Guillaume Junior Digital Developer Christina Bethencourt Sales Operations Manager Margaret Hoffmann Executive Administrative Assistant/Office Manager Dana Rivera Administrative Assistants Sara Mohamed Colette Puhalski IT Manager Kashif Javaid Office Coordinator Robert Sorensen
President Abigail Adair Account Group Supervisor Karie Gubbins Account Supervisor Deanna Martinez Senior Account Executives Jeremy Shannon Meg Spencer Business Development Advisor Saher Almaita
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TABLE OF CONTENTS
Personalized Medicine in Oncology, ISSN 2166-0166 (print); ISSN applied for (online), is published 10 times a year by Green Hill Healthcare Communications, LLC, 1249 South River Rd, Suite 202A, Cranbury, NJ 08512. Copyright © 2016 by Green Hill Healthcare Communications, LLC. All rights reserved. Personalized Medicine in Oncology logo is a trademark of Green Hill Healthcare Communications, LLC. No part of this publication may be reproduced or transmitted in any form or by any means now or hereafter known, electronic or mechanical, including photocopy, recording, or any informational storage and retrieval system, without written permission from the Publisher. Printed in the United States of America.
(Continued)
AERICAN ASSOCIATION FOR CANCER RESEARCH
214
Nivolumab Represents New Standard in Recurrent Head and Neck Cancer
215
Pembrolizumab Elicits Response in Patients with Merkel Cell Carcinoma
216
Chemotherapy Use in Breast Cancer Declines with Gene-Based Assay
217
Novel Regimen Outperforms Standard Therapy in HER2 Breast Cancer
218
To Reduce Breast Cancer Recurrence Risk, Exercise—A Lot!
219
Walking Reduces Markers of Inflammation in Smokers with Lung Cancer
220 Multivitamin Use During Chemotherapy May Reduce Risk of Peripheral Neuropathy 221 Biologic Agents and Cardiac Toxicity Among Patients with Hematologic Malignancies 222
Stool DNA Test Performs Well in Community-Based Setting
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MISSION STATEMENT
Personalized Medicine in Oncology provides the bridge between academic research and practicing clinicians by demonstrating the immediate implications of precision medicine – including advancements in molecular sequencing, targeted therapies, and new diagnostic modalities – to the management of patients with cancer, offering oncologists, oncology nurses, payers, researchers, drug developers, policymakers, and all oncology stakeholders the relevant practical information they need to improve cancer outcomes. This journal translates the new understanding of the biology of cancer into the day-to-day management of the individual patient with cancer, using a patient’s unique genetic makeup to select the best available therapy.
OUR VISION
Our vision is to transform the current medical model into a new model of personalized care, where decisions and practices are tailored for the individual – beginning with an incremental integration of personalized techniques into the conventional practice paradigm currently in place.
EDITORIAL BOARD
EDITORS IN CHIEF Sanjiv S. Agarwala, MD St. Luke’s Hospital Bethlehem, Pennsylvania
Prostate Cancer Oliver Sartor, MD Tulane University New Orleans, Louisiana
Al B. Benson III, MD, FACP, FASCO Northwestern University Chicago, Illinois
EDITORIAL BOARD Gregory D. Ayers, MS Vanderbilt University School of Medicine Nashville, Tennessee
SECTION EDITORS Biomarkers Pranil K. Chandra, DO PathGroup Brentwood, Tennessee
Lyudmila Bazhenova, MD University of California, San Diego San Diego, California
Darren Sigal, MD Scripps Clinic Medical Group San Diego, California Hematologic Malignancies Gautam Borthakur, MD The University of Texas MD Anderson Cancer Center Houston, Texas Pathology David L. Rimm, MD, PhD Yale Pathology Tissue Services Yale University School of Medicine New Haven, Connecticut Drug Development Igor Puzanov, MD Vanderbilt University Vanderbilt-Ingram Cancer Center Nashville, Tennessee Lung Cancer Vincent A. Miller, MD Foundation Medicine Cambridge, Massachusetts Predictive Modeling Michael Kattan, PhD Case Western Reserve University Cleveland, Ohio
Leif Bergsagel, MD Mayo Clinic Scottsdale, Arizona Mark S. Boguski, MD, PhD Harvard Medical School Boston, Massachusetts Gilberto Castro, MD Instituto do Câncer do Estado de São Paulo São Paulo, Brazil Madeleine Duvic, MD The University of Texas MD Anderson Cancer Center Houston, Texas Beth Faiman, PhD, MSN, APRN-BC, AOCN Cleveland Clinic Taussig Cancer Center Cleveland, Ohio Steven D. Gore, MD The Johns Hopkins University School of Medicine Baltimore, Maryland Gregory Kalemkerian, MD University of Michigan Ann Arbor, Michigan Howard L. Kaufman, MD Cancer Institute of New Jersey New Brunswick, New Jersey
Gastrointestinal Cancer Eunice Kwak, MD Massachusetts General Hospital Cancer Center Harvard Medical School Boston, Massachusetts
Katie Kelley, MD UCSF School of Medicine San Francisco, California
Genetic Counseling Cristi Radford, MS, CGC Moffitt Cancer Center Tampa, Florida
Kim Margolin, MD University of Washington Fred Hutchinson Cancer Research Center Seattle, Washington
Melanoma Doug Schwartzentruber, MD Indiana University Simon Cancer Center Indianapolis, Indiana
Gene Morse, PharmD University at Buffalo Buffalo, New York
Minetta Liu, MD Mayo Clinic Cancer Center Rochester, Minnesota
Nikhil C. Munshi, MD Dana-Farber Cancer Institute Boston, Massachusetts Steven O’Day, MD John Wayne Cancer Institute Santa Monica, California Rafael Rosell, MD, PhD Catalan Institute of Oncology Barcelona, Spain Steven T. Rosen, MD, FACP Northwestern University Chicago, Illinois Hope S. Rugo, MD University of California, San Francisco San Francisco, California Lee Schwartzberg, MD The West Clinic Memphis, Tennessee Lillie D. Shockney, RN, BS, MAS Johns Hopkins University Baltimore, Maryland Lawrence N. Shulman, MD Dana-Farber Cancer Institute Boston, Massachusetts Jamie Shutter, MD South Beach Medical Consultants, LLC Miami Beach, Florida David Spigel, MD Sarah Cannon Research Institute Nashville, Tennessee Moshe Talpaz, MD University of Michigan Medical Center Ann Arbor, Michigan Sheila D. Walcoff, JD Goldbug Strategies, LLC Rockville, Maryland Anas Younes, MD The University of Texas MD Anderson Cancer Center Houston, Texas
LETTER TO OUR READERS
Personalized Medicine in Oncology : Expanding Our Knowledge of Precision Medicine Dear Colleague,
T
his issue of Personalized Medicine in Oncology (PMO) is a testament to how far we’ve come in our understanding of, and novel approaches to, the treatment of cancer. Armed Al B. Benson III, with knowledge of molecular biomarkers, genetic mutations, genomics, immunotheraMD, FACP, FASCO peutics, and targeted therapies, we are better able to treat patients with cancer to obtain longer survival and higher quality of life than ever before. This month, Christos Fountzilas, MD, and Virginia G. Kaklamani, MD, DSc, provide a review of BRAF mutations and implications when considering treatment strategies for patients with this mutation. In our Interview with the Innovators department, we talk We are better able to treat with Chief Scientific Officer Paul W. Dempsey, PhD, and patients with cancer to obtain Chief Medical Officer Paul Y. Song, MD, of Cynvenio about longer survival and higher quality their multiple-template strategy that analyzes DNA from circulating tumor cells, circulating cell-free DNA in blood, of life than ever before. and tissue biopsies, as well as the initiation of their clinical trial in triple-negative breast cancer. We hope you find our exchange insightful and helpful. Is there a topic you would like to see discussed in PMO? An innovator in the oncology community you’d like to have interviewed? Please contact us with your comments and request at editorial@thelynx-group.com. As always, thank you for your loyal readership. It is our pleasure to serve you in your quest to provide personalized medicine to your patients. Sincerely,
Al B. Benson III, MD, FACP, FASCO Coeditor in Chief Personalized Medicine in Oncology
INTERVIEW WITH THE INNOVATORS
Early Recurrence Detection: Analyzing DNA from Circulating Tumor Cells and Circulating Cell-Free DNA An Interview with Paul W. Dempsey, PhD, and Paul Y. Song, MD, of Cynvenio
C
ynvenio is a cancer diagnostics company offering their LiquidBiopsy technology to provide molecular analysis of cancer biomarkers in blood. The company purports that molecular diagnostic approaches to cancer detection and monitoring can benefit from their multiple-template strategy that analyzes DNA from circulating tumor cells (ctcDNA) and circulating cell-free DNA (ccfDNA) in blood, as well as from tissue biopsies. They recently published the results from their National Cancer Institute–supported clinical trial showing that data gained through next-generation sequencing of ccfDNA and ctcDNA liquid biopsy templates differ but complement each other and should be considered simultaneously. Analysis of each template enables the capture of different moments in a tumor’s evolution, providing additional and complementary information to that acquired through tissue biopsy alone. Moreover, the information gained from examining circulating tumor cells (CTCs) enables the identification of both relevant mutations and other biomarkers (such as proteins and RNA expression) that can drive a particular cancer. Tumor-derived samples from tissue biopsy, CTC
populations, and ccfDNA represent different moments in a cancer’s progression and may not derive from the same biologic sources. Research suggests that ccfDNA samples genomic DNA fragments released from all tumor sites and may capture mutations not specifically associated with the disease, as well as disease-relevant ones. In contrast, CTCs reflect the mobile subset of Paul W. Dempsey, PhD tumor cells in blood; they are clearly related to the disease process and predict more aggressive as well as metastatic disease. Cynvenio is applying their multipletemplate approach in a new clinical research study in triple-negative breast cancer. To date, they have enrolled 150 women. Enrollment is still open. The publishers of PMO had the pleasure of speaking with Drs Dempsey and Paul Y. Song, MD Song about their multiple-template strategy that analyzes ctcDNA and ccfDNA in blood as well as the initiation of their clinical trial in triple-negative breast cancer.
Dr Dempsey is Chief Scientific Officer of Cynvenio. He is an immunologist with more than 20 years of experience in biomedical research and analysis. Before joining Cynvenio, Dr Dempsey was an Assistant Research Professor in the department of microbiology, immunology, and molecular genetics at the University of California, Los Angeles. Dr Song is Chief Medical Officer of Cynvenio overseeing translational and clinical research programs. He also serves as Chief Medical Officer at ATGen Co. Ltd, where he oversees all clinical aspects of the company’s NK Vue, an ELISA-based blood test that measures natural killer cell activity. Dr Song was formerly a faculty member at Cedars-Sinai Medical Center in the Samuel Oschin Comprehensive Cancer Center department of radiation oncology and biomedical sciences.
PMO Good morning, gentlemen. To begin, how do you define personalized medicine, and how does your company fit into this definition? Dr Song I believe personalized medicine has been incorrectly defined as synonymous to genomic profiling. It was over 15 years ago that Human Genome Sciences was able to clone the human genome and yet the lack of advances since that time really points to the limitations of focusing solely on genes. I spoke recently at the Personalized Medicine World Conference and addressed the frustrations of clinicians trying to obtain approval from insurance companies to get a “personalized analysis.” But if you obtain this report, many times it doesn’t translate into any meaningful improvement for the patient. There
INTERVIEW WITH THE INNOVATORS
may not be a targeted therapy for the identified gene, or maybe the genetic mutation is multifactorial, or perhaps you give a targeted therapy that still doesn’t work because of some other aspects of the patient. I’ve tried to redefine or question what the medical field has defined as personalized medicine. I think personalized medicine goes beyond genes to include consideration of exosomes, RNA, proteins, and additional markers. Dr Dempsey Personalized medicine comes in many different forms, and it’s not necessarily driven by the latest technologies but by information that’s most useful to a patient and his or her doctor. Tamoxifen is a great example of a targeted personalized treatment, and it’s been around for decades.
