August 2012, Vol 1, No 3
Incorporating Genomics Into Practice:
Interview with the Innovators
An Interview with Kimberly J. Popovits
Genomic Health, Inc, located in Redwood City, California, is a global cancer company founded in 2000. Genomic Health currently offers patients the Oncotype DX Breast Cancer Assay and the Oncotype DX Colon Cancer Assay. Genomic Health maintains that the key to effectively using clinical genomics to improve cancer treatment and outcomes lies in determining which sets of genes and gene interactions affect different subsets of cancers. Genomic Health studies which patterns of gene expression within a tumor are linked to a response to cancer therapy, or to the likelihood that the cancer will return or metastasize. The results of these genomic studies and research can then be used to develop clinically validated assays that provide the genomic profile of an individual’s tumor, helping to understand whether patients are likely to benefit from and respond to cancer therapies, or whether those patients are likely to experience a recurrence of their cancer. Personalized Medicine in Oncology recently had the pleasure of meeting with the President and CEO of Genomic Health, Ms Kimberly J. Popovits, to discuss Genomic Health’s approach to personalized medicine, her inspiration to work in this field, and the future of cancer treatment. The following are excerpts from that interview. To view the interview in its entirety, please go to www.PersonalizedMedOnc.com/videolibrary.
PMO How do you define personalized medicine in oncology, particularly as it relates to the treatment of patients with breast or colon cancer?
Ms Popovits I think one of the best ways to define personalized medicine is when disease happens to you or to somebody you love. Oftentimes we hear definitions of getting the right drug to the right patient in the right dose at the right time. I think specific to oncology and the areas that we’re in, breast, colon, and prostate cancer, it’s really about patients understanding their individual disease.
Cancer is many diseases. One tumor is not like another tumor, and it’s really important that patients understand the genomic makeup of their particular tumor. We would actually refer to that as the molecular signature of your breast cancer. Knowing how that is different from somebody else’s breast cancer, and by understanding that biology, we’re able to better direct treatment.
PMO It appears that personalized medicine in oncology is a concept that is implemented mainly at academic centers or initiated by a small set of physicians who understand the genetic principles behind molecular biomarkers and how to assess them appropriately. How can personalized medicine be made available to patients managed by community oncologists?
Ms Popovits I think one of the most important goals in oncology is to make sure that all patients have access to personalized medicine; that all patients have access to specific information about their own genome, about their own genetic makeup; and that their family history is incorporated into their treatment planning.
The dilemma we face is that 80% of patients actually present in the community and about 20% in the academic setting. We cannot assume that everybody is going to be sent to an academic center to get their cancer treatment.
There are a couple of barriers in our way right now, and a big one is education. We need to make sure that we are educating all physicians on the new information that’s before us right now. We’re in a world today where we have an unprecedented amount of data, and the key is going to be turning these data into really good actionable information for cancer patients. The tools are here, and folks are using the tools in a lot of places, but I don’t think it’s necessary that every community physician have a sequencer on their desktop. What’s important is that they have access to those tools through other resources, tools that they can present to their patients, so that the information then gets incorporated into treatment planning.
We have to work together. It’s going to be a collaborative effort, clearly driven by the academic institutions and the leading centers, but that information has to get to the community setting so that it’s available to all patients who present with cancer and need to have a personalized treatment plan.
PMO Most of us have been touched by cancer in some way. In fact, the inspiration for Genomic Health came from founder Randy Scott’s experience in watching a friend diagnosed with cancer in the late 1990s. Can you tell us what brought you to Genomic Health and about your inspiration to work in this field?
Ms Popovits When I thought about whether to enter this whole realm of personalized medicine, and in particular Genomic Health, I was working at Genentech and had the wonderful experience of being involved in the development of very important cancer therapeutics. What had occurred to me at that time was that we had a number of drugs in our pipeline at Genentech that might never see the light of day if we couldn’t figure out how to target them to the patients that would benefit.
We saw that first with Herceptin, a very important drug for the treatment of breast cancer, and it is a drug that I’m not sure we would have gotten to market if we hadn’t been able to develop a diagnostic test to find those patients who overexpress HER2.
