1. Eastman, Peggy

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WASHINGTON-As personalized care based on genetic and molecular markers becomes a key factor in cancer therapy, both physicians and patients are dealing with increased expectations, barriers to access, intricate decision-making processes, and increasing complexity in clinical practice. Speakers grappled with these issues at a forum here sponsored by the American Cancer Society Cancer Action Network (ACS CAN), the society's nonprofit, nonpartisan advocacy affiliate. ACS CAN prepared three overview white papers for the forum.

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Starting with a historical perspective, John R. Seffrin, PhD, CEO of both the ACS and ACS CAN, said, "Cancer has been around for millennia. There is evidence of cancer in dinosaurs and Egyptian mummies." But now, because of the precision of personalized medicine, "we might very well bring cancer under control as a major public health problem in this century."


But, he said in his prepared remarks, "Some cancers may prove to be difficult even with targeted therapies." And so he advised patience in integrating personalized medicine into clinical practice.


The sheer speed of new genetic and molecular tests and targeted therapies coming on the market is both exciting and daunting, said speakers. "This is an area that's moving very fast," said ACS CAN President Christopher W. Hansen. "We need to keep talking about the details. We're trying to use our ability to be a convener."


While the U.S. Food and Drug Administration has the authority to regulate laboratory-developed tests (LDTs), sometimes referred to as "homebrew" tests, the agency has not traditionally regulated them. At the forum, Elizabeth A. Mansfield, PhD, Deputy Office Director for Personalized Medicine in the Office of In Vitro Diagnostic Devices and Radiological Health in FDA's Center for Devices, said the agency hopes to publish a draft guidance document on LDTs sometime this year.


"It's not with the intent to crush LDTs," she noted. Rather, the intent is to make sure the tests are reliable, especially in high-risk areas of medicine. "This whole area is moving so fast that it's astonishing," she said. Last year the FDA approved the Illumina MiSeqDx gene sequencer, a testing platform with the capability of fully sequencing genetic areas of interest.


ASCO's New National Access Program

The pace of development in precision medicine is so rapid that "I can tell you, the payers really don't know what to pay for... they are looking to doctors for guidance," said Richard L. Schilsky, MD, Chief Medical Officer of the American Society of Clinical Oncology. And while payers wonder what to reimburse, for cancer patients, he noted, access to precision therapies remains a major barrier.


At the forum, Schilsky announced that ASCO is working with pharmaceutical companies on a new initiative tentatively titled the National Access Program, which will provide facilitated access to targeted cancer therapies based on molecular profiling at low or no cost, and will include a registry of patient outcomes.


"It will allow us to learn from the real-world practice of personalized medicine" in a way that will improve the use of precision therapies in clinical practice going forward, he said. The registry will act as an incentive to pharmaceutical companies because it will be a learning tool on drug efficacy.


Schilsky noted that genomic medicine is highly complicated and nuanced, and that not every oncologist is a genomics expert. When it comes to genetic and molecular tests, "doctors need guidance on what to order and how to interpret the results they get."


To that end, he said, ASCO will develop "much more focused guidance documents that go beyond practice guidelines." These more focused documents on molecularly based diagnosis and therapy are needed because, he said, "this is only going to get more complicated."


In an interview, Schilsky noted that "learning to manage cancer is learning to manage the evolutionary process," since genomic instability is a hallmark of cancer cells and cancerous tumors are adept at evolving and changing with new genetic mutations-leading to resistance to targeted therapies that were initially effective.


One major issue in clinical practice, he noted, is whether to use a combination targeted treatment approach up front, or to add therapies sequentially as drug resistance develops. The problem right now, he said, is that oncologists don't know which patients to select for which of these two approaches.


"What has changed are the tools we have to practice medicine; the practice of oncology will be vastly transformed by all these tools," said another speaker, Olufunmilayo Olopade, MD, Director of the Center for Clinical Cancer Genetics at the University of Chicago. "It's important for doctors to become scientists and scientists to become doctors... I think the onus is on the physician to be educated on these tests."


What this means is that "we all have to learn together," she stressed. Now, when a woman with breast cancer comes to Olopade's clinic, "the first thing I want to know is what type of breast cancer she has."