Ultimately, we would really like to redefine what personalized medicine is, but to do that, we need to provide the community with enough tools to consider other markers beyond just DNA fragments. Our goal is to generate tools and information that can help doctors make the best decision for each of their patients. That has always been the doctors’ aim, but in oncology we’ve been unable to leverage information the way we do in other fields—infectious disease, for instance. In infectious diseases you have specific information that you can collect longitudinally and understand the progress of an infection and treat the infection as it moves. I think therein is a gray line between group dynamics and individual personalization. We’re trying to provide information to the physicians so that they can make evidence-based decisions for the patient they have in front of them. Dr Song That describes our major objective with our technology. We want to move beyond current next-generation sequencing in genomics and offer the ability to find circulating tumor cells, to look for expression of surface targets, to interrogate the cells for RNA analysis, to look at proteins, to look at the serum for a secretome analysis, and the exosome. Ultimately, we would really like to redefine what personalized medicine is, but to do that, we need to provide the community with enough tools to consider other markers beyond just DNA fragments. PMO Can you describe your liquid biopsy test, the multiple-template approach, and how the 3 components of the test complement each other? Dr Dempsey Our test is a monitoring tool that
considers multiple different tumor-derived events. The components reveal different, but complementary, information. They’re complementary in the biomarkers you can analyze. RNA, proteins, and DNA segregate differently in different compartments, but also, these are invariably rare events. The tumor-derived template in blood is a tiny fraction of all the information that’s actually there and, frequently, you are going to be at or near the limits of detection for these. Having multiple templates that give you an increased chance of being able to generate useful information is incredibly important. Because the information comes from different mechanisms, they tell you different things about the disease. It doesn’t serve the patient and the doctor to be restricted to 1 class of biomarker in any circumstance because there’s always additional information to be considered. So we’re looking at many different technologies in addition to what we’ve already built. For example, as part of a study we’re doing now in triple-negative breast cancer, we’re using a technology that Dr Song brought to the United States and to Cynvenio from South Korea. It is a tool to measure the critically important immune response in patients. We’re successfully using this tool in our triple-negative study. This is a great example of how we’re incorporating technologies beyond the current platform to give us a broader picture of the disease. PMO Can you describe your ongoing trial for triple-negative breast cancer and how Cynvenio’s technology is utilized in this study? Dr Song Our platform has primarily been used in research, so my challenge as Chief Medical Officer was to show real clinical utility. I wanted to select a disease that would really highlight our platform in a way that was clearly unequivocal. Triple-negative breast cancer is a very aggressive type of breast cancer. It affects about 18% of all women who are diagnosed with breast cancer. The sad part about this particular disease is that 1 of 3 women will develop metastatic disease in about 2.8 years after completion of therapy and, unfortunately, there’s no biomarker to monitor these patients. There was a trial done in London last year that looked at 55 women with advanced breast cancer. They did traditional tumor profiling of specific genes, and they looked for evidence of those gene mutations in circulation with PCR [polymerase chain reaction] pretreatment and posttreatment. In those women who had disease in their blood posttreatment, 86% went on to develop a recurrence about 7 months after they found evidence of disease.
INTERVIEW WITH THE INNOVATORS
I wanted to expand upon their findings with our technology in a high-risk population. In triple-negative breast cancer, once these women complete therapy, they go back to their physicians every 3 months. The doctors poke around their nodes, then maybe draw some simple blood tests like liver function tests. But if the results are abnormal it’s too late, because that means the cancer has already spread to the liver. What we decided to do was to check these women, monitor them, and look for evidence of disease in circulation. But unlike the London trial that used PCR and was very limited in what they looked for, we actually built our own triple-negative breast cancer–specific gene panel of 27 genes. We scoured the literature for any gene that had been reported in major publications that was associated with triple-negative breast cancer, and we created a customized panel based on our findings. We use our platform to not only look for cell-free DNA but also to look for circulating tumor cells. If we find circulating tumor cells we are doing next-generation sequencing, but we’re also planning to then look for other potential markers that could benefit the patient. We’re looking on the surface for PD-L1 [programmed death-1 ligand 1] expression as immunotherapy is now emerging as a possible choice for these women once they recur. We believe that looking for PD-L1 expression on circulating tumor cells in the metastatic setting will be much more indicative of potential response to immunotherapy than the primary biopsy model, which looks at PD-L1 expression on the primary tumor specimen, because PD-L1 expression is an adaptive changing response. There may be little to no initial expression on the primary tumor, but as the disease progresses and mutates over time and eventually metastasizes, there may be a far different degree of expression that is much more indicative of the actual current disease state and a more accurate predictor of potential response. The other thing that we are very close to rolling out is our ability to take RNA from the CTCs for subsequent analysis. Another advance that we’re very excited about is the ability to take that RNA and look for androgen receptors and splice the variants like AR-V7. AR-V7 has primarily been reported for prostate cancer, but 90% of all breast cancers actually express androgen receptors. One of the emerging areas of breast cancer is the use of antiandrogen drugs that are typically used in prostate cancer. The AR-V7 analysis cannot be done with DNA or cell-free DNA; it has to be done strictly with RNA. The problem with the current methodology is that they have to use fresh blood, and many times patients and doctors cannot get the blood processed in a timely fashion, so the overall utilization of this information is not employed enough.
With our fixative process, we’re able to make it much easier for patients to get their blood drawn and for doctors to order this test, so we believe it’s going to actually increase the ability for people to incorporate this into their practice. We’re looking at cell-free DNA, we’re looking at CTCs, and we’re also looking at incorporating another test that looks at natural killer cell activity with a simple 1-cc ELISA test. There is literature showing that when natural killer cell activity is low, there’s a much higher incidence of circulating tumor cells in patients with metastatic disease.
We’re looking at cell-free DNA, we’re looking at CTCs, and we’re also looking at incorporating another test that looks at natural killer cell activity with a simple 1-cc ELISA test. We opened the trial on March 3, which was national Triple-Negative Breast Cancer Day, and in less than 3 months we have enrolled 150 patients. PMO How are the patients doing thus far? Dr Song This is a patient population that’s highly motivated because 1 of 3 will recur. Sadly, we have found many patients with recurrence in the blood but with no clinical evidence of disease yet. We’ve also had 1 patient at the time of enrollment with no clinical evidence of disease, but 2 weeks after she enrolled she presented with a lump in her neck. We not only found evidence of disease in her blood on that first sample, but we also identified actionable mutations that her oncologist could then use to personalize her treatment. PMO Can you treat based on the recurrence in the blood, before clinical evidence is present? Dr Song No, once we find evidence of disease in blood, we follow the patient serially. Let’s say we do your analysis and we find you have a 4% TP53 mutation frequency or a PIK3CA mutation, and then in another 3 months it’s gone up to 12%. Part of our trial is to prove that we can detect recurrence. But once they recur, we want the doctors to use our information to help guide the next salvage treatment. A long-term goal we have with hospital partners is to randomize patients once they’re found to have disease in the blood; giving half of them treatment and monitoring the other half to determine if early treatment translates into better outcomes. Dr Dempsey Your question is actually about breaking the circle. We have a system right now where women are treated for triple-negative breast cancer, and then they’re
INTERVIEW WITH THE INNOVATORS
told to wait. If we say we’re building a capability of detecting the recurrence earlier, the doctors will question what to do for these patients because the standard of care says they can’t treat until the patient presents with clinically manifest disease. That’s rather barbaric. For the patient, it’s difficult to wait when you know that a third of your group is going to have disease recurrence. So in order to break that circle, you have to start either by treating early or detecting early and then figuring out what best treatments you can use. This trial is initially about showing that we can detect the disease earlier, and then we’ll take on the steps of using that information to show that it can inform practical, specific, and personalized treatment decisions for those patients as they go into their care cycle again.
We found mutations that were shared in both the cell-free DNA and the CTC compartment. But in the cells, there was a specific mutation in BRAF that has never been published before in prostate cancer. We published a study earlier this year where we show that both cell-free DNA and CTCs can be detected in blood; they can be shown to be related to the tumor tissue, and for any given sample you may see a signal in one compartment or the other or both. So we’ve taken that technology, paired it with the immune monitoring test, and are looking to initially demonstrate that we can apply those technologies to capture and define the recurrence of disease at a time that’s earlier and therefore more likely to have a lower disease burden. PMO Can you speak to the complexities of the multiple-template strategy? Dr Song We’re really showing how all components of our platform work together to complement and really provide personalized medicine in a tangible way to help the patient. So let’s say we have a patient with triple-negative breast cancer who recurs, and we’ve been able to find an EGFR mutation, which is normally associated with lung cancer, for which there is targeted therapy that the doctor can try. We can also look at their cell for PD-L1 expression if they want to consider immunotherapy. Or, if we find the AR-V7 mutation, then they may plan to switch to androgen therapy. AR-V7 can predict resistance to certain hormonal therapies. You can’t do all this with just 1 liquid biopsy that focuses strictly on cell-free DNA.
Dr Dempsey We also sequence the germline DNA in every patient so as to not confuse polymorphisms with acquired somatic mutations. Now, we’re not making prognostic conclusions here, we’re making molecular conclusions based on various different biomarkers that we can access. Now when you put that together in a given example, you do see the difference of the different templates. So we have one example; it’s a clinical example where we had a patient with prostate cancer who had failed a series of chemotherapy cycles and presented for the liquid biopsy using the multiple-template approach. We found mutations that were shared in both the cell-free DNA and the CTC compartment. But in the cells, there was a specific mutation in BRAF that has never been published before in prostate cancer. But it’s a targetable mutation that’s seen in other cancers and for which there are drugs available. The mutation was specifically present in the cells because the cells are mobile, moving and driving the disease process, and the cell-free DNA hadn’t caught up yet. Down the road you might see it in the cell-free DNA, but it wasn’t available at the time that the patient needed the information. So he was given a drug that targeted that mutation and had a progression-free survival window of over 9 months as a result of that specific information. So it all builds on the technology and these monitoring tools that reveal biomarkers that are useful to the doctor and help to make clinical decisions. Dr Song That’s the argument I’ve been making to clinicians. I think we are doing patients and physicians a disservice by limiting choices. Some people say cell-free DNA is the best way to go, or CTC is the best way to go, or exosomes. We’re agnostic. We want to provide as much information as possible to physicians and patients so that collectively it can complement one another. That’s the fight, and that’s our theology that we’re trying to evangelize. PMO How accessible is this test for patients? Dr Song Patients can simply go to any doctor’s office or even take the kit to a lab, and they can draw blood, and there’s a fixative process that stabilizes the sample for 96 hours before it needs to be processed. It really makes it very easy. Now as far as third-party payers, it has been approved for breast cancer in the metastatic setting. Most third-party payers have reimbursed that. What we’re hoping for in the triple-negative trial is that we have compelling data that they will then allow approval for monitoring posttreatment in a very high-risk disease. PMO Where do you see this technology fitting in the long-term of patient care? Dr Song Speaking as a clinician, I think when more
INTERVIEW WITH THE INNOVATORS
and more people realize what’s possible with the platform, including the ability to interrogate exosomes and analyze RNA, and more clinically relevant information is discovered from that platform, it will be used more frequently. And it’s important to note, our platform allows all of that to happen from the same 1 blood collection from the patient. Dr Dempsey Over the next few years, Cynvenio will focus on 2 efforts. Having completed all the heavy lifting in terms of building the tech and the workflow, now we are focusing it in specific settings so that we can produce the clinical evidence that will ensure the uptake of the technology and the application of this ability in the clin-
ical setting. This is where Dr Song’s clinical trials fit in. So that’s one whole effort. And the other focused effort is to support distribution of the platform through our partners at Thermo Fisher Scientific so that the platform will go into institutions around the country and around the world. That will build many more applications by tweaking the system for different research settings, different clinical settings, and different cancers that we can’t reach ourselves. We’re supporting the distribution and education of this capability so that other people can access this technology as well and build their own tests. PMO Thank you for your time today, and best of luck in this endeavor. u
BRAF MUTATIONS
Implications of BRAF Mutations in Cancer Christos Fountzilas, MD; Virginia G. Kaklamani, MD, DSc Department of Medicine, Division of Hematology/Oncology, Cancer Treatment Research Center, The University of Texas Health Science Center at San Antonio, TX
S
ustaining proliferative signaling is one of the hallmarks of cancer as described by Hanahan and Weinberg.1,2 Signals from multiple receptor tyrosine kinases converge to the mitogen-activated protein kinase (MAPK) signal transduction pathway and regulate multiple aspects of cell biology (Figure).3 Guanine triphosphate–binding proteins of the RAS Christos family and regulators of α-fetoprotein (RAF) Fountzilas, MD serine-threonine kinases are altered and constitutively activated in a significant number of human malignancies,4,5 leading to activation of downstream molecules and sustained cell proliferation and survival.3 There are 3 different RAF kinases in humans: ARAF, BRAF, and CRAF (RAF1).6 Substitutions of BRAF glutamic acid to valine (V600E) or lysine (V600K) are the most common RAF mutations in human neoplasia.4 Virginia G. Kaklamani, Over the past decade, significant advances MD, DSc have been made in pharmacologic inhibition of BRAF as a treatment strategy for malignant melanoma, the tumor with the highest frequency of Dr Fountzilas is a Clinical Fellow in The Division of Hematology/ Oncology at The University of Texas Health Science Center in San Antonio. Dr Fountzilas completed his medical training with honors at the Aristotle University of Thessaloniki School of Medicine in Greece, and his residency in Internal Medicine at Lenox Hill Hospital in New York, NY. His research interests include oncolytic virotherapy and use of immunotherapy for gastrointestinal and thoracic malignancies. Dr Kaklamani is Professor of Medicine in the Division of Hematology/ Oncology at The University of Texas Health Science Center in San Antonio and is the Leader of the Breast Cancer Program at the Cancer Therapy and Research Center. Dr Kaklamani completed her medical training with honors at the University of Athens and her residency in Internal Medicine at Newton-Wellesley Hospital in Boston, MA. She completed her fellowship in hematology/oncology at Northwestern University. She also received a Master of Science in Clinical Investigation from Northwestern University. She was Head of the Translational Breast Cancer Program at Northwestern University and Codirector of the Cancer Genetics Program at the same institution. Her research interests include studying high-risk families and identifying genetic mutations that are associated with an increased risk for breast, colon, and prostate cancers.
BRAF mutations.7 In this article, we review recent clinical progress in the use of BRAF as a diagnostic as well as a therapeutic target.
