The very first woman to make a breakthrough that has influenced precision medicine was Rosalind Franklin via the famous Photo 51, an x-ray defraction image taken under her direction by one of her graduate students that showed the exquisite structure of DNA. Shown to James Watson without her knowledge, the image was an instrumental piece of evidence used to develop the chemical model of the DNA molecule.
Sadly, Franklin died before Watson and Crick won their Nobel prize, so she was not fully recognized, while still living, for the extent of the contribution Photo 51 made in the field.
Fast forward to today, and women are making more contributions to the advancement of precision medicine—both at the bench and in the boardroom—than ever before. This issue we publish the second of two installments highlighting some of the women helping to significantly advance the field: Bonnie Anderson, CEO, of diagnostics company Veracyte, Tina Hambuch, laboratory director at Invitae, and Cindy Perettie, CEO of Foundation Medicine.
What drew you to the field of precision medicine?
Precision medicine—at least the way that I think about it—has been around for a long time. My first foray into precision medicine was back in the 1980s early in my career with Coulter Corporation, working in flow cytometry and working to try to come up with testing that could help determine pathways of the best care for patients with HIV and AIDS. It was simple immunology-based tests that were done to stratify patients so that those who desperately needed to get on treatment because of low levels of CD4 could.
HER2 testing that was one of the flagship precision medicine markers that is decades old. I have always desired to be involved in a more efficient and more effective diagnostics testing platform to improve outcomes for patients.
When I founded Veracyte in 2008, we raised $21 million in an A round on just a business plan. The reason we were able to raise that kind of money without any science or people or lab or anything but just a business plan was because it laid out how we were going to deploy technology to help keep patients form unnecessary procedure or surgeries they didn’t benefit from.
So you essentially founded the company by proposing solutions, not one that had a proprietary technology?
That is true. And it’s interesting because, for many companies that were formed from the scientific perspective, their failures were often from trying to commercialize those tests. What we asked was what are the clinical questions that we can answer for which we know we will have a market.
Doctors will adopt a test because of the help it will give them in deciding what to do for the patient. More importantly, we felt payers would pay for our tests because we were delivering on an incredible business proposition for them. Our business plan was not about answering one question in our first indication for cancer. It was really about a market opportunity across many different clinical paradigms where we could improve the diagnosis and guide treatment decisions across many indications.
Today we are well down that pathway, with four commercial tests that are all delivering on that value proposition using a very rich scientific and technology backbone.
Broadly, what mark are you and your company Veracyte making to improve precision medicine?
I think we are looking at information across the patient journey and using our entry point early in the diagnostic work up so we have the potential to answer questions that today are not being answered until the patient is much later in their journey.
A good example is a cool, first-of-its-kind nasal swab test that we will launch next year in the U.S. market for early lung cancer detection. We have a long-term collaboration with Johnson & Johnson’s global lung cancer initiative, where ultimately they are trying to find patients with pre-cancer, to develop interceptive therapies that keep the patient from ever getting cancer.
That is their cure paradigm—a really big idea. We were fortunate to announce a long-term collaboration with them, using our nasal swab approach, where we basically can detect all of the transcriptome changes in the nasal airway, and use that information to inform on whether a patient with a lung nodule is likely to have cancer or not.
The reason that is so powerful, is that if we are able to find patients with a high likelihood of having cancer, their next step could be a treatment step. But on the other end of that if you can identify patients that have a nodule that only have a low likelihood of cancer, then those patients can safely be watched with CT and never taken in for a workup.
Veracyte is focused on running the studies needed to provide both evidence of clinical benefit of your tests, as well as the health economics benefit. Why is this work so important?
I think it is important to the industry as a whole. Part of what has held the field back is the lack of evidence in some of the tests that are considered higher priced tests than traditional diagnostics. We have a responsibility, as advanced genomic testing companies that are trying to have our tests inform on either a diagnostic or treatment decisions, to build the evidence that shows we can do that in a safe and effective manner.