So when the folks at Genomic Health called me in the very early days and said they had this idea of how we could better direct a lot of cancer treatment, and specifically chemotherapy, it really touched a cord with me in terms of the need for it in medicine, but also on a personal level. I think we are all touched by cancer in some way. It’s hard to run into somebody who doesn’t have a family member or a friend who’s had to make the really tough decision about whether to get chemotherapy treatment. I went through that with my mother about 19 years ago, and I am reluctant to say that she remains a survivor. My dad was less fortunate in that he died 4 years ago after a long battle with lung cancer. And I lost a very good friend to breast cancer just Mother’s Day weekend this year.
All of that is motivation to want to make this difference, and to really bring personalized medicine to a reality.
PMO Please describe how the gene panels for the breast and colon cancer assays were developed and validated.
Ms Popovits The colon cancer and breast cancer assays are different in the sense that they look at different genes. One of the things that’s really important to think about when we look at breast cancer or colon cancer, and now of course we’re looking at prostate cancer as well, is that all cancers are not driven by the same genetic or genomic profiles.
Starting with the breast cancer assay, we asked ourselves a question, can we figure out who those good and bad actors are that come to the party? What are the good genes and what are the bad genes playing out in breast cancer? And so we started with a number of genes in breast cancer. It was several hundred genes that we started with, and then we pared that number down to what we thought were the most important genes.
We are measuring RNA expression with the Oncotype DX assays, looking at overexpression and underexpression of genes. With the breast cancer assay we ended up looking at 21 genes, an algorithm was developed, and a Recurrence Score produced.
It’s the same thing with colon cancer except it’s a different number of genes, and they’re different genes. One of the things that is at play here is that different pathways impact different cancers. What we have shown both in breast cancer and in colon cancer, and what we hope to show in prostate cancer as well, is that looking at a number of pathways is more powerful than just looking at 1 pathway or 1 gene alone.
PMO How does this differ from the DCIS Oncotype DX score?
Ms Popovits The DCIS score that we developed is based on the same set of 21 genes as the invasive breast cancer assay, but it’s looking at an earlier stage of breast cancer, using a specific algorithm to determine whether that disease is likely to recur over a period of time.
PMO How does the Recurrence Score correlate with the likelihood of distant recurrence?
Ms Popovits The Recurrence Score predicts the likelihood of disease aggressiveness, so what we were attempting to do when we did the test for invasive breast cancer was to figure out which women had disease that would be more aggressive and could potentially benefit from more aggressive treatment. And what we discovered when we developed that assay, the 21-gene assay, was that not only could we predict which patients had a likelihood of their disease recurring over a 10-year period, we did subsequent studies to show that we could also predict whether those women would benefit from chemotherapy.
We ended up in a situation where we had 50% of women in a low-risk group, 25% in an intermediate-risk group, and 25% in a high-risk group. Even better than that, we were able to give an individual score to each patient. When we designed the studies initially, we were hoping to be able to identify risk groups, and we were very pleased that not only could we identify certain risk groups, we could actually give women an individual score to show them their likelihood of recurrence. For example, if you get a Recurrence Score of 7, that correlates to a specific likelihood of recurrence over a 10-year period. We can also tell you if your cancer is likely to benefit from chemotherapy.
One fact that a lot of people are unaware of is that about 100,000 women are diagnosed each year with early-stage breast cancer, ie, estrogen receptor–positive, node-negative breast cancer. Most of those women, prior to Oncotype DX being available, would have been recommended chemotherapy based on cancer practice guidelines.
What’s unfortunate there is that while most would have been recommended chemotherapy and most would have received it, most would not have benefited, because we know that only 3% to 4% of women with early-stage breast cancer actually benefit from chemotherapy. So we’re treating 100 women to find 3 or 4 who get some benefit, and that’s what we were trying to change.
The Oncotype DX assay allows us to tell 50% of these women that they have very low-risk disease. Their likelihood of recurrence is very low, and further, we can tell them that their disease isn’t likely to be impacted by chemotherapy. Conversely, we can tell those women who are in the high-risk group that they have a high risk for disease recurrence, and while that’s not necessarily good news, the good thing for these women is that chemotherapy actually will help them a good bit.
PMO How is the DCIS score result different from the Recurrence Score result?
Ms Popovits The DCIS score uses the same 21 genes from the invasive assay, with a distinct algorithm optimized for this earlier cancer, to predict which women with DCIS have more aggressive disease and which have less aggressive disease. And we were successful in doing that.