Melanoma BRAF V600E/K is present in 50% to 60% of malignant melanoma.4 BRAF inhibition with small molecules such as vemurafenib at a dose of 960 mg orally twice daily, or dabrafenib at a dose of 150 mg orally twice daily, has been proved to be a very effective treatment strategy with an overall response rate (ORR) of 51% in phase 2 trials.8 In phase 3 trials, BRAF inhibition was superior to cytotoxic therapy with dacarbazine 1000 mg/m2 intravenously (IV) every 3 weeks, with a progression-free survival (PFS) benefit of approximately 3.7 months (hazard ratio [HR] for progression or death 0.26 for vemurafenib [P <.001] and 0.30 for dabrafenib [P <.0001]), as well as a 6-month overall survival (OS) benefit in the BRIM-3 trial.9,10 The major toxicities of BRAF inhibitors are hyperkeratosis, nausea/vomiting, arthralgias, palmoplantar dysesthesia (hand-foot syndrome), pyrexia, and fatigue. An important toxicity is the development of squamous abnormalities, including squamous cell carcinomas, of the skin in 6% to 12% of the patients, necessitating close dermatologic follow-up for excision of those lesions should they occur. The mechanism is thought to be paradoxical hyperactivation of the MAPK pathway in BRAF wild-type cells.11 Inhibition of the downstream serine-threonine kinase MEK has also been proved efficacious in the treatment of BRAF-mutated melanoma. In a phase 3 study, Flaherty and colleagues randomized 322 patients with BRAF V600E/K mutation–positive melanoma naive to BRAF or MEK inhibition to the MEK inhibitor trametinib 2 mg orally once daily or dacarbazine 1000 mg/m2 IV every 3 weeks.12 The study met its primary end point with a PFS of 4.8 versus 1.5 months with trametinib and dacarbazine, respectively (HR, 0.45; P <.001). Response rates were 22% versus 8% for trametinib and dacarbazine, respectively. The major side effects of trametinib are nausea/vomiting, diarrhea, rash, fatigue, peripheral edema, and hypertension. Ocular events occur in 9% of the patients, with reversible chorioretinitis being the most severe. Retinopathy and retinal vein occlusion are rare but serious adverse events, and serial ophthalmologic evaluation is warranted.
BRAF MUTATIONS
Figure MAPK Pathway
RAF P
MEK 1/2
P
ERK 1/2
P
P P
RAS
P
GTP
P
Growth Factor/Growth Factor Receptor Complex
P
Gene TranscripFon
ProliferaFon
Survival
Adhesion And MigraFon
Cell Cycle RegulaFon
DifferenFaFon
Metabolism
RAS = rat sarcoma viral oncogene homolog RAF = regulator of α-‐fetoprotein GTP = guanine triphosphate ERK1/2 = extracellular signal-‐regulated protein kinase 1/2 P = phosphorus MEK1/2 = mitogen-‐acFvated protein kinase/ERK kinase 1/2
Combination strategies with BRAF and MEK inhibition have been developed and proved superior to BRAF inhibition alone, setting a new standard for BRAF-mutated melanoma. In a phase 1/2 study, the combination of dabrafenib/trametinib was superior to dabrafenib alone, with a response rate of 76% versus 54% and a PFS of 9.4 versus 5.8 months, respectively.13 Subsequent phase 3 trials randomizing more than 1500 patients with advanced melanoma to a BRAF/MEK combination versus monotherapy with a BRAF inhibitor confirmed the superiority of the combination approach (Table 1).14-16 Toxicities are not significantly increased with combination therapy, and there was a decrease in cases of cutaneous squamous lesions with BRAF/MEK combination strategies. Unfortunately, resistance is a common theme, and the disease does progress after approximately 10 months of therapy.
Thyroid Cancer BRAF is commonly mutated in well-differentiated thyroid cancer.7 In DECISION, a randomized, double-blind, placebo-controlled phase 3 trial, 417 patients with iodine-refractory disease were randomized 1:1 to sorafenib, a multikinase (including RAF) small molecule inhibitor, or placebo.17 The study reached its primary end point with a significant improvement in PFS with
KEY POINTS BRAF mutations are common in a variety of human malignancies ➤ Inhibition of BRAF is an attractive treatment strategy for melanoma and lung cancer harboring activating mutations ➤ Treatment with BRAF inhibitors has not been successful in all disease types, the best example being colorectal cancer ➤
sorafenib compared with placebo (10.8 vs 5.8 months, respectively; HR, 0.59; P <.0001). Clinical benefit was noted for all patients regardless of mutation status, and there was no difference in OS between groups. The benefit of sorafenib in thyroid cancer may not have been secondary to BRAF inhibition per se, but more a result of inhibition of multiple targets, especially the vascular endothelial growth factor (VEGF) receptor pathway.
Non–Small Cell Lung Cancer (NSCLC) The relative success of BRAF inhibition in melanoma opened the road for evaluation in other malignancies with various levels of success (Table 2). BRAF is uncom-
BRAF MUTATIONS
Table 1 Phase 3 Clinical Trials of BRAF and MEK Inhibitor Combinations in Malignant Melanoma Clinical Trials
Treatment Arms
N
ORR (%)
PFS (Months)
OS (%)
Long et al, 201414
Dabrafenib 150 mg twice daily/trametinib 2 mg once daily vs dabrafenib 150 mg twice daily
423
67 vs 51
9.3 vs 8.8
HR 0.75 P = .03
6 months: 93 vs 85
HR 0.63 P = .02
Robert et al, 201515
Dabrafenib 150 mg twice daily/trametinib 2 mg once daily vs dabrafenib 150 mg twice daily
704
64 vs 51
11.4 vs 7.3
HR 0.56 P <.001
12 months: 72 vs 65
HR 0.69 P = .005
Larkin et al, 201416
Vemurafenib 960 mg twice daily/cobimetinib 60 mg once daily 3 weeks on 1 week off vs vemurafenib 960 mg twice daily
945
68 vs 54
9.0 vs 6.2
HR 0.51 P <.001
9 months: 81 vs 73
HR 0.69 P = .005
HR indicates hazard ratio; ORR, overall response rate; OS, overall survival; PFS, progression-free survival.
monly mutated in lung cancer (2% of cases, in the range of ALK and ROS1 mutations). In a phase 2 basket trial of vemurafenib 960 mg orally twice daily in BRAF-mutated nonmelanoma cancers, 8 of 20 patients in the NSCLC cohort attained a partial response (PR) and another 8 had stable disease, for a disease control rate of 80%.18 In a retrospective review of off-label use of da brafenib, vemurafenib, or sorafenib in a cohort of pa-
BRAF inhibition was thought to be a reasonable therapeutic target in colorectal cancer, but results from early studies were disappointing with a very low observed response rate and a PFS of only 2 months. tients with NSCLC harboring a BRAF V600E/K mutation, overall response and disease control rates were 53% and 85%, respectively; median PFS and OS were 5.0 and 10.8 months, respectively.19 In a recently reported nonrandomized phase 2 study of patients with BRAF V600E mutationâ&#x20AC;&#x201C;positive NSCLC, naive to BRAF or MEK inhibition, the response rate with dabrafenib monotherapy at a dose of 150 mg orally twice daily was 33%, and the disease control rate was 53%. Duration of response was 9.9 months and PFS 5.5 months.20 There were no new safety concerns. Twelve percent of the patients developed squamous cell carcinoma of the skin. The interim results of the BRAF/MEK combination therapy cohort
have been presented in abstract form.21 The response rate with dabrafenib 150 mg orally twice daily and trametinib 2 mg orally once daily was 63%, and 88% of patients had their disease controlled for more than 3 months. A total of 6% of the patients developed squamous cell carcinoma of the skin or keratoacanthoma. Final data have not yet been reported.
Colorectal Cancer (CRC) BRAF mutations are present in <10% of patients with CRC.22 Whereas in the early disease setting, the presence of a BRAF mutation correlates with the presence of microsatellite instability and nongermline mutations in mismatch repair (MMR) proteins and a good prognosis, in the advanced setting the prognosis in this patient population is poor with a median OS of up to 14 months.23,24 BRAF inhibition was thought to be a reasonable therapeutic target in this patient population, but results from early studies were disappointing with a very low observed response rate and a PFS of only 2 months.25,26 Preclinical studies revealed a rapid feedback activation of the epidermal growth factor receptor (EGFR) as a potential mechanism of resistance.27,28 In the phase 2 study by Hyman et al, of the 27 patients with BRAF-mutated CRC treated with vemurafenib 960 mg orally twice daily and the anti-EGFR antibody cetuximab (400 mg/ m2 IV loading dose followed by 250 mg/m2 IV weekly thereafter), 4% had a PR and 69% had stable disease.18 Seventy-four percent of the patients developed a rash (grade 3 in 4% of the patients), 50% had grade 1/2 fa-
BRAF MUTATIONS
Table 2 Clinical Trials of BRAF Inhibitors in Non–Small Cell Lung Cancer and Colorectal Cancer Trial
Disease
N
Treatment
ORR (%)
DCR (%)
PFS (Months)
OS (Months)
Hyman et al, 201518
NSCLC
20
Vemurafenib
42
84
7.3
Not reached
Planchard et al, 201620
NSCLC
84
Dabrafenib
33
53
5.5
12.7
Planchard et al, 201521
NSCLC
33
Dabrafenib + trametinib
63
88*
NR
NR
Kopetz et al, 201526
CRC
21
Vemurafenib
5
38
2
7.7
Hyman et al, 201518
CRC
10
Vemurafenib
0
50
4.5
9.3
Hyman et al, 201518
CRC
27
Vemurafenib + cetuximab
4
73
3.7
7.1
Yaeger et al, 201529
CRC
15
Vemurafenib + panitumumab
16
100
NR
NR
Corcoran et al, 201531
CRC
43
Dabrafenib + trametinib
12
68
3.5
NR
Bendell et al, 201432
CRC
19
Dabrafenib + panitumumab ± trametinib
66/NR
100/88
NR
NR
Geel et al, 201534
CRC
18
Encorafenib + cetuximab ± BYL179
33/11
NR
NR
NR
*Disease control for >12 months. CRC indicates colorectal cancer; DCR, disease control rate; NR, not reported; NSCLC, non–small cell lung cancer; OS, overall survival; PFS, progression-free survival.
tigue, and 33% grade 1/2 photosensitivity reaction; 15% of the patients developed a squamous carcinoma, mainly in the skin. Yeager and colleagues reported in abstract form the results of a phase 2 trial of the anti-EGFR antibody panitumumab in combination with vemurafenib in a similar patient population.29 The ORR was 16%, and another 16% of the patients had disease stabilization for more than 2 months. Minor responses (not fulfilling the criteria for PR by RECIST) were noted in 66% of the patients. No cases of squamous cell cancers were noted, and the treatment was generally well tolerated. BRAF gene amplification is also a possible resistance mechanism that can potentially be bypassed by combined BRAF/MEK inhibition.30 In a phase 2 trial of patients with BRAF-mutated CRC, the combined BRAF/ MEK inhibition with dabrafenib 150 mg orally twice daily and trametinib 2 mg orally once daily resulted in a response rate of 12%, and a total of 56% of patients had stable disease as best response. The median PFS was 3.5 months.31 Toxicities were as expected for BRAF/MEK
combination therapy, with the most common adverse events being nausea/vomiting, pyrexia/chills, diarrhea, and fatigue. The only grade 3/4 adverse events in >10% of patients were anemia (16%) and pyrexia (12%). In a phase 1 study in a similar patient population reported in
Minor responses (not fulfilling the criteria for PR by RECIST) were noted in 66% of the patients. No cases of squamous cell cancers were noted, and the treatment was generally well tolerated. abstract form, panitumumab was safely combined with dabrafenib or the dabrafenib/trametinib combination.32 The most common toxicity was acneiform rash (grade 1 or 2). Preliminary efficacy results show response in 4 of 6 patients in the 3-drug combination cohort and stable disease in 7 of 8 patients with the 2-drug combination.
BRAF MUTATIONS
Combined BRAF and phosphatidylinositol 3-kinase (PI3K) inhibition may be another strategy to overcome resistance of BRAF-mutated CRC cells to BRAF inhibition.33 A phase 1 study evaluated the combination of the BRAF inhibitor encorafenib in combination with cetuximab and the PI3K inhibitor BYL179 in BRAF-mutated CRC.34 Treatment was well tolerated, and the preliminary efficacy results were promising (1 of 3 patients treated with all 3 medications attained a PR). The study is ongoing.
Feedback activation of EGFR, BRAF amplification, and PI3K mutations have been implicated as potential factors for resistance explaining the low efficacy of single-agent BRAF inhibitors. The most promising results for the treatment of patients with BRAF-mutated metastatic CRC come from a small phase 2 study from Italy, where 15 patients with BRAF-mutated metastatic CRC were treated with 5-fluorouracil/leukovorin, oxaliplatin, irinotecan, and the VEGF-Aâ&#x20AC;&#x201C;targeting antibody bevacizumab (FOLFOXIRI-Bev).35 The median survival was 24 months and the PFS 9 months, exceeding historical controls for this patient population.
