February 2014, Vol 3, No 1
Partners HealthCare Center for Personalized Genetic Medicine: Utilizing Genetics and Genomics to Improve Care of Patients
Interview with the Innovators
An Interview With Scott T. Weiss, MD, MS, and Heidi L. Rehm, PhD
Harvard Medical School and Partners HealthCare System established the Harvard-Partners Center for Genetics and Genomics (HPCGG) in 2001. The center was launched in recognition of the excitement of the Human Genome Project and as an early commitment to the importance of genetic and genomic knowledge in human health. HPCGG offered a framework for aiding genetic discovery, stimulating research that would lead to the integration of genetic knowledge into patient care, developing an information infrastructure that would facilitate the application of genetic and genomic data in research and clinical settings, applying genetic discoveries and technological advances in the development of molecular diagnostic tests that could be used in everyday medical practice, and building an education program that would expand the number of clinicians and investigators trained in genetics and genomics.
In late 2008, the name of the center was changed to Partners HealthCare Center for Personalized Genetic Medicine (PCPGM) to reflect a heightened focus on translational issues related to moving genetics and genomics into clinical practice. Previous direct discovery components were moved out of the center and into affiliated academic medical centers. The name change also affirms Partners HealthCare’s emphasis on personalized medicine.
The publisher of Personalized Medicine in Oncology (PMO) had the pleasure of interviewing the Scientific Director of PCPGM, Dr Scott T. Weiss, as well as clinical molecular geneticist, Dr Heidi L. Rehm of PCPGM at the recent meeting of the Personalized Medicine Coalition, where Drs Weiss and Rehm were presenters.
Scott T. Weiss, MD, MS, is the Scientific Director of Partners HealthCare Center for Personalized Genetic Medicine and Associate Director of the Channing Division of Network Medicine at Brigham and Women’s Hospital.
Heidi L. Rehm, PhD, is Chief Laboratory Director of the Laboratory for Molecular Medicine at PCPGM. She is a board-certified clinical molecular geneticist and Associate Professor of Pathology at Harvard Medical School, with appointments at Brigham and Women’s Hospital, Massachusetts General Hospital, and Boston Children’s Hospital.
PMO Dr Weiss, as the scientific director of the Partners HealthCare Center for Personalized Genetic Medicine, and Dr Rehm, as a clinical molecular geneticist, how do you define the term “personalized medicine”?
Dr Weiss Personalized medicine is providing the right care for the right patient at the right time. It’s about knowing the patients’ genetic and genomic background and how they’re going to respond to a particular drug. It’s understanding the particular molecular makeup of their disease and tailoring therapy to that molecular makeup.
Dr Rehm In my mind, personalized medicine is what physicians have always practiced. You take the patient’s symptoms and the information from the tests that you run and then figure out the best plan for the individual. In a way, the approaches we’ve taken to treat an individual have always been personalized based on the context of the data available. We’re in a different era now because we can add genetics to that.
I sometimes like to talk about personalized genetic medicine, because I think that’s what most people are really talking about – the use of genetics in stratifying populations and deciding what the best treatments are for those individuals.
PMO Harvard Medical School and Partners HealthCare System launched the Harvard-Partners Center for Genetics and Genomics in 2001 in recognition of the excitement for the Human Genome Project and to explore the importance and impact of genetic and genomic knowledge in health. The center later updated its name to Partners HealthCare Center for Personalized Genetic Medicine to emphasize the ability of genetic information to personalize treatment for patients. We’d like to ask you each to talk about the goals of the center and its impact on personalizing medicine.
Dr Weiss I think that the initial goal of the center was more along the lines of a traditional academic program focused on research. Since I’ve been the director over the past 5 years, the mission has been focused directly on more applied personalized medicine and actually improving personalized medicine for both the patients and the doctors who are part of the Partners HealthCare System. Enhancing research in medical diagnostics, prognostics, and therapeutics is part of the center’s mission.
Partners HealthCare encompasses 2 anchor academic medical centers: Massachusetts General Hospital and Brigham and Women’s Hospital. In addition, we have a large number of affiliated hospitals that extend from Faulkner Hospital in the south, Newton-Wellesley Hospital to the west, to North Shore Medical Center north of Boston.