We have been strong proponents that evidence matters and I’ve always said the evidence behind our tests will guide reimbursement. In fact they have, because we have taken the time to build large scale validation studies where our test performance proves out to be exactly what we predicted it would be. And, secondly, the cost effectiveness studies show that, where our tests are adopted, there is lower cost of care with improved patient outcomes.
As an industry, we have a responsibility. If we truly want to see these precision diagnostic tests become mainstream, then there is a responsibility to raise the capital and invest in those kinds of studies that are going to prove it.
Describe how your company can contribute to the provision of precision medicine and inform development of better patient treatments.
Providing information at the time of diagnosis is key. When you think of how a patient goes through a care journey, they get referred for the workup of a thyroid nodule, for instance. Usually that is determined because they’ve had some thyroid hormone test that was off. They get sent over to an endocrinologist, and the endocrinologist does an ultrasound and discover they have a nodule. So they are going to do a fine needle aspiration biopsy to collect the cellular material right in their office and send it off for a test.
We classify about 70% of those patients as benign and estimate that we have helped over 75,000 avoid surgery—patients who likely would have gone off to surgery before our test was available.
But because our test is running on a whole-transcriptome assay at the same time, if we didn’t move a patient to a benign diagnosis—meaning they likely had cancer—we could also report on all the NTRK fusions, BRAF variants, you name it. Being able to get this (from one test) is how our LOXO oncology collaboration came along.
LOXO came to us and said that these variants are only present in some of these targeted treatments 4 or 5% of the time and they need to find that 4 or 5%. Prior to our platform data being available, they would have to send 100 surgical tissue samples off and pay $3,500 to process those samples to find eligible patients. Think about the inefficiency of that.
What we are doing is taking it the next level and saying there is no reason to run another test, we can answer all of that in the fine needle aspiration biopsy that we get for the diagnosis, which is going to be much more efficient and find the right patients—we found a few hundred RET variant patients in a year just because of the sheer volume of testing we are doing in thyroid cancer.
I’m excited about the technology giving us the ability to combine these answers and not think about them as segregated decision points at different points in time for the patients, but to be able to now utilize the rich science to answer what the patient’s diagnosis is and inform on those treatment decision at the same time.
Clinical Laboratory Director
What was it that interested you in the life sciences earlier in life and led you down this path?
Very early on I always had an interest in medicine and animals. It was this fascination with how things work and particularly how life works—what allows life to happen. We don’t understand it completely yet. Unlike some things where you find an answer and then you are done, every answer reveals a new set of questions, so it really stimulates that ongoing interest.
When I went to college, I thought I’m going to go pre-med because that made sense for my interests. But when I was in college, I was fortunate enough to have a premed program that also required me to take some more broad biological courses. So, I took a genetics course. I took an evolution class. I took population genetics and philosophy of science—a lot of classes outside of what I thought of as a focused premed program. It exposed me to these subjects and I had a bit of an identity crisis. I thought I might be a medical doctor, but I wasn’t so sure and thought I might want to go and focus on these other subjects.
After graduating from college, I took a couple of years and worked in a laboratory at UCLA doing research working on leukemia. I felt like I needed some time to decide if I wanted to go the medical route, or to go the science and research route.
At the end of those two years, I opted for science and went to Berkeley for graduate school where I did a Ph.D. on the genes that help the immune system—the HLA genes. These genes are some of the most diverse in all our bodies and the rationale for that is straightforward: the more diversity you have, the more foreign things you can recognize and fight off. I was interested in how genetic diversity is being shaped by these kinds of interactions.
Tell us about your experiences after you received your Ph.D.
After my Ph.D., I became interested in the pathogen genetics side. Obviously, the drive for genetic diversity in humans, in hosts, is predicated by the pathogens they are exposed to. It is this sort of dance between the two organisms.
I did a postdoctoral fellowship at the Centers for Disease Control, working on infectious diseases and I was there from 2000 to 2002, which included the terrorist attacks and, shortly after that, the anthrax attacks.
