May 2014, Vol 3, No 3

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Perspectives on the Landscape of Personalized Medicine

An Interview with Gail E. Herman, MD, PhD; Barbara L. McAneny, MD; and Charles L. Sawyers, MD

Gail E. Herman, MD, PhD

Interview with the Innovators

Gail E. Herman, MD, PhD, is President of the American College of Medical Genetics and Genomics (ACMG).

Barbara L. McAneny, MD, is Chief Executive Officer of New Mexico Cancer Center, New Mexico Oncology Hematology Consultants, Ltd.

Charles L. Sawyers, MD, is Chair of the Human Oncology & Pathogenesis Program at Memorial Sloan Kettering Cancer Center.

The Personalized Medicine Coalition (PMC) was launched in 2004 to educate the public and policymakers and to promote new ways of thinking about healthcare. Today, PMC represents a broad spectrum of more than 225 innovator, academic, industry, patient, provider, and payer communities seeking to advance the understanding and adoption of personalized medicine concepts and products for the benefit of patients.

Through our partnership with PMC, the publisher of Personalized Medicine in Oncology (PMO) had the pleasure of interviewing several faculty members at the recent PMC conference about personalized medicine and their direct involvement in this movement. Those interviewed include a geneticist, Gail E. Herman, MD, PhD; a community oncologist, Barbara L. McAneny, MD; and an academic oncologist, Charles L. Sawyers, MD. The insightful exchange is presented below.

PMO Thank you all very much for meeting with us today. To start our discussion, we’d like each of you to provide your definition of personalized medicine.

Dr Herman I would define it as using the information in our genome to make better healthcare decisions, both as healthcare providers and also as patients.

Dr Sawyers I prefer the term precision medicine rather than personalized medicine as this term implies a more accurate diagnosis. Further, using information in the tumor genome to better understand the root cause of the cancer has been shown to predict the best therapy. “Personalized” implies that every patient’s tumor is different and might even need a different treatment, and while it’s true that every tumor might be different at the DNA level, I think it’s impractical to assume everyone would receive a custom treatment.

Dr McAneny I think patients tend to think of personalized medicine as a nurse navigator who’s going to hold your hand through your process. So I think we’re going to have to work to change that definition. As a cancer doctor, I think of finding the right treatment to fit that exact patient’s needs. That’s where personalized medicine comes in, being able to use genomic markers of the patient and the tumor to find the right treatment that works best for that individual.

PMO Dr McAneny and Dr Sawyers, how have your practices, the New Mexico Cancer Center and the Human Oncology & Pathogenesis Program at Memorial Sloan Kettering, incorporated personalized medicine principles into patient care? Have there been obstacles to their adoption?

Dr McAneny We stay current on the markers that will lead to a change in therapy. We have created a pathway system to integrate this information into the care.

An obstacle we face is economic, with denials by the payers. In some cases, the labs may charge the payers for 1 test at a time, and sometimes that’s not acceptable to the payers, who question why a patient is receiving a second test and a third test.

Interestingly, the patients are not an obstacle. When we ask to test their genome to find out if their cancer will respond to a very specific drug that targets our finding, patients are very accepting. I occasionally work in a clinic in the Navajo Nation, and they do not like the idea of taking private information and making it more accessible. But when we explain the utility, there’s no problem. They’re willing to go ahead with the tests and thrilled to have less toxic treatments.

Dr Sawyers I’m the inaugural chair of a research program at Sloan Kettering called Human Oncology & Pathogenesis Program (HOPP). Its purpose is to attract the best and the brightest physician scientists who have 1 foot in the lab and 1 foot in the clinic to help bridge the movement of new exciting ideas into the clinic.

Personalized medicine in the form of genomic sequencing of tumors has been a major part of the research by almost all the investigators in the HOPP program. I would say it’s mostly been positive. Some of the obstacles have been just the pace at which the technology is changing. In order to move something into the clinic, you have to secure a method and prove that it’s reliable and effective. It’s a challenge to remain constantly innovative and also still be impacting the clinic.