Olopade noted that even with precision medicine, if oncologists treat only one mutation, "inevitably resistance may arise" because of tumor heterogeneity. "We're beginning to learn about the tumor landscape," she said, which means learning about tumor heterogeneity and multiple mutations. Eventually, she said, "We hope that cancer treatment will become like treatment of high blood pressure," which often requires a combination of drugs to bring the condition under control.


"Precision medicine is a must for children with cancer; our warranty has to extend for 80 years," emphasized Peter C. Adamson, MD, Chair of the Children's Oncology Group (COG) and Chief of the Division of Clinical Pharmacology and Therapeutics at Children's Hospital of Philadelphia. Adamson said the question in childhood cancers is how to leverage the established pediatric cancer clinical trial infrastructure to fulfill the promise of personalized medicine.


Quality and Reliability

Several speakers stressed that with the plethora of genetic and molecular tests coming on the market, quality and reliability are vitally important. "The first step is developing a test that one can trust," said Vincent Miller, MD, Chief Medical Officer of Foundation Medicine and a former attending physician at Memorial Sloan Kettering Cancer Center for nearly 20 years.


"Once you nail that test... that's not where it ends. That's sort of where it begins." On the question of access to personalized care, Miller put in a plea: "We must engage community oncologists... How do we make them stake players in this game?"


Key Points

The following are some of the key points emerging from the forum:


* Given differences in patient populations and different ways of using molecular and genetic tests and targeted drugs in personalized medicine, monitoring and learning from real-world experiences in clinical care remain an important challenge and must be done to ensure the best patient outcomes.


* The cancer clinical trial system, which Miller said is not very well suited to cancer genomics, will have to adapt and change. A step forward is the new master protocol for squamous cell lung cancer (LungMAP), which will simultaneously test for multiple lung cancer genetic signatures in patients whose disease has not responded to first-line therapy and then treat them with investigational targeted therapies based on test results (four targeted drugs and an immunotherapy drug will be used).



"Our hope is that this can be a model in many cancer types," said Roy S. Herbst, MD, PhD, Ensign Professor of Medicine, Professor of Pharmacology, Chief of Medical Oncology, Director of the Thoracic Oncology Research Program, and Associate Director for Translational Research at Yale Comprehensive Cancer Center and Yale School of Medicine.


* Cancer patients have an expectation that targeted therapies will have fewer and milder side effects, and while this is true in some cases, it is not always so. Therefore, patients need accurate, comprehensive, lay-language information on a therapy that helps them make informed decisions and explains what side effects they may experience. Patients also need information on ongoing therapy as opposed to time-limited therapy, if the benefit to be derived stems from continual administration of a targeted therapy throughout their lives.


* There is a growing problem of needing to use multiple individual molecularly based tests to determine which of several personalized medicine therapies are best for a given cancer patient. For example, there could be 12 different tests for one tumor in one patient, with 12 different therapies. In the future it will be important to analyze genetic signatures in a comprehensive way, such as by testing a broad panel of genetic signatures at once or by fully sequencing the tumor's genome.


* As the number of targeted cancer therapies continues to rise, physicians are faced with the challenge of staying current on targeted treatment advances and how to use them with patients. While evidence-based clinical treatment guidelines are helpful, they must be kept up to date in a rapidly changing field. There need to be other innovative and effective ways to deliver ongoing genomics education to physicians in order to translate genomic discoveries into clinical care.


* The identification of genetic signatures that occur with higher than normal frequency in certain subpopulations presents the opportunity to deliver effective therapies to underserved patients experiencing disparate health outcomes. However, health providers and policy makers must ensure that the underserved patients in these populations have access to targeted tests and therapies in order for their promise to be realized and for patient outcomes to improve.


* With new payment models of cancer care that move away from the fee-for-service model, it is vitally important to have quality metrics to ensure that the tools of personalized medicine deliver high-quality care consistently in clinical practice. For example, in solid tumor testing, "It's complicated to know what to biopsy and when to biopsy," ACS Deputy Chief Medical Officer J. Leonard Lichtenfeld, MD, told OT. "We are not there yet. There's still a long journey to get everyone on the right page."