Other Disease Types BRAF V600E mutation is a very specific (100%) genetic abnormality for hairy cell leukemia (HCL),36 and it is present in 60% of Langerhans cell histiocytosis (LCH) cases.37 In 2 phase 2 studies in patients with relapsed/ refractory HCL, the ORR was 98% (48% with complete response) with vemurafenib 960 mg orally twice daily; all patients with complete response had minimal residual disease in the bone marrow by immunohistochemistry.38 The median relapse-free survival was 9 months and duration of response 24 months. Responses have also been observed with a lower dose.39 In the study by Hyman et al, the ORR to vemurafenib in the LCH cohort was 43% (7% with complete response), and 57% of patients had stable disease.18 BRAF mutations are present in 22% of cholangiocarcinomas.40 In the cholangiocarcinoma cohort of the basket study by Hyman et al, of the 8 patients enrolled, 1 had a PR with vemurafenib (12%); 50% of the patients had stable disease.18 Conclusion RAF serine-threonine kinase has a pivotal role in signal transduction through the MAPK pathway. BRAF
V600E/K inhibition has been a successful strategy for the treatment of melanoma positive for these mutations either alone or in combination with inhibition of downstream MEK. BRAF inhibition appears to be an effective treatment for patients with relapsed/refractory HCL and a promising treatment strategy for the small subgroup of BRAF-mutated NSCLC, but its efficacy in BRAF-mutated metastatic CRC is limited. Feedback activation of EGFR, BRAF amplification, and PI3K mutations have been implicated as potential factors for resistance explaining the low efficacy of single-agent BRAF inhibitors as discussed above. In the study by Kopetz et al, there was no difference in PFS based on the presence or not of PI3K pathway activation or expression of EGFR by immunohistochemistry.26 In the study by Corcoran et al, the majority of patients with hotspot exon 9 or 20 PI3K mutations, phosphate and tensin homolog (PTEN) mutations, or transforming growth factor beta pathway alterations, had some decrease in the target lesion size by RECIST with BRAF/MEK combination therapy, there was no correlation between PTEN or microsatellite status or total EGFR and PFS.31 The number of patients was small for definitive conclusions. This is a cautionary tale for treatment strategies that rely only on the molecular composition of each tumor without taking histology into consideration.
Disclosure The authors have no conflicts of interest. Acknowledgments This work was supported by the Dolores Knes Fund. Dr Christos Fountzilas is a recipient of a Cancer Prevention and Research Institute of Texas (CPRIT) Cancer Research Training Award (RP140105). u References
1. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000;100:57-70. 2. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011; 144:646-674. 3. Roskoski R Jr. ERK1/2 MAP kinases: structure, function, and regulation. Pharmacol Res. 2012;66:105-143. 4. Davies H, Bignell GR, Cox C, et al. Mutations of the BRAF gene in human cancer. Nature. 2002;417:949-954. 5. Bos JL. ras oncogenes in human cancer: a review. Cancer Res. 1989;49:4682-4689. 6. Marais R, Marshall CJ. Control of the ERK MAP kinase cascade by Ras and Raf. Cancer Surv. 1996;27:101-125. 7. Vakiani E, Solit DB. KRAS and BRAF: drug targets and predictive biomarkers. J Pathol. 2011;223:219-229. 8. Ascierto PA, Minor D, Ribas A, et al. Phase II trial (BREAK-2) of the BRAF inhibitor dabrafenib (GSK2118436) in patients with metastatic melanoma. J Clin Oncol. 2013;31:3205-3211. 9. Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011;364:2507-2516. 10. Hauschild A, Grob JJ, Demidov LV, et al. Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet. 2012;380:358-365. 11. Hatzivassiliou G, Song K, Yen I, et al. RAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth. Nature. 2010;464:431-435. 12. Flaherty KT, Robert C, Hersey P, et al. Improved survival with MEK inhibition in BRAF-mutated melanoma. N Engl J Med. 2012;367:107-114.
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13. Flaherty KT, Infante JR, Daud A, et al. Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N Engl J Med. 2012;367:1694-1703. 14. Long GV, Stroyakovskiy D, Gogas H, et al. Combined BRAF and MEK inhibition versus BRAF inhibition alone in melanoma. N Engl J Med. 2014;371:1877-1888. 15. Robert C, Karaszewska B, Schachter J, et al. Improved overall survival in melanoma with combined dabrafenib and trametinib. N Engl J Med. 2015;372:30-39. 16. Larkin J, Ascierto PA, Dréno B, et al. Combined vemurafenib and cobimetinib in BRAF-mutated melanoma. N Engl J Med. 2014;371:1867-1876. 17. Brose MS, Nutting CM, Jarzab B, et al. Sorafenib in radioactive iodine-refractory, locally advanced or metastatic differentiated thyroid cancer: a randomised, double-blind, phase 3 trial. Lancet. 2014;384:319-328. 18. Hyman DM, Puzanov I, Subbiah V, et al. Vemurafenib in multiple nonmelanoma cancers with BRAF V600 mutations. N Engl J Med. 2015;373:726-736. 19. Gautschi O, Milia J, Cabarrou B, et al. Targeted therapy for patients with BRAF-mutant lung cancer: results from the European EURAF cohort. J Thorac Oncol. 2015;10:1451-1457. 20. Planchard D, Kim TM, Mazieres J, et al. Dabrafenib in patients with BRAFV600E-positive advanced non-small-cell lung cancer: a single-arm, multicentre, open-label, phase 2 trial [published online April 11, 2016]. Lancet Oncol. 21. Planchard D, Groen HJM, Kim TM, et al. Interim results of a phase II study of the BRAF inhibitor (BRAFi) dabrafenib (D) in combination with the MEK inhibitor trametinib (T) in patients (pts) with BRAF V600E mutated (mut) metastatic nonsmall cell lung cancer (NSCLC). J Clin Oncol. 2015;33(suppl). Abstract 8006. 22. Tol J, Nagtegaal ID, Punt CJ. BRAF mutation in metastatic colorectal cancer. N Engl J Med. 2009;361:98-99. 23. Van Cutsem E, Köhne C-H, Láng I, et al. Cetuximab plus irinotecan, fluorouracil, and leucovorin as first-line treatment for metastatic colorectal cancer: updated analysis of overall survival according to tumor KRAS and BRAF mutation status. J Clin Oncol. 2011;29:2011-2019. 24. Tie J, Gibbs P, Lipton L, et al. Optimizing targeted therapeutic development: analysis of a colorectal cancer patient population with the BRAF(V600E) mutation. Int J Cancer. 2011;128:2075-2084. 25. Kopetz S, Desai J, Chan E, et al. PLX4032 in metastatic colorectal cancer patients with mutant BRAF tumors. J Clin Oncol. 2010;28(suppl). Abstract 3534. 26. Kopetz S, Desai J, Chan E, et al. Phase II pilot study of vemurafenib in patients with metastatic BRAF-mutated colorectal cancer. J Clin Oncol. 2015;33:4032-4038. 27. Corcoran RB, Ebi H, Turke AB, et al. EGFR-mediated re-activation of MAPK signaling contributes to insensitivity of BRAF mutant colorectal cancers to RAF in-
hibition with vemurafenib. Cancer Discov. 2012;2:227-235. 28. Prahallad A, Sun C, Huang S, et al. Unresponsiveness of colon cancer to BRAF(V600E) inhibition through feedback activation of EGFR. Nature. 2012;483:100-103. 29. Yaeger R, Cercek A, O’Reilly EM, et al. Pilot trial of combined BRAF and EGFR inhibition in BRAF-mutant metastatic colorectal cancer patients. Clin Cancer Res. 2015;21:1313-1320. 30. Corcoran RB, Dias-Santagata D, Bergethon K, et al. BRAF gene amplification can promote acquired resistance to MEK inhibitors in cancer cells harboring the BRAF V600E mutation. Sci Signal. 2010;3:ra84. 31. Corcoran RB, Atreya CE, Falchook GS, et al. Combined BRAF and MEK inhibition with dabrafenib and trametinib in BRAF V600-mutant colorectal cancer. J Clin Oncol. 2015;33:4023-4031. 32. Bendell JC, Atreya CE, André T, et al. Efficacy and tolerability in an open-label phase I/II study of MEK inhibitor trametinib (T), BRAF inhibitor dabrafenib (D), and anti-EGFR antibody panitumumab (P) in combination in patients (pts) with BRAF V600E mutated colorectal cancer (CRC). J Clin Oncol. 2014;32(suppl). Abstract 3515. 33. Mao M, Tian F, Mariadason JM, et al. Resistance to BRAF inhibition in BRAF-mutant colon cancer can be overcome with PI3K inhibition or demethylating agents. Clin Cancer Res. 2013;19:657-667. 34. Geel RV, Elez E, Bendell JC, et al. Phase I study of the selective BRAF V600 inhibitor encorafenib (LGX818) combined with cetuximab and with or without the α-specific PI3K inhibitor BYL719 in patients with advanced BRAF-mutant colorectal cancer. J Clin Oncol. 2014;32(suppl). Abstract 3514. 35. Loupakis F, Cremolini C, Salvatore L, et al. FOLFOXIRI plus bevacizumab as first-line treatment in BRAF mutant metastatic colorectal cancer. Eur J Cancer. 2014;50:57-63. 36. Tiacci E, Trifonov V, Schiavoni G, et al. BRAF mutations in hairy-cell leukemia. N Engl J Med. 2011;364:2305-2315. 37. Badalian-Very G, Vergilio JA, Degar BA, et al. Recurrent BRAF mutations in Langerhans cell histiocytosis. Blood. 2010;116:1919-1923. 38. Tiacci E, Park JH, De Carolis L, et al. Targeting mutant BRAF in relapsed or refractory hairy-cell leukemia. N Engl J Med. 2015;373:1733-1747. 39. Dietrich S, Pircher A, Endris V, et al. BRAF inhibition in hairy cell leukemia with low dose vemurafenib [published online March 3, 2016]. Blood. 40. Tannapfel A, Sommerer F, Benicke M, et al. Mutations of the BRAF gene in cholangiocarcinoma but not in hepatocellular carcinoma. Gut. 2003;52:706-712.
CLINICAL TRIALS TRACKER
Select Ongoing Trials Currently Enrolling Patients with Colorectal Cancer
T
he following are a selection of key clinical trials that are currently recruiting patients for inclusion in investigations of new therapies or new combinations of available therapies for patients with colorectal cancer. Each clinical trial description includes the NLM Identifier to be used as a reference with ClinicalTrials.gov. The information below can help oncology practice managers and providers direct their eligible patients to one of these clinical trials.
1
Xilonix in Patients with Advanced Colorectal Cancer This randomized, parallel-assignment, double-blind, phase 3 clinical trial evaluates whether Xilonix, a monoclonal antibody, can prolong life in patients with co lorectal carcinoma that is refractory to standard therapy. Men and women aged ≥18 years with pathologically confirmed metastatic or unresectable colorectal carcinoma and with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 may be eligible for enrollment if other criteria are met. Eligible patients will be randomized to receive Xilonix or placebo. The primary outcome measure is overall survival. The secondary outcome measures include change in lean body mass, quality of life, progression-free survival, and objective response rate. This study plans to enroll 600 patients at multiple locations across the United States. For more information, contact Michael Stecher, MD, at 512-386-2900. The NLM Identifier is NCT01767857.
2
Fruquintinib versus Best Supportive Care in Patients with Advanced Colorectal Cancer After Previous Chemotherapy This phase 3, randomized, parallel-assignment, double-blind clinical trial evaluates the efficacy and safety of fruquintinib in the treatment of patients with metastatic colorectal cancer that has progressed after second-line or higher standard chemotherapy. Men and women aged 18 to 75 years with an ECOG performance status of 0 or 1, and with at least 1 measurable lesion, may be eligible for enrollment if other criteria are met. Eligible patients will be randomized to receive fruquintinib or placebo. The primary outcome measure is overall survival. The secondary outcome measures include progression-free survival, objective response rate, disease control rate,
and safety and tolerance. This study expects to enroll 400 patients at multiple locations in China. For more information, contact Ye Hua, MD, at yeh@hmplglobal. com; or Songhua Fan, MD, at songhuaf@hmplglobal. com. The NLM Identifier is NCT02314819.
3
Intraoperative Chemotherapy with 5-FU for Patients with Colorectal Cancer Receiving Curative Resection This phase 3, single-blind, parallel-assignment, randomized study is assessing the efficacy and safety of intraoperative chemotherapy with fluorouracil (5-FU) for patients with colorectal cancer receiving curative resection. Men and women aged 18 to 75 years with histologically confirmed adenocarcinoma of the colon and rectum and with an ECOG performance status of 0 or 1 may be eligible for enrollment if other criteria are met. Eligible patients will undergo surgery alone or surgery plus chemotherapy with 5-FU. The primary outcome measure is disease-free survival. The secondary outcome measures include disease-free survival and safety profiles. This study plans to enroll 1246 patients in China. For more information, contact Xiaojun Wu, MD, PhD, at wuxj@sysucc.org.cn. The NLM Identifier is NCT01465451.
4
Masitinib plus FOLFIRI versus Placebo plus FOLFIRI in the Second-Line Treatment of Patients with Metastatic Colorectal Cancer The purpose of this phase 3, single-group, open-label clinical trial is to compare the efficacy and safety of masitinib in combination with FOLFIRI (irinotecan, fluorouracil, and folinic acid) versus placebo plus FOLFIRI in the second-line treatment of patients with colo rectal cancer. Men and women aged ≥18 years with nonresectable metastatic colorectal cancer with a life expectancy of >3 months and an ECOG performance status ≤2 may be eligible for enrollment if other criteria are met. Eligible patients will receive masitinib plus FOLFIRI or placebo plus FOLFIRI. The primary outcome measure is overall survival. The secondary outcome measures include survival rate, progression-free survival, time to disease progression, best response, quality of life, pharmacogenomics assessment, and safety profile. This study expects to enroll 550 patients in Canada. For more information, contact Olena Vlasyuk, MD, at olena.vlasyuk@ab.