PMO Also for Drs Sawyers and McAneny, in your tenure as oncologists, can you describe the most significant advances that impacted your ability to provide better care for your patients?

Dr McAneny It is difficult to identify just one because there’s a tsunami of information that’s coming at us now, allowing us to fine-tune treatments for patients. I would think that the most significant scientific change is the genomic markers and being able to tailor treatment for a given patient.

I think the most significant process-oriented change is bringing many of the services that a patient needs together under 1 roof so that we can provide care in a way that’s very convenient and easy for patients.

Dr Sawyers I was involved at the very beginning of the development of the drug Gleevec for chronic myeloid leukemia in the late 1990s when most people were predicting that the drug would not work for a couple of reasons. One, cancers are complicated. Why would a drug that only is blocking 1 alteration in a cancer be expected to work?

Obviously, that proved to be a concern that was not warranted. Second, this was the first tyrosine kinase inhibitor. Tyrosine kinases all do 1 thing: they take ATP [adenosine triphosphate] and put it onto a substrate. Even though Gleevec appeared to be relatively specific for BCR-ABL, the driver in chronic myeloid leukemia, it did work by blocking ATP binding, so it was assumed that there would be horrible toxicity, but that was not the case.

This was a remarkable experience. I’m very proud of our role in moving the field forward, and I think it’s going to continue to drive the way we develop cancer drugs in the future.

PMO And Dr Herman, from the geneticist’s perspective, can you describe the most significant advances you have witnessed that impact our ability to care for patients?

Dr Herman Given my background in pediatrics, the first advance that comes to mind is expanded newborn screening. When I started training, there were many rare metabolic disorders that we couldn’t treat, and as a result, children died. The standardized newborn screening panel tests for more than 30 disorders. There are kids that would have died prior to this panel that now are growing up, living normal lives. The college [ACMG] was central to this progress, establishing the criteria for adding a disorder to the panel. And now the college has obtained a grant to look at outcomes. It’s the newborn screening translational network.

Of course, other advances are new targeted drugs, options in treating genetic diseases, and the revolution in diagnostics.

PMO As we gain increased understanding of genetics in cancer, it’s increasingly important to incorporate molecular measurements into clinical trials for all kinds of cancer. Can you describe how the introduction of companion diagnostics and the discovery of biomarkers in oncology will impact clinical trial enrollment and design?

Dr Sawyers The companion diagnostic model has already had a huge impact on not just clinical trial design but also clinical practice. The idea is that if you’re giving a targeted agent, you need to give it to patients whose tumor has the target. The clinical trials have to demonstrate 2 things; the first is that you can measure the target reliably with a diagnostic test, and second, that that test picks out a subpopulation of patients with that kind of cancer that respond dramatically to the treatment.

There are many examples now, particularly in lung cancer and melanoma in recent years, where this has worked beautifully. But it turns out that it actually is almost out of date as a concept even though it’s working well, because the new generation of molecular diagnostic tests is large panels of genes, whereas a typical companion diagnostic is just measuring 1 mutation.

I think the whole field recognizes this, including the regulatory authorities at the FDA, and I think we have to figure out how to capitalize on this new technology in a way that ensures the accuracy of the testing, so that patients are not misdiagnosed, but enables the power of these multigene panels to be deployed right away in the clinic.

Dr McAneny Also, I think our current system – where we have certain centers that are able to provide clinical trials, and patients are supposed to travel at the time of their life when they least want to travel away from their friends and family, to enroll in a trial – is perfectly designed to achieve the 3% that we enroll. If we want to continue enrolling only 3%, we should keep doing it as we are.

If we intend to use companion diagnostics and personalized medicine as a way to screen the population and find that subset of patients who will respond to a given therapy and therefore can be enrolled on a trial, then we need to widen that network so that it extends into the community practices, where we see the vast majority of the patients, and offer the trial to the patient in that setting. We need to restructure how we conduct clinical trials in this country, or we will never get better than 3% enrollment.

PMO Is the Affordable Care Act financially compatible with the growth of personalized medicine overall and specifically in oncology, or will its additional cost reduce the spread of personalized medicine overall and in oncology in particular?