The approach that the center is taking is really a 3-pronged approach that emphasizes different aspects of the delivery of personalized care to patients. The first is enhancing research across the Partners HealthCare System by a series of core laboratories and providing the huge investigative community of Partners HealthCare with resources in terms of the genomics capability, a large biorepository for samples, and consented samples from Partners’ patients. It’s directly linked to the electronic medical record.
The second piece of the center’s mission is the actual delivery of genetic and genomic tests to patients. We run the largest molecular laboratory across the system focused on providing approximately 5000 genetic tests per year to patients, both at Partners and throughout the world, focused on the germline, whereas the 2 molecular labs within the pathology department are focused on the cancer testing. Our focus is germline content delivery for patients.
The third area is an IT infrastructure that is focused on delivering genetic and genomic content to practitioners. Whether it’s cancer testing that’s been in the molecular pathology labs or germline testing that’s been in our lab, all of it is eventually going to filter and funnel through the GeneInsight suite of software, which will deliver content to practitioners.
It’s really those 3 prongs. An IT infrastructure for personalized medicine, a laboratory to deliver clinical test results and enhancing translational research in genetics and genomics in personalized medicine, which are the ways that the center is trying to drive this forward.
Dr Rehm I will add that our goals are about translating both discoveries and new technologies into medical practice in ways that are efficient and effective.
Within the center, one of the things we did early on was to position all of our core facilities that support research in genomics in the same space with our clinical lab so we could very quickly translate the technologies being used in research into clinical tests that could be used in medical practice.
We have really focused on bringing novel discoveries and developing tests that aren’t available elsewhere, and doing that as early and quickly as possible. We bring new technologies to improve existing tests and then work not just to launch them but also to integrate them into care and understand how they are used in the context of medicine.
PMO In the advent of personalized medicine and companion diagnostics, biopharmaceutical companies face exciting and evolving scientific opportunities. Please comment on the ways in which your center is working to advance the scientific processes to meet patient needs.
Dr Weiss I’d just like to pick on 2 specific examples in the grant area where the center is working to advance personalized medicine. The first goes back to this issue of curation of the genome.
Part of the problem with the technology as it exists today is that the curation of these variants is not very accurate. We’re discovering tons of variants, and we’ve already looked at a subset of those variants, but we don’t really know what their relationship is to the disease. Is it really a causative variant? Is it something that’s an unknown variant and we really don’t know what it does? Is it noncausal?
Dr Rehm is one of the coprincipal investigators in the community of clinical geneticists across the country who are working to curate the variants more accurately so we can improve the interpretation of what’s going on with whole exome and whole genome sequencing, whether it’s for somatic variation or for germline. That’s one area.
I think the other area that the center is working in relates to another grant that we just got funded from the National Heart, Lung, and Blood Institute to try to improve the translation of genetic and genomic discoveries and move them into commercialization. In that grant, it’s a collaboration between research ventures and licensing of partners – a medical technology device group called CIMIT [Center for Integration of Medicine and Innovative Technology], Harvard Medical School, Massachusetts General Hospital, and Brigham and Women’s Hospital – all working together with venture capital to take discoveries like our panel test for pulmonary disease and try to figure out a way that we can commercialize these things and move them into the commercial environment in a more rapid fashion.
I think those 2 specific examples both come from grants that the center is involved in. One, better curation of the medical genome and, second, a more rapid path to commercialization for genomic discoveries are 2 of the many ways that the center is working to improve personalized medicine.
PMO Thank you, Dr Weiss. Dr Rehm, can you speak to how the center is advancing science to meet patient needs?
Dr Rehm This is related to what I was talking about before. One of the dilemmas with companion diagnostics is that in order to decide to use a drug, you need to run a diagnostic. But the problem with the approaches that we want to take in genetics is that we don’t even have enough tumor tissue, for example, to run 25 different companion diagnostic tests to then decide which of the 25 treatments might be appropriate. And it also costs too much money to run them all individually.
I think one of the challenges that we all face in the era of companion diagnostics is how to pair and appropriately decide on the right drug using these companion diagnostics and balance that with large-scale approaches that allow us to accomplish our goal, which is to take a broad view and pick out the needle in the haystack.
This has been an evolving process over the past few years to decide how to logistically go about realizing the benefit of companion diagnostics, but also realizing the practicalities of how we test tumor specimens today.
PMO Yes, tumor sample size is an issue, and the ability to run 1 test to detect many genetic mutations could be of great value. What about heterogeneity of tumors?