CLINICAL TRIALS TRACKER
science.com. The NLM Identifier is NCT02605044.
5
Perioperative FOLFIRI versus Adjuvant FOLFIRI in Resectable Advanced Colorectal Cancer After Oxaliplatin Therapy This phase 3, open-label, parallel-assignment, randomized clinical trial is comparing perioperative FOL FIRI and adjuvant FOLFIRI in patients with resectable advanced colorectal cancer who were previously exposed to oxaliplatin. Men and women aged 18 to 80 years with histologically confirmed colorectal adenocarcinoma and with an ECOG performance status of 0 or 1 may be eligible for enrollment if other criteria are met. Eligible patients will be randomized to receive perioperative FOLFIRI or adjuvant FOLFIRI. The primary outcome measure is progression-free survival. The secondary outcome measures include overall survival, R0 resection rate, toxicity, and quality of life. This study expects to enroll 360 patients in China. For more information, contact Jian Xiao, MD, at xiao_ jian@139.com. The NLM Identifier is NCT02087475.
6
FOLFIRI plus Cetuximab Until Disease Progression versus FOLFIRI plus Cetuximab for 8 Cycles Followed by Cetuximab Alone Until Disease Progression in First-Line Treatment of Patients with RAS and BRAF Wild-Type Metastatic Colorectal Cancer This randomized, open-label, parallel-assignment, phase 3 clinical trial is investigating whether cetuximab alone (given until progression or cumulative toxicity) after 8 cycles of FOLFIRI plus cetuximab results in a noninferior progression-free survival when compared with continuous FOLFIRI plus cetuximab (given until progression or cumulative toxicity). Men and women aged ≥18 years with a histologically proven diagnosis of colorectal adenocarcinoma with RAS and BRAF wildtype disease and with an ECOG performance status of 2 may be eligible for enrollment if other criteria are met. Eligible patients will be randomized to receive FOLFIRI plus cetuximab until disease progression or FOLFIRI plus cetuximab for 8 cycles followed by cetuximab alone until disease progression. The primary outcome measures are progression-free survival and the incidence of grade 3/4 adverse events. The secondary outcome measures include response rate, early tumor shrinkage assessed by response rate at week 8, overall survival, cetuximab-related skin toxicity, safety profile, and quality of life. This study plans to enroll 600 patients in Italy. For more information, contact Armando Orlandi, MD, PhD, at armando. orlandi@edu.rm.unicatt.it. The NLM Identifier is NCT02484833.
7
Pembrolizumab versus Chemotherapy in Microsatellite Instability-High or Mismatch Repair Deficient Stage IV Colorectal Cancer The purpose of this phase 3, randomized, open-label, parallel-assignment clinical trial is to determine whether pembrolizumab will prolong progression-free survival compared with standard chemotherapy in patients with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) stage IV colorectal cancer. Men and women aged ≥18 years with a locally confirmed dMMR or MSI-H stage IV colorectal carcinoma and with an ECOG performance status of 0 or 1 may be eligible for enrollment if other criteria are met. Eligible patients will be randomized to receive pembrolizumab or standard chemotherapy. The primary outcome measure is progression-free survival. The secondary outcome measures include overall response rate and overall survival. This study expects to enroll 270 patients at multiple locations in the United States and abroad. For more information, call 888-5778839. The NLM Identifier is NCT02563002.
8
Capecitabine plus Bevacizumab versus Capecitabine plus Bevacizumab and Irinotecan as First-Line Therapy in Patients with Metastatic Colorectal Cancer This randomized, single-group assignment, open-label, phase 3 clinical trial is assessing the efficacy of capecitabine plus bevacizumab versus capecitabine plus bevacizumab plus irinotecan in patients with metastatic colorectal cancer. Men and women aged ≥18 years with stage IV colorectal cancer and with an ECOG performance status of 0 or 1 may be eligible for enrollment if other criteria are met. Eligible patients will receive capecitabine plus bevacizumab followed by capecitabine plus irinotecan and bevacizumab in case of disease progression, or capecitabine plus irinotecan and bevacizumab. The primary outcome measure is time of failure strategy. The secondary outcome measures include objective response rate, overall survival, quality of life, and progression-free survival. This study plans to enroll 516 patients in Germany. For more information, contact Volker Heinemann, MD, at volker.heinemann@med. uni-muenchen.de. The NLM Identifier is NCT01249638.
9
Oxaliplatin, Leucovorin Calcium, and Fluorouracil with or without Celecoxib in Patients with Stage III Colon Cancer Previously Treated with Surgery This phase 3, randomized, double-blind, parallelassignment clinical trial is evaluating the efficacy of oxaliplatin plus leucovorin calcium and fluorouracil with
CLINICAL TRIALS TRACKER
or without celecoxib in patients with stage III colon cancer that was previously treated with surgery. Men and women aged ≥18 years with a histologically documented adenocarcinoma of the colon and an ECOG performance status of 0 to 2 may be eligible for enrollment if other criteria are met. Eligible patients will be randomized to receive FOLFOX plus placebo (12 treatments), FOLFOX plus celecoxib (12 treatments), FOLFOX plus placebo (6 treatments), or FOLFOX plus celecoxib (6 treatments). The primary outcome measure is disease-free survival, and the secondary outcome measure is overall survival. This study plans to enroll 2500 patients at multiple locations in the United States and abroad. For more information, contact Jeffrey A. Meyerhardt, MD, MPH, at 617-632-5136. The NLM Identifier is NCT01150045.
10
Colectomy in Patients with Asymptomatic and Unresectable Stage IV Colon Cancer This randomized, parallel-assignment, open-label, phase 3 clinical trial is assessing whether overall survival and quality of life are improved in patients with asymptomatic colon cancer and unresectable liver metastasis that has been treated with resection of the primary tumor followed by chemotherapy versus chemotherapy alone. Men and women aged 18 to 75 years with pathologically confirmed colon adenocarcinoma and an ECOG performance status of 0 or 1 may be eligible for enrollment if other criteria are met. Eligible patients will be randomized to receive colectomy followed by chemotherapy versus chemotherapy alone. The primary outcome measure is overall survival. The secondary outcome measures include quality of life, postoperative complications, progression-free survival, time to metastatic progression, and the rate of secondary curative resection. This study expects to enroll 278 patients in France. For more information, contact Mehdi Karoui, MD, PhD, at 331-42-17-56-51. The NLM Identifier is NCT02363049.
11
Regorafenib as Single Agent in Patients with Metastatic Colorectal Cancer with Any RAS or BRAF Mutation Previously Treated with FOLFOXIRI plus Bevacizumab This open-label, single-group assignment, phase 2 clinical trial is evaluating the efficacy of single-agent regorafenib in the second-line treatment of patients with metastatic colorectal cancer with any RAS or BRAF mutation who were previously treated with FOLFOXIRI plus bevacizumab in terms of progression-free survival at 6 months. Men and women aged ≥18 years with stage IV
metastatic colorectal cancer with any RAS or BRAF mutation and an ECOG performance status of 0 or 1 may be eligible for enrollment if other criteria are met. Eligible patients will receive regorafenib. The primary outcome measure is progression-free survival at 6 months. The secondary outcome measures include objective response rate, disease control rate, time to progression, and overall survival. This study expects to enroll 53 patients in Spain. For more information, contact Inmaculada Ruiz de Mena, PhD, at ttd@ttdgroup.org. The NLM Identifier is NCT02175654.
12
Regorafenib or Standard of Care After Adjuvant FOLFOX in Patients with Stage IIIC Colorectal Cancer The purpose of this randomized, open-label, parallel-assignment, phase 2 clinical trial is to determine whether the addition of regorafenib after the completion of FOLFOX improves treatment compared with standard of care (no further treatment). Men and women aged ≥18 years with stage IIIC colorectal cancer and an ECOG performance status of 0 or 1 may be eligible for enrollment if other criteria are met. Eligible patients are randomized to receive regorafenib or standard of care. The primary outcome measure is finding the starting dose of regorafenib and the number of patients completing all 6 cycles. The secondary outcome measures include overall survival, number of adverse events, and disease-free survival. This study plans to enroll 264 patients in Florida. For more information, contact Melissa Pope at 281-863-6544, or melissa.pope@mckesson.com. The NLM Identifier is NCT02425683.
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Pembrolizumab plus Azacitidine in Patients with Chemorefractory Metastatic Colorectal Cancer This open-label, single-group assignment, phase 2 clinical trial is evaluating the antitumor activity, safety, and tolerability of pembrolizumab in combination with azacitidine in patients with chemorefractory metastatic colorectal cancer without any further standard treatment options. Men and women aged ≥18 years with metastatic colorectal cancer that has been previously treated with currently approved standard therapies and an ECOG performance status of 0 or 1 may be eligible for enrollment if other criteria are met. Eligible patients will receive pembrolizumab and azacitidine. The primary outcome measure is objective response rate. This study expects to enroll 40 patients in Pennsylvania. For more information, contact Natalie Streeter at
CLINICAL TRIALS TRACKER
412-235-1276, or streeternr@upmc.edu. The NLM Identifier is NCT02260440.
14
Gemcitabine plus Docetaxel in Patients with Relapsed or Refractory Metastatic Colorectal Adenocarcinoma This single-group assignment, open-label, phase 2 clinical trial is assessing the efficacy of gemcitabine plus docetaxel chemotherapy in patients with relapsed or refractory metastatic colorectal cancer with methylated CHFR and/or microsatellite instability phenotype. Men and women aged ≥18 years with a histologically or cytologically confirmed metastatic or unresectable adenocarcinoma of the colon or rectum and an ECOG performance status of 0 or 1 may be eligible for enrollment if other criteria are met. Eligible patients will receive gemcitabine plus docetaxel. The primary outcome measure is response rate. The secondary outcome measures include progression-free survival, overall survival, CHFR methylation, global methylation, and quality of life. This study expects to enroll 40 patients in the United States and the Netherlands. For more information, contact Rosalind Walker, RN, at 410-955-9628, or rwalker3@jhmi.edu. The NLM Identifier is NCT01639131.