Dr McAneny The Affordable Care Act basically is insurance reforms. People need to have better insurance policies that will allow us to do what we need to do as physicians.
I think the Affordable Care Act will expand the group of people for whom personalized care is available. Right now, if I have patients who are uninsured, I can’t get them the drugs, I can’t get them the testing. I can give them some of my time, but frankly, as a cancer doctor, that’s useless unless I have my tools.

I’m excited about this. In my state with 24% uninsured, this opens up good therapy to a lot of people, so I think it will help.

I don’t think the cost of this is going to be exorbitant. What we have to prove is that if you order a personalized medicine test, a genomic marker test, and you find a specific treatment that works, that provides a lot more value than treating people with the random chemotherapies that we try to use in the one-size-fits-all model. The value we’ll prove will be in better outcomes.

Dr Sawyers I think this question is getting at not so much whether personalized medicine is incompatible with the Affordable Care Act but whether the price of new oncology-targeted drugs can be sustained.

I think payers are willing to pay for treatments where the evidence overwhelmingly supports their effectiveness, and targeted therapies given to the right patient tend to be remarkably effective. The problems arise when a targeted therapy has a rather modest benefit and perhaps in only a small number, a minority of patients, yet the clinical trial demonstrates superiority over the standard treatment, but only by a small amount. I personally feel it’s hard to justify paying $80,000 to $100,000 a year for such a treatment.

I’m much more in favor of rewarding real game-changing treatments where we understand the reasons patients benefit, and we can select those patients. I think in the long run that will prove to be an economically cost-effective model of delivering care.

PMO Value is more than cost, it is the balance of cost, quality, and access. How long will it take for personalized medicine to begin paying dividends economically, as it already pays dividends clinically, and become attractive to payers by showing value?

Dr McAneny I think we’re going to have to prove the case with data. And I think a lot of the value will come in avoiding therapies that do not work. That obviously has value for the patients who spend some of their remaining life span receiving a treatment that isn’t working, enduring the toxicities and getting no value, and for the payers who end up paying for something that isn’t working.

Payers respond to data. If we are able to demonstrate good outcomes in relation to reasonable costs, then we’ll be able to make a rational decision.

Dr Sawyers This is the major question. Why shouldn’t payers pay for molecular diagnostic testing right away? Because we don’t have the evidence that it is beneficial to all patients. With roughly 10 years of experience in lung cancer with different targeted agents, it’s pretty clear that a patient with lung cancer should have a panel of mutations run.

I don’t think a payer is going to argue with that, because it’s going to directly impact the treatment decision, and it’s going to be cost-effective in the long run because patients won’t get put on 1 or 2 or 3 drugs empirically and fail them and then finally get the right drug. But arguing that every cancer patient should have such a gene panel covered by the payer won’t happen until we, as a community, generate the evidence through research.

How do we generate those research projects? That’s another very difficult question, particularly in this era of restricted medical research budgets. I think it actually may be in some payers’ interest to join some funding consortia, perhaps with the drug development community, the academic community, and the government, to build the evidence base, or at least build the infrastructure, so that the occasional examples of one-offs of genomes and treatments that are done in cancer practice get collected and can be learned from.

PMO How would you articulate the value proposition justifying the cost of personalized medicine to the clinical business and government sectors and to patients?

Dr Sawyers The value proposition to government is in the savings downstream to Medicare by more cost efficient delivery of care. But in order to realize that economy, I think a lot of R&D money needs to be spent to generate the evidence base.

In some ways I think patients might have to be the catalyst to drive this issue, because patients are the ones who stand to benefit the most. We live in a world where data sharing is difficult for a number of reasons, including privacy, but at least in cancer the dominant theme I hear from patients is they want to share their data.

I think our field should seriously consider patient-driven efforts to deposit genomic data in a secure way and correlate it with clinical outcome so that this evidence base can start to be generated.

Dr McAneny We will be able to justify costs by identifying that subset of patients who are very likely to respond, use that drug in that population and only in that population; then the value proposition will become obvious.