PMO Can you estimate how often the results of these assays change treatment decisions?
Ms Popovits One of the most important factors in personalized medicine, with the onset of the technology and the amount of data that are available to us today, is really making these data actionable. We knew that when we presented the breast cancer assay to physicians, and to payers specifically, some of the questions that we were going to get were, tell me that this is going to make a difference; tell me that patients are not going to get chemotherapy if they don’t need it.
One of the biggest fears was that we would introduce a diagnostic test into this treatment planning or pathway, and that no decisions would change.
We have embarked on over 15 decision impact studies across the United States, and now also outside the United States, to really look at what’s happening. So when patients get a Recurrence Score result and they are at high risk for recurrence or at low risk of recurrence, are they following that result?
The results of those studies have been amazingly consistent. Treatment decisions are changing on the order of 30% to 40% of the time when the patients have a Recurrence Score in front of them. That’s a significant change for a payer.
The other thing that we’ve done is to monitor chemotherapy use across different payer systems and different clinical settings, and we are definitely seeing a decrease in the amount of chemotherapy being used as a direct result of the Recurrence Score being available for patients to consider in their treatment planning.
PMO What would you say to the breast cancer patient who has a low Recurrence Score but wants to initiate cytotoxic chemotherapy as “insurance”?
Ms Popovits Often we are asked if the Recurrence Score should be the final deciding factor in whether a patient gets chemotherapy. In personalized medicine, there are so many factors that have to be considered in making a treatment decision in any disease, but especially in cancer.
So you’ll factor in the patient history, patient preference, tumor size, tumor grade. What we do know is that the Recurrence Score is the most powerful predictor. However, it has to be used in context with everything else that’s going on in a patient’s world at that given time.
People will ask us, well, if I have a high Recurrence Score, is it really terrible that I decide not to get chemotherapy? Or, I have a low Recurrence Score, but because my mom had breast cancer I am just not going to be comfortable not getting chemotherapy. And my personal feeling is that it’s a good decision if it’s made with all of the relevant information in front of you.
So if you decide that you want chemo even though you have a low Recurrence Score, knowing that the low score means that you have a very low likelihood of your disease recurring, and further, are not going to get very much of a benefit from chemotherapy, if you understand that and you’ve been taken through the data and those facts, and you still decide that you want to proceed with chemotherapy, that’s a personal choice, and that to me is personalized medicine.
PMO Regarding the Genomic Health pipeline, you’re hoping to offer genomic assays in prostate cancer, as well as non–small cell lung cancer, renal cell carcinoma, and melanoma. Regarding an assay for prostate cancer, a test that could provide insight into the individual biology and behavior of newly diagnosed prostate cancers would be helpful in treatment planning for prostate cancer patients and their physicians, particularly to identify patients who are at low risk of disease progression and thus would be ideal candidates for close monitoring. Where are you in the process of bringing this assay to patients?
Ms Popovits We have a really exciting pipeline at Genomic Health; we started in breast cancer, and we moved into colon cancer. I’m happy to say that we have helped over 300,000 patients make really important treatment decisions, but each year over 1.6 million patients are diagnosed with cancer in the United States alone.
The other big cancer that we haven’t tackled yet is prostate cancer. We have a validation study under way. We expect to be able to launch that test in 2013, should we be successful in this study, the results of which we hope to be able to announce toward the end of this year or early next year.
The need in prostate cancer is very similar to the need in breast cancer and colon cancer. Well over 200,000 men are diagnosed each year. Most are faced with a very important decision around how to handle their disease. Many opt for aggressive surgery, and that surgery has very significant lifelong side effects that include incontinence and impotence, which will dramatically impact their life.
We know prostate cancer is unlikely to present future problems for most men. Ninety percent of men should do fine with no treatment at all, yet we’re in a situation today where 90% of men are actually getting fairly aggressive treatment.
What we’re really hoping to answer in prostate cancer is whether we can tell men that they can be comfortable that they have a very low-risk disease, and that they should be able to monitor that disease according to how they and their physician decide to monitor it, but there’s no need for them to go and get aggressive surgery or treatment at this point.
PMO Given the high incidence of breast, colon, prostate, and lung cancers, will it make sense for Genomic Health to develop assays that impact smaller patient populations, such as melanoma or other tumor types?