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FOLFOX plus Bevacizumab versus FOLFOXIRI plus Bevacizumab as First-Line Treatment of Patients with Previously Untreated Metastatic Colorectal Cancer and ≥3 Circulating Tumoral Cells This phase 3, randomized, open-label, parallelassignment clinical trial is evaluating FOLFOX (folinic acid, fluorouracil, and oxaliplatin) plus bevacizumab versus FOLFOXIRI (folinic acid, fluorouracil, oxaliplatin, and irinotecan) plus bevacizumab as first-line treatment for patients with previously untreated metastatic colorectal cancer and ≥3 circulating tumoral cells. Men and women aged 18 to 70 years with histologically confirmed adenocarcinoma of the colon or rectum, an ECOG performance status of 0 or 1, and a life expectancy of at least 3 months may be eligible for enrollment if other criteria are met. Eligible patients will be randomized to receive FOLFOX6 plus bevacizumab or FOLFOXIRI plus bevacizumab. The primary outcome measure is progression-free survival. Secondary outcome measures include overall survival, response rate, and adverse events. This study plans to enroll 350 patients in Spain. For more information, contact Inmaculada Ruiz de Mena, PhD, at ttd@ttdroup. org. The NLM Identifier is NCT01640405. u
GENETIC COUNSELING
Inherited Ovarian Cancer: What Have We Learned? Cristi Radford, MS, CGC Invitae
C
ompared with other cancers, ovarian cancer is relatively rare, accounting for just 1.3% of all new cancer cases in the United States. However, it has a high death rateâ&#x20AC;&#x201D;the highest of any female reproductive system cancer. Only around 1 in 7 women with ovarian cancer are diagnosed at the local stage. For these women, the 5-year survival is optimistic at 92%. However, most Cristi Radford, MS, CGC women present with advanced disease, for which the overall 5-year survival is estimated to be 45%.1 The low survival rate is primarily due to the inability to detect ovarian cancer at an early, curable stage. Whereas the average woman has approximately a 1.5% chance of developing ovarian cancer in her lifetime, a high-risk woman with a BRCA mutation may have anywhere from a 15% to a 68% lifetime risk.2
Although bilateral salpingo-oophorectomy is a proven ovarian cancer prevention strategy, it is also an invasive procedure, affects quality of life, and may have health hazards. Screening options for ovarian cancer are extremely limited, and, to date, there are no proven effective surveillance strategies. Both the US Preventive Services Task Force and the American College of Obstetricians and Gynecologists recommend against ovarian cancer screening in the general population.3 For women at high risk who have elected not to proceed with risk-reducing surgery, transvaginal ultrasound with CA-125 levels can be considered every 6 months beginning at age 30 years or 5 to 10 years earlier than the youngest age of ovarian cancer diagnosis in the family.4 Even in this population, however, available surveillance options have not been shown to decrease ovarian cancer morbidity or mortality.3 In fact, it has been suggested that providing women with the option of surveillance for ovarian cancer gives them false hope, and when surveillance is not offered, they are more likely to proceed with risk-reducing surgery.5 Although bilateral salpingo-oophorectomy is a proven ovarian cancer prevention strategy, it is also an in-
vasive procedure, affects quality of life, and may have health hazards. Additionally, for bilateral salpingooophorectomy to be effective in high-risk women, they have to be identified, and the majority of women with inherited mutations do not know they have them.6 Moreover, as only 7% to 10% of ovarian cancer cases occur in mutation carriers, this would not be an effective public health strategy to reduce ovarian cancer mortality and morbidity.3 Therefore, additional surveillance and prevention options are needed. Data have demonstrated that at least some highgrade serous carcinomas originate in the fallopian tube. Therefore, one suggestion is the option of bilateral salpingectomy in premenopausal, high-risk women and for all women at the time of routine gynecologic surgery.3 However, to determine the impact of this procedure in preventing ovarian cancer, the proportion of cancers arising in the fallopian tubes would need to be known. It would also need to be determined if there is a genotypic correlation, so that individuals receive appropriate genetic counseling. Presently, the only proven intervention is bilateral salpingo-oophorectomy. It is essential that new screening and imaging technologies be developed to improve the outcome and quality of life for women at high risk for ovarian cancer. Due to the high mortality rate and lack of effective surveillance methods, identifying women at increased risk for ovarian cancer is crucial, as it allows them to have the option of risk-reducing surgery. Historically, it was believed that 5% to 12% of invasive ovarian carcinomas were due to hereditary susceptibility.7 The 2 most common hereditary ovarian cancer syndromes were believed to be hereditary breast and ovarian cancer (HBOC) syndrome and Lynch syndrome. HBOC is associated with mutations in the BRCA1 and BRCA2 genes, whereas Lynch syndrome is associated with mutations in the MLH1, MSH2, MSH6, PMS2, and EPCAM genes. As has been seen with other disease sites, the availability of multigene inherited cancer tests and their incorporation into clinical practice has altered the understanding of hereditary cancer, and this is also true for ovarian cancer. Studies continue to demonstrate that BRCA1/2 account for the majority of known inherited epithelial ovarian cancer cases. However, multigene testing op-
GENETIC COUNSELING
tions have demonstrated that the remaining identifiable mutations represent a diverse spectrum, with Lynch syndrome typically representing a small percentage of known mutations. This was initially demonstrated in 2011 by Walsh and colleagues, who screened an unselected cohort of 360 women with primary ovarian, peritoneal, or fallopian tube carcinoma for mutations in 21 genes.8 Approximately 1 in 4 (82 of 360) women were found to carry a germline, loss-of-function mutation, and a total of 85 mutations were identified. BRCA1/2 represented 74% of mutations, whereas mutations in genes associated with Lynch syndrome only represented 2% of mutations. The remaining 24% of mutations were found in 9 genes, with the greatest proportion being CHEK2 (5 of 85) and BRIP1 (4 of 85). Since this study was undertaken, several others have reported on the results of inherited cancer panels in specific patient populations. The cohorts analyzed have included those that have particular age of onset and/or family history criteria, those that meet defined clinical criteria, and patient samples submitted to a specific genetic testing company.9 A laboratory cohort presented at the 2014 meeting of the American Society of Clinical Oncology reviewed the mutation spectrum of 263 patients diagnosed with ovarian cancer who were tested with a 25-gene inherited cancer panel. Again, BRCA1/2 accounted for over half the mutations identified (59.6%), and mutations in genes associated with Lynch syndrome represented 5.8%. The remaining 35% of mutations were represented by 8 genes, with the most mutations being identified in ATM, BRIP1, and NBN.10 A cohort from a different laboratory analyzed data for the contribution of 19 genes in a BRCA1/2-negative population of 911 patients with a personal history of breast and/or ovarian cancer. When the patients with breast cancer only were removed from the data set, 558 patients remained (466 with a personal history of ovarian cancer and 92 with a personal history of breast and ovarian cancer). In 41 of these individuals, 42 mutations were found. Unlike the other reported data sets, the most mutations were found to be in the Lynch syndrome genes, followed by BRIP1, CHEK2, and ATM. The common theme in all of these data sets is that a variety of genes have a role in ovarian cancer risk, and simply testing for BRCA1/2 or Lynch syndrome will miss a large percentage of cases. In addition to the diverse spectrum of mutations found in genes associated with a moderate or high risk of ovarian cancer, multigene testing options have also uncovered expanded phenotypes. In the Walsh study, none of the ovarian cancer patients found to have a mutation associated with Lynch syndrome or Li-Fraumeni syndrome had family histories consistent with the
TAKE-HOME POINTS 1 in 4 ovarian cancers have an inherited, genetic component ➤ Identifying individuals at high risk of developing ovarian cancer is essential so these women can be offered risk-reducing procedures ➤ As the only effective intervention is bilateral salpingo-oophorectomy—which is an invasive procedure, can result in surgical menopause, and possibly has adverse health effects—new imaging and screening technologies are needed to improve the outcome and quality of life for women at high risk ➤ Lynparza (olaparib) became the first FDAapproved PARP inhibitor for women with BRCA mutations who have ovarian, fallopian tube, or primary peritoneal cancer and have had ≥3 lines of chemotherapy ➤ In addition to preventive opportunities, genetic testing for inherited ovarian cancer now has therapeutic implications for high-risk women ➤
syndromes as currently described in the literature.8 Minion and colleagues also reported on individuals found to have germline mutations in Lynch syndrome genes that did not meet Lynch syndrome clinical criteria, as well as individuals meeting Lynch syndrome clinical criteria who were found to have mutations in other genes associated with increased ovarian cancer risk.11 Therefore, if clinicians rely on a testing strategy that analyze only genes associated with defined clinical criteria associated with a syndrome, they may miss an identifiable mutation.
The common theme in all of these data sets is that a variety of genes have a role in ovarian cancer risk, and simply testing for BRCA1/2 or Lynch syndrome will miss a large percentage of cases. Many of the genes analyzed in the previously mentioned data sets are part of the homologous recombination (HR) pathway. Cells contain multiple types of DNA repair mechanisms, and one of these is HR, which helps repair DNA damage, including singlestranded DNA, double-stranded DNA breaks, and DNA cross-links. Additionally, HR has a role with DNA replication forks. BRCA1/2 are involved in the
GENETIC COUNSELING
repair of DNA double-strand breaks via HR, and studying genes in this pathway has uncovered other genes associated with breast and/or ovarian cancer risk. As BRCA1/2 are involved in the repair of DNA double-strand breaks via HR, cells with BRCA1/2 mutations have a decreased ability to repair doublestrand breaks.
Individuals with BRCA mutations start off with cells prone to problems repairing DNA; PARP inhibitors make it even more difficult for tumor cells to correct themselves. Ovarian cancers that have impaired HR ability are more sensitive to poly (ADP-ribose) polymerase, or PARP, inhibitors. PARP inhibitors keep cells from repairing themselves once they have been damaged by chemotherapy.12 Individuals with BRCA mutations start off with cells prone to problems repairing DNA, and PARP inhibitors make it even more difficult for tumor cells to correct themselves. Knowledge of the molecular mechanisms of BRCA1/2 has now permitted therapeutic interventions. On December 19, 2014, the FDA announced the approval of the first PARP inhibitor, Lynparza (olaparib), for patients with germline BRCA1/2 mutations and ovarian cancer who have had 3 or more lines of chemotherapy.13 Additional studies
are needed to determine if the use of PARP inhibitors would be beneficial in other genes in the BRCA pathway or in other cancer sites. u
References
1. National Cancer Institute. SEER Stat Fact Sheets: Ovary Cancer. http://seer. cancer.gov/statfacts/html/ovary.html. Accessed March 19, 2015. 2. Antoniou A, Pharoah PD, Narod S, et al. Average risk of breast and ovarian cancer associated with BRCA1 and BRCA2 mutations detected in case series unselected for family history: a combined analysis of 22 studies. Am J Hum Genet. 2003;72:1117-1130. 3. Daly M, Dresher CW, Yates MS, et al. Salpingectomy as a means to reduce ovarian cancer risk. Cancer Prev Res (Phila). 2015;8:342-348. 4. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology. (NCCN Guidelines). Genetic/Familial High-Risk Assessment: Breast and Ovarian. Version 2.2014. www.nccn.org/professionals/physician_gls/pdf/genetics_ screening.pdf. Accessed March 19, 2015. 5. van Driel CM, de Bock GH, Arts HJ, et al. Stopping ovarian cancer screening in BRCA1/2 mutation carriers: effects on risk management decisions & outcome of risk-reducing salpingo-oophorectomy specimens. Maturitas. 2015;80:318-322. 6. Lancaster JM, Powell CB, Chen LM, et al; SGO Clinical Practice Committee. Society of Gynecologic Oncology statement on risk assessment for inherited gynecologic cancer predispositions. Gynecol Oncol. 2015;136:3-7. 7. Pal T, Permuth-Wey J, Betts JA, et al. BRCA1 and BRCA2 mutations account for a large proportion of ovarian carcinoma cases. Cancer. 2005;104:2807-2816. 8. Walsh T, Casadei S, Lee MK, et al. Mutations in 12 genes for inherited ovarian, fallopian tube, and peritoneal carcinoma identified by massively parallel sequencing. Proc Natl Acad Sci U S A. 2011;108:18032-18037. 9. Kurian AW, Kingham KE, Ford JM. Next-generation sequencing for hereditary breast and gynecologic cancer risk assessment. Curr Opin Obstet Gynecol. 2015;27:23-33. 10. Langer LR, McCoy H, Moyes K, et al. A study of ovarian cancer patients tested with a 25-gene panel of hereditary cancer genes. J Clin Oncol. 2014;32:(suppl). Abstract 1511. 11. Minion LE, Dolinsky JS, Chase DM, et al. Hereditary predisposition to ovarian cancer, looking beyond BRCA1/BRCA2. Gynecol Oncol. 2015;137:86-92. 12. Lupo B, Trusolino L. Inhibition of poly(ADP-ribosyl)ation in cancer: old and new paradigms revisited. Biochim Biophys Acta. 2014;1846:201-215. 13. FORCE website. FDA review of olaparib. www.facingourrisk.org/our-role-andimpact/advocacy/current-actions/FDA-review-of-olaparib.php. Accessed March 19, 2015.
AMERICAN ASSOCIATION FOR CANCER RESEARCH
Nivolumab Represents New Standard in Recurrent Head and Neck Cancer
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rogrammed death 1 (PD-1) inhibitor treatment with nivolumab significantly improves survival in patients with squamous cell cancer of the head and neck that progresses after platinum-based therapy, according to data from the phase 3 CheckMate-141 trial. Based on these data, “nivolumab therefore Maura L. Gillison, represents a new standard of care option for MD, PhD patients with recurrent/metastatic head and neck cancer after platinum-based therapy,” announced lead investigator Maura L. Gillison, MD, PhD, at the American Association for Cancer Research Annual Meeting.