I also think that it’s going to become necessary for us to figure out a way to better subsidize the process of getting a drug to market, because we cannot have drugs that cost $100,000 a year, $200,000 a year, to be able to keep a patient alive. That’s an unfair burden to put on patients and the system.

PMO Dr McAneny, you were awarded a grant from the Center for Medicare & Medicaid Innovation to test how private oncology practices could better care for patients with cancer at lower costs. Can you provide an update on your findings and how they can be incorporated into other cancer centers?

Dr McAneny It requires a basic mindset change of the way practices are structured. This is our goal as we create an oncology medical home. The idea is that “home” is a place that’s centered around you, the patient. Instead of the current structure of a patient being sick today, but the doctor will see that patient a week from next Thursday, we encourage every person in the practice to have the mindset that if the patient is sick, our job is to get the patient what they need when they need it; to intervene early and to be the place where patients go early in the course of their illness. This will ultimately keep patients out of emergency departments, shorten length of stays in hospitals, and build that doctor/patient relationship so the patient regards the oncology practice as their home.

We succeeded in implementing this philosophy with some very specific triage pathways that look at the common problems that patients on chemotherapy or radiation therapy encounter. We set up processes to intervene early and then aggressively manage those side effects so that we have fewer patients in the hospital. We prevent 2 to 3 emergency department visits just in my practice per evening by being open until 8:00 o’clock and aggressively getting patients to come to the office. That’s a huge amount of savings.

We will also be using the pathways to improve the quality of what we do, and we’re embedding the genetic markers into these pathways.

PMO Dr Herman, the ACMG has put forth policy statements and guidelines regarding next-generation sequencing. Can you give us a glimpse of the types of guidelines the college will work toward during your tenure as president?

Dr Herman We are focusing on next-generation sequencing for clinical efforts, and we just recently published a guide for laboratories performing next-generation or exome sequencing. There is discussion of how far the depth of coverage should be and how to approach incidental findings. These are findings that may be medically actionable or important but are unrelated to the reason or diagnosis for which the test was ordered. One of the recommendations we received was to put a work group together to figure out how to add additional genes. We’re in the process of doing just that.

We have a work group now that’s writing an update to interpretation of genomic variants, ie, DNA sequence changes. They’re working very hard in the next-generation area and figuring out how to categorize variants and whether they are pathogenic or benign.

Also, we just recently started a work group focused on the issues surrounding informed consent for clinical exome and genomic sequencing.

PMO Dr Herman, you brought up an issue of particular interest – the college’s recent recommendations for reporting of incidental findings in clinical exome and genome sequencing reports. The college points out that there are insufficient data on clinical utility to fully support these recommendations. Considering this, can you briefly discuss the potential utility in secondary findings discovered in the course of research in a clinical context?

Dr Herman That’s a really important issue. The report touched on the fact that they were talking about clinical sequencing and not research. I think the National Human Genome Research Institute at NIH is very interested in trying to come up with some guidance and standards on what the research community should be doing or thinking about in this regard.

There was a time years ago when we, as researchers, tried to give research results out to families. Now there’s a big push again to provide research results in a responsible fashion – meaning, results that are known to be of significance and are validated in a CLIA-approved clinical lab should be given to families.

I think the problem with research results, including DNA sequencing, is the quality of the sequencing and interpretation may not be up to the standards in the clinical lab. Not all research labs have the same standards, and I think the worst thing we could do is to give out information that’s wrong or premature.

PMO Dr Sawyers, with the new immunotherapy products coming down the pipeline, do you view that as a personalized or precision approach to treating cancer patients?

Dr Sawyers Immunotherapies are potentially a different kettle of fish because they don’t work by targeting the tumor. Checkpoint blockade inhibitors, such as ipilimumab, and different antibodies that target PD-1 or PD-1 ligand don’t work in every patient, but there might be some profile within the tumor that would predict who’s going to respond to checkpoint blockade therapy. The tools of genomics that we have available should lead to the answer, and I expect in the next couple of years we’ll know a lot more.

PMO We’d like to thank you each for your time today. Your insights on the dynamics of personalized medicine are much appreciated. Our very best to you for continued success in your endeavors.

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