Dr Rehm The other thing we’ve always appreciated in cancer is that the tumor evolves over time, and it acquires new mutations. Even if you found the right treatment at one point in time, eventually resistance will evolve.
So one of the questions is that if we look at a tumor and we test for just 1 factor, we may be missing a concurrent factor, or the next factor that may be evolving at a low level now but will grow into a prominent role in the tumor’s progression. So by using a multianalyte testing approach, you can pick out not only 1 factor but sometimes multiple factors and thereby predict how that tumor may progress and evolve over time by seeing an early glimpse of the next stage of that tumor. The tools that allow us to take broad views also enable us to possibly predict the multistep progression of tumors.
PMO Are the payers more inclined to reimburse 1 multianalyte diagnostic test?
Dr Rehm It is a delicate balance, and they certainly take the view that they don’t want to pay for more than is clinically indicated.
Now, if I say to them that these 5 different analytes are clinically indicated for this patient, and if I were to run each of them separately, it’s going to cost $1000. On the other hand, I could run them all as 1 test, and it’s going to cost $800. Hopefully they’d be okay with that.
So there’s a balance there. Yes, it’s okay to cast a broader net if you’re not incurring more costs than what is clinically indicated.
PMO So, for example, they have no problem with you testing for ALK in lung cancer or EGFR in lung cancer mutations, but if you want to test for BRAF and there’s no evidence behind that, they’re not going to pay for it?
Dr Rehm That’s exactly right. I think they’re probably going to take different views as to whether you should even be looking at those results. They may say, sure, run the technical platform any way you want, but you should only be looking at what’s clinically relevant versus another group that might be okay with you looking at everything as long as it doesn’t cost more.
PMO Dr Weiss mentioned a strong IT infrastructure at your center to facilitate personalized medicine. Dr Rehm, you’ve conducted research on the use of IT enabling personalized medicine. Can you discuss your findings from that research?
Dr Rehm One of the projects that we’ve worked closely on is a project called RISGIM (refining IT support for genetics in medicine), led by Dr David Bates. This project centered on launching a genetics application for physicians where we would electronically deliver genetic test reports to the physicians so they can get access in real time to the results of their patients, and also receive updates when new knowledge is learned about their genetic test results, even if they were run years ago.
So every time new knowledge is learned on a variant, the physicians who have a patient with that variant get an e-mail alert with a hyperlink into their record: they can then click on that, go into the record, review what the new knowledge is and then decide whether to bring the patient back in and treat him or her differently based on that new knowledge.
The study was really about how this system can enable improved care of these patients. Is it a system that a physician can easily figure out how to use without any training, because physicians don’t want to take a course to learn how to use most medical applications? So it’s about whether we can make a system that’s so easy and straightforward that physicians can just jump on it the day it comes out, figure out how to use it, and make it useful in the clinic.
That was what the study was about, and the outcome of it was, yes, they loved this application. The alerts we sent, they clicked on them 98% of the time and learned that new information, and they found the tool very useful. There were subtle things that they gave us feedback on that we were able to then integrate into updated versions of the software to make it even easier for them to use. That was a really nice study showing that an application we developed was useful and could serve the needs of the physicians. And then we were able to show that the time it took for new knowledge to be given to patients and the physicians was dramatically decreased with the software compared with how we were doing it prior to that software. That software is called GeneInsight Clinic.
PMO In your tenure as a geneticist, can you describe the most significant advances that impacted your ability to provide better care for patients?
Dr Rehm Next-generation sequencing in my mind dramatically changed what we can offer patients from a diagnostic standpoint in genetics. With the previous cost of sequencing, we could only offer the most likely genes that might be involved. Because of that the physician could only test these most obvious genes. So when you confirmed that most likely assumption, you didn’t really change how the patients were treated.
When we launched next-generation sequencing, all of a sudden we had the ability to put everything under the sun into a test. That has some downside also, but the upside was that we started making diagnoses that the physicians never thought about and certainly weren’t treating their patients accordingly. For example, 2% of patients with left ventricular hypertrophy, a thickened heart, actually have Fabry disease instead of hypertrophic cardiomyopathy. So when we are able to run a broad test and include the GLA gene that no physician ever ordered, 2% of the patients are positive. That’s the only gene for that disease – and there’s a treatment. They can put them on enzyme replacement therapy.