CheckMate-141 was a randomized, global, phase 3 clinical trial designed to evaluate nivolumab compared with investigator’s choice single-agent chemotherapy with docetaxel, methotrexate, or cetuximab. About 50% of patients with squamous cell carcinoma of the head and neck experience recurrence within 5 years of initial treatment, which includes combinations of surgery, radiation, and platinum-based chemotherapy. Patients who experience recurrence within 6 months of platinum-based therapy have an average survival of ≤6 months. Previously, no anticancer agent had been shown to improve survival in this patient population, and no new treatments have been approved in more than a decade. CheckMate-141 was a randomized, global, phase 3 clinical trial designed to evaluate nivolumab compared with investigator’s choice single-agent chemotherapy with docetaxel, methotrexate, or cetuximab, which is the current standard of care in this setting. Patients in the trial experienced progression within 6 months of having received platinum-based chemotherapy. “This was a very heavily pretreated population,” said Dr Gillison, Professor, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus. “Over 90% had previous radiation treatment and 55% had received 2 or more
prior lines of systemic chemotherapy for their cancer before enrolling in the trial.” Of the 361 patients enrolled, 240 were randomly assigned to nivolumab and 121 to single-agent chemotherapy of investigator’s choice. At an interim analysis performed after 218 events, patients assigned to nivolumab were found to have a 30% reduction in the risk of death compared with those assigned to chemotherapy of investigator’s choice. Median overall survival was 7.5 months for those assigned to nivolumab versus 5.1 months for those assigned to therapy of investigator’s choice (P = .0101). “What we think is most important about this trial is the proportion of patients who survived to a year; it doubled with nivolumab therapy in comparison to investigator’s choice,” she said. At 1 year, 36% of the patients assigned to nivolumab were alive compared with 17% of those assigned to therapy of investigator’s choice. The effect of nivolumab on survival was evaluated by PD-1 ligand 1 (PD-L1) expression and human papillomavirus (HPV) status. A survival benefit with nivolumab was observed in patients who had PD-L1 expression ≥1% as well as those with PD-L1 expression <1%, and in patients who were HPV-positive and HPV-negative. “However, the magnitude of the reduction in risk of death was greater for patients whose tumors expressed PD-L1 ≥1% or who were HPV-positive. In those 2 groups, the risk of death was reduced by approximately half.” Among patients with HPV-positive disease, median overall survival was 9.1 months in the nivolumab arm versus 4.4 months for those assigned to investigator’s choice; among patients with HPV-negative disease, median overall survival was 7.5 months in the nivolumab group versus 5.8 months in the investigator’s choice arm. No new safety signals emerged with nivolumab treatment in this population. Only 58.9% of patients in the nivolumab arm experienced a treatment-related toxicity, compared with 77.5% in the investigator’s choice arm. There were also fewer grade 3/4 adverse events in the nivolumab arm compared with the investigator’s choice arm. In patients with recurrent or metastatic squamous cell carcinoma of the head and neck, nivolumab “fulfills an incredible unmet need in the clinic,” said Dr Gillison. u
AMERICAN ASSOCIATION FOR CANCER RESEARCH
Pembrolizumab Elicits Response in Patients with Merkel Cell Carcinoma
I
mmunotherapy with the programmed death 1 (PD1) inhibitor pembrolizumab induced durable responses in a phase 2 clinical trial of a virus-related cancer. Among 26 patients with Merkel cell carcinoma (MCC) treated in the trial, 12 of 14 patients (86%) who responded to pembrolizumab have ongoing responses after a median follow-up of 7.6 months, and the objective response rate (ORR) was 62% in patients with virus-positive tumors, reported Paul Nghiem, MD, PhD, at the American Association for Cancer Research Annual Meeting. Currently, no drugs are approved to treat MCC. Typically, platinum-based chemotherapy serves as firstline treatment of MCC, and although the ORR to chemotherapy is about 55%, these responses are transient, said Dr Nghiem, Professor of Medicine, Division of Dermatology, University of Washington School of Medicine, Seattle. The Merkel polyomavirus (MCPyV) drives about 80% of MCC cases. More than 40% of patients with MCC develop advanced disease within 3 months of initiating chemotherapy, and 90% will have disease progression by 10 months. Median survival is just 9.5 months after a diagnosis of metastatic MCC. The rationale for testing pembrolizumab in MCC is that PD-1 on the T cells has been shown to be present in MCPyV-specific T cells in up to two-thirds of patients with virus-positive MCC. The single-arm, open-label trial that Dr Nghiem presented here included 26 patients with advanced/ metastatic MCC who had received no prior systemic therapy. Seventeen of the 26 patients had MCPyV-positive disease. All patients received pembrolizumab 2 mg/kg every 3 weeks, with response assessed every 9 to 12 weeks. At the time of data analysis, treatment duration with pembrolizumab was 9 to 49 weeks. The ORR was 56% in all patients enrolled. The response rate is higher than that seen with PD-1 inhibitors in the treatment of other solid tumors. “Maybe that’s because historically, this has been a very immune-associated cancer,” Dr Nghiem said. “Viral status is a very interesting story and an evolving one.” Of the 16 patients with MCPyV-pos-
itive tumors, 62% had responses, compared with 44% of the 9 patients with virus-negative tumors. “That was not a statistically significant difference between the virus-positives and -negatives, but maybe suggests…there may be a better story there for virus positives,” he said. “We believe that the immune system is likely ‘seeing’ different targets in the vi- Paul Nghiem, MD, PhD rus-positive and virus-negative patients,” he said. Virus-positive tumors produce viral proteins required for tumor growth, and these viral proteins may be recognized by the immune system. In contrast, virus-negative MCC has extremely high numbers of mutations caused by ultraviolet exposure and is more likely to be recognized by the immune system.
The rationale for testing pembrolizumab in MCC is that PD-1 on the T cells has been shown to be present in MCPyV-specific T cells in up to two-thirds of patients with virus-positive MCC. Four patients had a complete response, 3 of whom had virus-positive disease, and 10 patients had a partial response, 7 of whom had virus-positive disease. Responses were already evident by the first scan at 3 months, and many of these responses were “profound,” said Dr Nghiem. Responses are ongoing in 12 of 14 patients (86%). The median progression-free survival (PFS) was 9 months compared with a historical median PFS of about 3 months for MCC patients treated with chemotherapy, he said. The median 6-month PFS was 67%. An additional 24 patients are being recruited into the trial to confirm the results. Adverse events in this trial were similar to those observed in other anti–PD-1 trials and were largely managed with corticosteroid treatment and drug cessation. Responses are ongoing in 2 patients in whom pembrolizumab was discontinued for toxicity. u
AMERICAN ASSOCIATION FOR CANCER RESEARCH
Chemotherapy Use in Breast Cancer Declines with Gene-Based Assay
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omen with clinicopathologic highrisk breast cancer received chemotherapy almost half as often with no increased risk of metastatic recurrence when a cancer gene assay was used to guide decisionmaking, results of a randomized trial showed. Patients at low risk by the 70-gene MammaPrint assay had a 5-year distant metastaMartine Piccart, sis-free survival (DMFS) of 94.4% without MD, PhD chemotherapy versus 95.9% with chemotherapy, a difference that did not reach statistical significance. In the setting of clinical low risk and a high-risk score by the assay, the 5-year DMFS was 95.8% with chemotherapy and 95.0% without. Use of the gene assay to inform use of adjuvant therapy in clinically high-risk patients was associated with a 46% reduction in prescriptions for chemotherapy, Martine Piccart, MD, PhD, reported at the American Association for Cancer Research Annual Meeting.
Use of the gene assay to inform use of adjuvant therapy in clinically high-risk patients was associated with a 46% reduction in prescriptions for chemotherapy. “These results provide level 1A evidence of the clinical utility of MammaPrint for assessing the lack of a clinically relevant chemotherapy benefit in the clinically high-risk population,” said Dr Piccart, Director of Medical Oncology at the Jules Bordet Institute in Brussels, Belgium. “Patients who were clinically high risk but genetically low risk, which included 48% of node-positive patients, had a 5-year distant metastasis-free survival in excess of 94%, whether randomized to adjuvant chemotherapy or no chemotherapy.” Clinical trials in early breast cancer have shown that adjuvant chemotherapy confers a 2% to 12% absolute improvement in survival. However, chemotherapy has well-recognized toxicities that add to the cost of care. More than a decade ago, a validated prognostic model based on clinicopathologic risk factors became available as an aid to deciding whether to administer
adjuvant chemotherapy to a patient with early breast cancer. More recently, tumor gene expression profiling has emerged as an option for defining breast cancer risk. Dr Piccart reported findings from the MINDACT trial, which compared the clinicopathologic criteria with the 70-gene assay for providing guidance about the use of adjuvant chemotherapy. From 2007 to 2011, investigators in 9 countries enrolled 6693 patients who had undergone surgery for early breast cancer, including node-positive disease. Every patient was evaluated by the clinical prognostic model and the genetic test. Patients who had lowrisk disease by both methods received no chemotherapy, and all patients who were high risk by both methods did receive chemotherapy. Dr Piccart said 3348 patients had discordant results—high risk by one method, low risk by the other. The patients with discordant results received radiation therapy and were randomized to clinical or genetic risk assessment to decide whether they would receive adjuvant chemotherapy. The primary end point was 5-year DMFS, and the trial was considered positive if the results showed a 5-year DMFS of 92.0% in the subgroup of patients who had clinically high-risk disease but had a low risk of recurrence by the gene assay. After a median follow-up of 5 years, DMFS for the entire study population was 97.6% for patients who had low-risk disease by clinical/pathologic factors and the gene test versus 90.6% for those who had high-risk disease by both criteria. Dr Piccart said women with high-risk disease tended to have larger tumors and were more likely to have node-positive and HER2-positive disease. For the primary analysis, women with high clinical/ low genetic risk had a 5-year DMFS of 94.7% without chemotherapy, meeting the statistical criteria for a positive study. In the United States, clinicians have access to both the MammaPrint and the Oncotype DX gene-based recurrence scores, said Nancy Davidson, MD, Professor of Oncology at the University of Pittsburgh Cancer Institute, PA. Currently, Oncotype DX is more widely used. Whether the MINDACT results influence clinicians’ choice or use of a recurrence score remains to be seen, she said. u
AMERICAN ASSOCIATION FOR CANCER RESEARCH
Novel Regimen Outperforms Standard Therapy in HER2 Breast Cancer
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n ongoing trial of a novel strategy to evaluate new regimens for early-stage breast cancer has identified another neoadjuvant combination worthy of a phase 3 trial involving patients with HER2-positive disease. The combination of ado-trastuzumab emtansine (TDM1) and pertuzumab resulted in an estimated pathologic complete response (pCR) rate of 52% in a phase 2 evaluation, compared with 22% for the combination of trastuzumab and paclitaxel. The novel regimen has a 94% likelihood of success in a phase 3 comparison against the standard combination. Similar advantages for the novel combination were observed in patients with hormone receptor (HR)-positive and HR-negative disease, as reported at the American Association for Cancer Research Annual Meeting. “On the basis of these results, the probability that the novel combination of T-DM1 and pertuzumab is superior to trastuzumab and paclitaxel combination is greater than 99%, and the probability of success versus trastuzumab and paclitaxel in a phase 3 trial is 94%,” said Angela M. DeMichele, MD, Associate Professor of Medicine at the University of Pennsylvania in Philadelphia. “T-DM1 and pertuzumab graduated [to phase 3], both in the overall HER2-positive patient population, as well as in both hormone receptor subsets.” “[The novel combination] had a very different toxicity profile than that seen with the standard of care,” she added. “Neuropathy, hypertension, and alopecia were much less common. I would argue that these are side effects of treatment that really matter to women, that can really affect their day-to-day function.” The findings are the latest from the ongoing I-SPY2 trial. Investigators in the trial use a biomarker-driven adaptive trial design that relies on genetic and biologic marker data derived from patients’ own tumors to inform treatment choices for subsequent patients enrolled in the trial program. The underlying objective of the trial design is to identify effective neoadjuvant regimens for specific biomarker-defined breast cancer “signatures” and advance the regimens to phase 3 trials requiring as few patients as possible. Investigators at multiple sites simultaneously evaluate several different regimens in small phase 2 trials. Novel regimens that demonstrate superiority versus
current standards qualify to “graduate” to phase 3 trials. Dr DeMichele reported findings from a phase 2 trial involving 52 patients randomized to T-DM1/pertuzumab and 32 to trastuzumab-paclitaxel. Patients in both groups also received doxorubicin and cyclophosphamide. In addition to the overall results, subgroup analysis yielded an estimated pCR rate of 64% with the T-DM1/ pertuzumab regimen and 33% with the trastuzumabpaclitaxel combination in patients with HR-negative disease. The probability of superiority was 98%, and the likelihood of success in a phase 3 trial was 90%. In the HR-positive subgroup, estimated pCR rates were 46% with the novel regimen and 17% with conventional therapy. The probability of success for the novel regimen was 99% in the phase 2 trial and 93% in a phase 3 trial.
The combination of T-DM1 and pertuzumab resulted in an estimated pCR rate of 52% in a phase 2 evaluation, compared with 22% for the combination of trastuzumab and paclitaxel. The frequency and severity of adverse events were similar for T-DM1/pertuzumab and trastuzumab-paclitaxel. When the doxorubicin-cyclophosphamide component of the regimens was included, patients in the T-DM1/pertuzumab arm had higher rates of neutropenia, thrombocytopenia, and elevated liver enzymes (ALT and AST). The trastuzumab-paclitaxel regimen was associated with more hypertension, neuropathy, and alopecia. The 84 patients in the trial were among 249 with HER2-positive breast cancer. The remaining patients were randomized to other investigational neoadjuvant regimens, results of which have yet to be reported. “These results demonstrate the benefit of the adaptive trial design and the standing platform of the I-SPY2 trial and show that we can see this benefit in a relatively modest number of patients,” said Dr DeMichele. “Using the standard platform, where we continuously evaluate drugs, enables us to get results out very quickly.” u
AMERICAN ASSOCIATION FOR CANCER RESEARCH
To Reduce Breast Cancer Recurrence Risk, Exercise—A Lot!
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or protection against breast cancer recurrence, one recently reported study can best be described as “good news, bad news.” At the American Association for Cancer Research Annual Meeting, researchers reported a statistically significant dose response for the effects of physical activity on breast cancer recurrence. The catch is that the effect was seen only among the most active tertile: women who exercised at least 20 hours a week. Teresa Lehman, PhD, Chief Scientific Officer, Bio Serve Technologies, Ltd, Beltsville, MD (a molecular biology service company with a repository of 600,000 tissue specimens), presented the study of 2435 patients surveyed and 215 who experienced a breast cancer recurrence.
The study was a secondary analysis of data from the Global Epidemiological Study, a multinational study that assesses disease risk factors and is linked to this biorepository. “There is reasonable evidence that increased physical activity is associated with a reduced risk of breast cancer, but its role in the recurrence of breast cancer has not been established,” Dr Lehman said. The study was a secondary analysis of data from the Global Epidemiological Study, a multinational study that assesses disease risk factors and is linked to this biorepository. Patients provided their personal
history, including age, body mass index, and information on diet and physical activity. The study examined the association between physical activity and breast cancer recurrence. Although the sample size was “relatively small,” Dr Lehman acknowledged, a significant effect was nevertheless observed.