Ms Popovits There’s a number of things that we are really excited about getting into as we move forward. Prostate cancer is the big focus right now as we extend our pipeline, but as you know, there are many cancers that we haven’t touched yet, including melanoma and ovarian and bladder cancer. Those are all cancers that we’re interested in.
What we have started with are the cancers that have a very low likelihood of presenting significant risks to patients, so it’s early-stage breast cancer, it’s early-stage colon cancer, it’s prostate cancer. In some of the other cancers that often get detected at a little later stage, our interest is to maybe look at therapeutic response, look at targeted therapies and try to determine if we can do a better job of helping patients choose a particular drug, given that we know that their cancers perhaps are a little bit more aggressive.
So, yes, we’re interested in moving toward other cancers, but right now the major ones that we have on our plate – breast, colon, and prostate cancer – will be our focus for the near term. We really hope to be able to say that we are with patients on their journey; to be able to be involved in looking at predisposition to cancer, looking at diagnosis of cancer, looking at drug monitoring through cancer, so that we stay with patients through their entire journey of cancer and cancer treatment.
PMO Genomic Health is transitioning from an RT-PCR [reverse transcriptase-polymerase chain reaction] platform to next-generation sequencing as the basis for development of its future cancer diagnostic assays. Can you describe the opportunities and challenges associated with this transition?
Ms Popovits This is a really exciting time in the field of genomics because of how the technology has evolved, and we’re very interested in using next-generation sequencing, specifically to discover more about the biology of cancer. We have been using the next-generation sequencing platform in our research area for a number of years now, and what we’re finding is that we’re able to see the biology of disease even better than we ever have using RT-PCR as our platform.
As we further our work with next-generation sequencing, we’re uncovering more and more genes that are these good and bad actors in cancer, and certainly we’re going to use this platform to develop more powerful assays in the future to help treatment decisions for patients with cancer.
PMO It seems that education of providers, pharmacists, payers, and patients is vital in achieving personalized medicine in oncology. What efforts is Genomic Health making in educating these stakeholders?
Ms Popovits Education is clearly going to be the cornerstone of personalized medicine being successful. Genomic Health has put a tremendous amount of resources into education – educating physicians, payers, and patients. We have worked very closely with the advocacy communities, and we knew going in that it was going to be very difficult to move a test like Oncotype DX into standard of care if we didn’t have payers on board, if we weren’t able to demonstrate that the test was making a difference in treatment planning. Getting payers on board, getting physicians to embrace the concept of personalized medicine, the understanding of genomics, and how to present genomics to their patients has been very, very important.
Again, we have worked closely with advocacy communities and done a number of educational programs. We’re very focused on working with the opinion leaders, both in the academic and in the community setting, to make sure that this information is available, and to make sure that we’re doing our job in promoting the education around genomics to make sure that personalized medicine is successful in the future.
PMO Can you describe the corporate culture of Genomic Health?
Ms Popovits Well, I’m probably a little biased as the CEO, but Genomic Health is a pretty special place to work. We have nearly 600 employees now spread across the world, all drawn together with a single purpose. We really want to change the way cancer is treated. We want to change the way that patients are presented information. We want to change the way physicians use diagnostic tools. We want to change the way molecular pathology is incorporated into cancer treatment. You can feel that purpose here every day in our hallways, which makes this a very special place to work. It’s something that I personally guard very carefully.
You’ll see pictures of patients in our hallways, you’ll hear stories of patients at our all-employee meetings because patients are at the center of all we do.
Every test result that goes out of our door makes a significant impact in the life of somebody, and I don’t ever want people to forget that.
Nearly 3000 abstracts were selected for presentation at the recent ASCO 2012 Annual Meeting, many of them related to some aspect of personalized medicine. Below are some highlights selected from the meeting that focus on potential genomic predictors of aggressive versus indolent disease and on potential biomarkers. 6-Gene Model Identifies [ Read More ]
Key Points Key stakeholders are increasingly considering new measures to protect and advance innovation and investment in diagnostics Efforts are under way to establish more appropriate and least burdensome regulatory policies to address stakeholder concerns specific to in vitro diagnostic tests FDA is concerned with the risk of false-positive and [ Read More ]