This is making a difference in the outcome of these patients. We can take a much broader view of the possible etiologies for a given patient’s disorder and find those things that they possibly hadn’t thought about. That’s certainly also true now with exome and genome approaches, where you can take the broadest of possible approaches to thinking about a question.
PMO Dr Weiss, your research has been predominantly in the field of asthma genetics, asthma pharmacogenomics, COPD [chronic obstructive pulmonary disease] genomics, and predictive medicine. Are there lessons from other specialties in the area of genetics and genomics that impact your research, and can you give an example?
Dr Weiss I can tell you that it’s very clear that cancer is leading the translational aspects of personalized medicine, but that doesn’t mean that other complex traits are all that far behind. I want to give a very clear example from my own research about how genetics and genomics are influencing healthcare. It’s a little bit different from cancer, but I think it’s very instructive.
In 1996 I became a professor at Harvard Medical School, and I realized that all of the research that had been done up until that time was really not going to carry me forward in terms of being competitive in the future. I started to work to develop my understanding of genetics and genomics and so by 2000, when the human genome was mapped, I was fully funded to do genetics and genomics research.
One of the grants I received was to fine-map a region on chromosome 12q. Fine-mapping involves using either microsatellite markers in the linked region that are linked to a phenotype and relating those markers to the phenotype, or more fine-mapping would be done with single nucleotide polymorphisms and relating them to the phenotype.
That work identified the vitamin D receptor as a potential asthma gene, and we published the genetic association study that showed this relationship. Another group, Tom Hudson’s group at the Montreal Genome Centre, confirmed it. But there were other genetic association studies that had negative results for this gene.
But then we did an interesting thing. We said, we know that asthma is an early life disease. Let’s look at the intake of vitamin D during pregnancy and see what the relationship of that is to asthma and asthma occurrence.
We did 2 studies where we looked at the mother’s intake of vitamin D and showed in both studies that the higher the intake of vitamin D, the less asthma in the offspring. In fact, both of these studies suggested that in the mothers who had the highest intake, we saw about a 50% reduction in asthma. We then wrote a grant to do a clinical trial where we give vitamin D to pregnant women. That trial is now in its fifth year, and we’re following the children up until age 3, and our results will be ready next year.
Here’s an example where we went from genetics and genetic association to a clinical trial to a potential preventive for asthma in less than 10 years.
So, do I believe that personalized medicine is going to extend beyond cancer? Absolutely. Is this going to happen for diseases like asthma and COPD? Absolutely. I think the problem is that most of what we’re doing now in personalized medicine is focused on the medical exome. The medical exome encompasses the simplest aspects of molecular biology, really protein coding function.
What we know from genome-wide association studies is that 80% of what we’re finding in those studies in complex traits, diseases like asthma or coronary disease, high blood pressure, preeclampsia, multiple sclerosis, rheumatoid arthritis, you name it, 80% of the variation in those disorders is in the regulatory portion of the genome, the noncoding portion of the genome.
You’ve got 2 different revolutions going on in personalized genetics and genomics. One, where we are right now, which is focused on the exome, and this coming wave that is going to be focused on regulatory variation, and I think that the vitamin D story is a great example of low-hanging fruit. Now there’s the opportunity to go back and look at more of the molecular mechanisms around how the vitamin D is protective.
There’s a whole host of reasons for that.
But I think this is an example – if the trial is successful and we can actually prevent a portion of childhood asthma – where genetics and genomics are going to have a big impact in an area that people never thought about.
PMO How will the introduction of companion diagnostics and the discovery of biomarkers in medicine impact clinical trial enrollment and design?
Dr Rehm It’s a great question. I have spoken to one pharmaceutical company about this. On the one hand you can make the argument that if you really could look at not just 1 marker but lots of markers or even the whole exome, you’d be able to do a better job stratifying your population and enhancing the likelihood that your drug works in a specified group.
On the other hand, there’s this added complexity to the questions you’re asking. There is this hesitation, even though the perspective is that the science is better, that it complicates the story so much when you’re going through the FDA approval process for your drug. If you add all the complexity of many targets to the process, it can make it more difficult to get your drug approved.
I think the pharmaceutical companies are struggling with what is the practical right approach, even though scientifically having the world at their hands is certainly the most scientifically valid approach. But just from a practical standpoint to get their drug through the FDA process and have a clean set of data, it is challenging to take these broader approaches. I don’t know what the right answer is.