Substantial Reduction in Recurrences “On the univariate analysis, physical activity had a significant impact on recurrence, and on the multivariate analysis, after adjusting for age, body mass index, and cancer stage, the effect was even greater,” Dr Lehman said. Subjects in the highest tertile of physical activity, who reported brisk walking and other moderate exercise for at least 20 hours a week, were 39% less likely to have a breast cancer recurrence, compared with women reporting no exercise (odds ratio [OR] = 0.61; 95% CI, 0.40-0.93). In the multivariate analysis, they were 45% less likely (OR = 0.55; 95% CI, 0.34-0.89). The dose-response relationship was statistically significant (P = .05), Dr Lehman reported. Patients in the second tertile, who exercised 1 to 20 hours a week, actually had no reduction in recurrence risk (OR = 1.13 on the univariate analysis and 1.24 on the multivariate analysis). In the first tertile, the reference, women reported no brisk exercise. Dr Lehman acknowledged that 20 hours of exercise is a challenge for most women. “You have to really make an effort to do this,” she said. u
AMERICAN ASSOCIATION FOR CANCER RESEARCH
Walking Reduces Markers of Inflammation in Smokers with Lung Cancer
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f you can’t get your lung cancer patients to stop smoking, at least encourage them to exercise. That’s the message from research conducted on a huge cohort of individuals in the National Health and Nutrition Examination Survey (NHANES), showing that markers of inflammation were significantly reduced among male smokers with lung cancer if they exercised. The interesting findings were presented at the American Association for Cancer Research Annual Meeting by Marisa A. Bittoni, PhD, of The Ohio State University Comprehensive Cancer Center. “Our results are in line with those of our [previous] prospective cohort study, which showed substantial reductions in lung cancer deaths (30%-50%) from increased physical activity and healthier eating, primarily in smokers and males,” Dr Bittoni said. “The theory was that smokers with lung cancer had more of an inflammatory environment because of the smoking.” Little effect was observed among females, especially nonsmokers, she added.
Inflammation and Cancer Chronic inflammation is associated with adverse lifestyle factors, including poor diet, lack of physical activity, and smoking. Systemic inflammation plays an impor tant role in carcinogenesis for several cancers, including lung cancer. C-reactive protein (CRP) is an acute-phase protein that is elevated in response to acute inflammation, infection, and tissue damage. CRP levels have been shown to be moderately elevated in persons with chronic inflammatory diseases, including cancer, the researchers noted. The purpose of this study was to simultaneously examine the associations between lifestyle factors and CRP levels and to look for differences according to smoking and gender, she said. Third NHANES Data from cancer-free individuals aged 40 years and older in the Third NHANES (1988-1994) were examined to assess relationships between exercise habits, dietary patterns (measured by the Healthy Eating Index), and inflammation. The researchers identified 5405 persons with nor-
mal CRP (<3 mg/L) and 3545 with elevated levels (CRP ≥3 mg/L). Elevated CRP was more likely among smokers (56.5%) than nonsmokers (53.6%; P <.0001). Persons with poor diets were also more likely to have elevated CRP (35.7%) versus normal CRP (31.4%), whereas the reverse was true for those with healthy diets, in whom elevated CRP rates were low (31.7%) and normal CRP rates were higher (34.8%; P <.0001).
The purpose of this study was to simultaneously examine the associations between lifestyle factors and CRP levels and to look for differences according to smoking and gender. In the multivariate analysis, smoking raised the risk of having elevated CRP by 41% (P <.0001), and exercise reduced the risk by 22% (P = .0001). Other types of physical activity were also significantly related to lower CRP levels, but walking had the strongest association. In the univariate analysis, the odds ratio (OR) for walking 1 mile within the past 30 days was 0.43. Although walking for 1 mile in the past month is not a very strenuous definition of physical activity, Dr Bittoni acknowledged, she suggested that a “yes” answer may identify persons who tend to exercise more regularly. With regard to other lifestyle factors, the OR estimates for selenium remained similar and statistically significant in all groups (P <.05). The ORs for serum vitamin D levels (OR = 0.90; P <.01) and Healthy Eating Index score (OR = 0.92; P = .001) were only significant for smokers and males. The greatest effect on CRP levels, she reiterated, was seen with walking, “which was out-doing healthy eating” as a means of reducing inflammation. Reduction in inflammation is important, she emphasized. “Inflammation is part of the tumor microenvironment,” she said. “If you reduce inflammation, you reduce the chance of getting cancer. Anything that does that should be helpful.” u
AMERICAN ASSOCIATION FOR CANCER RESEARCH
Multivitamin Use During Chemotherapy May Reduce Risk of Peripheral Neuropathy
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ultivitamin supplement use was associated with a reduction in chemotherapy-associated peripheral neuropathy in a subanalysis of the SWOG S0221 trial. Patients who were using multivitamins before chemotherapy had 40% less neuropathy, and those using them during or after treatment had a 23% reduced risk. The results were reported at the American Association for Cancer Research Annual Meeting by Gary R. Zirpoli, PhD, a Postdoctoral Fellow at Roswell Park Cancer Institute, Buffalo, NY. “We didn’t see any association with individual vitamin supplements, but we found that multivitamin users reported less chemotherapy-induced peripheral neuropathy (CIPN), compared to patients not using them,” Dr Zirpoli said. “To our knowledge, this has not been reported before.”
Women were classified as supplement users if they used a supplement at least once a week. The analyses were adjusted for age, BMI, race, smoking status, physical activity level, alcohol intake, and treatment. Although vitamin supplements have been explored for their potentially protective effects, “promising candidates have not panned out,” he noted. “There really seems to be no good data showing their benefit.”
Study Details SWOG 0221 evaluated the benefit of weekly versus biweekly paclitaxel (plus doxorubicin/cyclophosphamide) in breast cancer patients at high risk for recurrence. Embedded within the trial design was a questionnaire about diet and other lifestyle factors. Dr Zirpoli’s study included 1225 participants who completed questionnaires before and at diagnosis, of whom 1068 also completed a 6-month follow-up questionnaire to capture supplement use during treatment. Symptoms of CIPN were measured using the physician-assessed National Cancer Institute Common Ter-
minology Criteria for Adverse Events (CTCAE) and the self-reported Functional Assessment of Cancer Therapy/ Gynecologic Oncology Group-Neurotoxicity (FACT/ GOG-Ntx) subscale. The subscale measures hand and foot numbness, hand and foot discomfort, joint and muscle pain, weakness, ringing in the ears, and trouble hearing, buttoning, feeling small objects, and walking. Answers of “quite a bit” and “very much” were grouped together to represent severe neuropathy. “Somewhat” was considered moderate, and “a little bit” was considered mild. Women were classified as supplement users if they used a supplement at least once a week. The analyses were adjusted for age, body mass index, race, smoking status, physical activity level, alcohol intake, and treatment.
Reductions in CIPN with Multivitamin Use Before and During Treatment As measured by the CTCAE, grade 3/4 CIPN was reported by 62% of patients who took multivitamins before diagnosis compared with 38% who did not; grades 0 to 2 were reported by 52% and 48%, respectively. This translated into a reduction in CIPN of 40% (odds ratio [OR] = 0.60; 95% CI, 0.42-0.87), primarily among the severe group. There were numerical differences favoring vitamin C and vitamin E, but the effect was not statistically significant. As measured by the FACT/GOG-Ntx, there was a 22% reduction for women taking a multivitamin before diagnosis (OR = 0.78; 95% CI, 0.61-1.00). For supplement use during treatment, risk was reduced by 23% for multivitamin users, according to the FACT/ GOG-Ntx survey. No significant reductions were observed on the CTCAE instrument. “Our results indicate that the use of multivitamins, but not individual dietary supplements, during treatment may reduce CIPN symptoms, although these findings require replication in larger studies,” Dr Zirpoli said. “It’s important for other studies to verify these results, because it’s possible there is some other characteristic that helps explain why patients taking multivitamin supplements have less neuropathy,” he added. u
AMERICAN ASSOCIATION FOR CANCER RESEARCH
Biologic Agents and Cardiac Toxicity Among Patients with Hematologic Malignancies
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argeted therapies used to treat hematologic malignancies can cause unintended cardiac toxicity in some patients and can lead to cardiacrelated mortality, according to study results presented at the American Association for Cancer Research Annual Meeting. “Unanticipated cardiac toxicity occurred in about 4% of patients with hematologic malignancies over a 10-year period. This was not dose dependent. It was caused by the targeted therapy. For most patients, the cardiac toxicity was reversible,” said lead author Jan S. Moreb, MD, University of Florida, Gainesville. “Most patients [who develop cardiac toxicity on targeted therapy] do well with cardiac drug regimens that lead to stable compensated cardiac function with objective improvement in left ventricular ejection fraction seen in about 25%. Two patients had non–ST-segment elevated myocardial infarction without coronary artery disease or significant drop in left ventricular ejection fraction,” he continued. The retrospective study, which is being conducted by hematologists/oncologists, cardiologists, and pharmacists, looked at 820 patients with hematologic malignancies and cardiac problems treated between 2005 and 2014 at the University of Florida, Gainesville. Fifty-three patients received any of the following drugs: tyrosine kinase inhibitors such as imatinib, dasatinib, ponatinib, and nilotinib; proteasome inhibitors such as bortezomib and carfilzomib; immunomodulatory agents such as thalidomide, pomalidomide, and lenalidomide; monoclonal antibodies such as rituximab and alemtuzumab; and hypomethylating agents such as azacitidine and decitabine. Cardiac toxicity was confirmed in 44 of these patients. Cardiac toxicity was defined as left ventricular ejection fraction <50%, arrhythmias, or ischemic car-
diovascular event. Ten patients were excluded from the study because of preexisting cardiac disease. In the 34 remaining patients, the distribution of hematologic malignancies was as follows: multiple myeloma (n = 16), B-cell non-Hodgkin lymphoma (n = 10), follicular non-Hodgkin lymphoma (n = 4), Philadelphia chromosome–positive acute lymphoblastic Jan S. Moreb, MD leukemia (n = 3), and myelodysplastic syndrome (n = 1). Median age was 66 years; 19 patients were male and 15 female; 26 were Caucasian; and 15 were alive at the time of the study. Median time from exposure to drug to development of cardiac toxicity was 120 days (range, 1-300 days). Unanticipated cardiac toxicity was reported in 4% of patients, and among these, 17.6% died of cardiac toxicity.
The retrospective study, which is being conducted by hematologists/oncologists, cardiologists, and pharmacists, looked at 820 patients with hematologic malignancies and cardiac problems. These findings are in contrast to cardiac toxicity with anthracyclines, which is anticipated and dose dependent, Dr Moreb said. The authors of this study are working to identify clinical and genetic factors that can be used to predict which patients are at risk for these complications. In the meantime, patients taking these drugs should have their cardiac function assessed as part of a clinical visit. u
AMERICAN ASSOCIATION FOR CANCER RESEARCH
Stool DNA Test Performs Well in CommunityBased Setting
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noninvasive screening test for colo rectal cancer demonstrated potential for identifying cancer and advanced adenomas in community-based patients who previously had not followed national screening recommendations. Almost 90% of patients completed the Cologuard stool DNA test when offered the opMark Prince, MD tion, and 15% had positive tests that led to referral for diagnostic colonoscopy. Although none of the 393 patients in the study had undergone screening colonoscopy within the previous 10 years, 90% of those with a positive stool DNA test followed through with the colonoscopy referral. Colonoscopy revealed cancer in 4 patients and advanced adenomas in 21, as reported at the American Association for Cancer Research Annual Meeting.
Although derived from a retrospective chart review, the results provided “real-world” support for the pivotal multicenter trial that led to FDA approval of the stool DNA test as a screen for colorectal cancer. “The availability of the multitargeted stool DNA test provided significant medical benefit to our previously screening-noncompliant Medicare population,” said Mark Prince, MD, Director of Gastroenterology at USMD Physician Services in Dallas, TX. “Patients with clinically critical advanced colorectal neoplasia were identified in this cohort due to high compliance with both stool DNA screening and follow-up diagnostic colonoscopy.” Although derived from a retrospective chart review, the results provided “real-world” support for the pivotal multicenter trial that led to FDA approval of the stool DNA test as a screen for colorectal cancer. The pivotal trial, involving 10,000 patients, showed the test had 92% sensitivity for detecting colorectal cancer, 42% sensitivity for colonic adenomas, and an 87% specificity. Number-needed-to-treat values were 154 with colonoscopy,
166 with the multitargeted stool DNA test, and 208 with the fecal immunochemical test (N Engl J Med. 2014;370:1287-1297). Whether the results from the prospective trial might be extrapolated to the community setting remained unclear. To investigate the issue, Dr Prince and colleagues reviewed medical records of patients in the USMD Health System and identified 393 Medicare beneficiaries who had not undergone screening colonoscopy in the previous 10 years or completed a fecal occult blood test within 1 year. The patients had a mean age of 69.8 years, and women accounted for 64% of the study population. All of the patients had an average risk for colon cancer. Dr Prince said 77 providers offered the stool DNA test to the 393 screening-noncompliant patients, and 347 completed the test, representing a compliance rate of 88.3%. The test yielded positive results in 51 of the 347 patients (14.7%). All patients with positive results were referred for colonoscopy, and 46 (90.2%) complied with the recommendation. Of the remaining 5 patients, 3 refused colonoscopy and 2 were lost to follow-up. Colonoscopy results for the 46 patients showed that 4 had colon cancer, 21 had advanced adenomatous polyps, 9 had nonadvanced adenomas, and 12 patients had neither polyps nor cancer. None of the patients had symptoms prior to the positive stool DNA test. The results supported those of the pivotal trial, suggested good compliance with the test in the community setting—even among patients who have been noncompliant with other screening methods—and provided additional evidence that “colon cancer screening saves lives,” said Dr Prince. “Colonoscopy is the best form of colon cancer screening, but for patients who will not have a colonoscopy, a noninvasive screening test like Cologuard is needed.” However, he cautioned that every patient with a positive stool DNA test should be referred for colonoscopy, which remains the definitive method for detecting colon cancer and advanced adenomas of the colon. Dr Prince added that the applicability of the result to patients with private insurance remains unclear. u