Dr Weiss I think there are 2 ways that genomic discoveries are going to impact clinical trial design. One is this whole issue of segmentation, where you’re going to be focusing clinical trials on specific subsets of the population.
I think the second way is actually influencing trial designs. People are going to use more adaptive trial designs in which they’re going to reshuffle and restratify patients on the basis of a genotype or a transcriptome or some other omics stratifier that will actually be built into the trial design.
One is preselection of patients, and the other is actually changing trial design based on these omics diagnostics or prognostics.
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, when it already pays dividends clinically, and become attractive to payers by showing value? How would you articulate that value proposition?
Dr Rehm One example is tyrosine kinase inhibitors that had been approved as third-line therapy for patients. Many patients with lung cancer eventually get to the need for a third-line therapy. So you’re essentially paying for it in a lot of people. On the other hand, if we run EGFR testing, only 20% of them are positive and therefore only 20% of them should be getting that drug, and 20% is a lot cheaper for the insurers than 100%.
So in my mind, by dictating who has the mutation and therefore has a reasonable likelihood of response, it’s not only optimizing outcomes for the patients who should get the drug, it’s even more from a value proposition, getting rid of 80% of the costs and not paying for those who aren’t going to respond because they don’t have the mutations. That’s where the value proposition comes in, and it’s not just about improving quality of care in this arm, it’s about saving healthcare costs on that arm.
Dr Weiss If you look at what has happened over the past 5 years – the rapid increase in diagnostics, prognostics, the increase in the number of companies that are providing these, and the change in the way clinical practices are being performed – I think that it’s a mistake to think that there’s going to be kind of an abrupt time point that’s sort of pregenomics/postgenomics. I would say we’re in the continuum now. I think we’re still in the relatively flat phase of an accelerating curve that’s going to dramatically increase, but as these curation efforts improve, as our ability to translate these discoveries into commercialization improves, I think this is only going to become more and more and more a part of clinical practice.
I think there’s the issue of the value proposition, and in particular third-party payers. I think we can already see that for whole exome sequencing; it’s being adopted by third-party payers because the diagnostic odyssey, in which a small number of tests accumulate for a patient who doesn’t have a diagnosis, may be more costly than simply going directly to whole exome testing and getting the answer. I think it is a clear-cut, sort of simple cost-effectiveness example.
We have issues of healthcare in this country, issues that go well beyond personalized medicine. But I think it’s a false dichotomy to set up that third-party payers are going to have to pay for all of this, no questions asked. We’re going to have to show at every step of the way that these things are not just cost-effective, but that there really is value added to this, and that’s as it should be. But I think we’re in this revolution now. It’s clearly happening now.
I think that everything we do in medicine has to be justified in some way in terms of showing that it’s cost-
effective. Let’s go back to the vitamin D example.
If it turns out that we can prevent half of all asthma by giving pregnant women vitamin D – and we know that 70% of all pregnant women in the United States are vitamin D deficient – you’re going to have an unbelievable impact. You don’t need to do a fancy cost-effectiveness analysis, because vitamin D costs a couple of dollars, and you can show pretty clearly on the back of an envelope that treating pregnant women with vitamin D to prevent asthma is hugely cost-effective.
I also don’t believe you have to do a randomized control trial of every technology or every novel therapy to show cost-effectiveness. But absolutely, I believe that we should be looking at these aspects of personalized medicine that are the most cost-effective, that are going to give us the greatest potential benefit, and close in on those as being the things that we implement most readily.
People tend to focus on the biggest things. You know, when will it be that whole genome sequencing will be standard of care? I don’t think that’s necessarily the way that the personalized medicine field ought to be thinking about this. I think we ought to be thinking about this as an incremental improvement and looking continuously at what we’re doing and saying, how do we benefit the patients as a result of these discoveries, and if we do that, I think we’ll see the implementation of a lot of things that have huge potential benefit to patients.
Just based on my own research experience, I think there’s going to be much more of this that’s nondrug related that could be unique in the area of preventive genomics, if you will, where you’re going to see benefits. Again, that’s one of the reasons I like the vitamin D example, because it’s something that’s not cancer and not tied to a therapeutic, but just an example of something that went from a basic science discovery to a clinical trial in less than 10 years that could have huge public health impact and huge cost savings to society.
PMO Thank you both very much for your time today. You’re insights are stimulating. We wish you both continued success.
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