(Eventually), they put me on smallpox and the vaccine that controlled smallpox. Of course, that had been eradicated but there had been very little genetic study of the disease or of the vaccines. We did know that different strains of vaccines had very different immunogenicity. We were looking at the genetics of the different vaccine strains to understand how they were different and link those difference to what we understood about their biological impact in people.
What was your first job in the commercial sector?
I got a job at Ambry Genetics and at that point it was 25 people. It was a fantastic experience to start with a company that was so early in this space. They were doing great work sequencing cystic fibrosis genes and helping to refine diagnoses for cystic fibrosis. I worked in the R&D group, but because there were only 25 people, I worked with everybody. My job was to help identify and design tests for other genetic diseases that we thought doctors would find useful.
It was a fascinating time, because the development of sequencing technology is so critical to how my career came about. It worked in parallel.
So you were applying the knowledge you gained from your doctorate and postdoc in a commercial setting right on the cusp of the introduction of next-generation sequencing?
Exactly. I was very lucky in that I fell in love with a subject that was just about to explode. At Ambry, we were using capillary sequencing and it was very expensive. This was something we could use for some of the genes and diseases that I designed tests for like Tay-Sachs—these classically genetic, early onset, fatal diseases. The expense of getting a correct diagnosis was quickly justified. But it was a huge effort to sequence just a single gene, or pieces of a single gene.
Then the genome analyzer came out, and Ambry invested in it, and it felt like all of my interests were congealing into one space. The opportunity to look broadly across many genes at once and integrate information across many genes at once was now a reality. We did not understand what most of the genetic variants meant, but now we could start learning and begin to figure it out. For me, that was a pivotal moment.
Pivotal because you were excited about this new technology and its implications?
Yes. I was so excited it turns outs, that when I was being trained on the machine by the Illumina folks, they said: “We would like to launch a clinical laboratory, so maybe you should come work for us.”
So I went to Illumina. We launched our laboratory in 2009. At that time, our whole-genome sequencing tests was $45,000, and it did not include a lot in the way of sophisticated interpretation. We didn’t expect it to be something that would be embraced broadly, and it shouldn’t have been. Because at that time it was so nascent it would have been inappropriate to start trying to use if for clinical apllications.
We had an ethics advisory board that was deeply involved because there are a lot of important and scary implications of working with this technology. Within a few months we started getting calls about things like a baby with severe combined immunodeficiency according to the newborn screen, but not a proper diagnosis for the baby. The only way to get a proper diagnosis is to find a genetic defect that clearly confirms the diagnosis. We started seeing more and more cases like that where the treatment of the management of the child was dependent on the information that the genetics could find.
You’ve since moved to Invitae. How do you hope to make an impact there?
Invitae has the same long-term goals and vision that are what I’m hoping for. It believes that genetic and genomic information has the potential to be more powerful and useful if both patients and the community have clarity, transparency, and access to it.
Rather than creating a paradigm where the doctor orders a test and you are not sure what that test is, where the test was done, or even the details of if was it one gene or many genes, you are now in the position, as a patient, to know “I’m having these genes tested and I have an opportunity to get a copy of that information back.”
We provide educational support for clinicians and patients, because most clinicians have little or no genetics training, and that makes it very difficult for them to know how to use these tests appropriately. But I have lots of genetic training, and I would love to be a partner and support the clinicians and the patients.
We don’t expect everybody to become a geneticist, so we are creating tools, educational support, and people support to enable those who aren’t geneticists to access and use their genetic information.
That is one component. The other component is being able to understand and appropriately share information, such as donating to ClinVar, where we are seeing variants in patients who have specific symptoms or a diagnosis and learning what the clinical implications of those variants are. Then we share those so the rest of the medical community has real data to work with to help diagnose other patients. That is critical.
This does have the very difficult challenge of ensuring that patients have the rights and control of their information. One of the ways that I hope I can help—and that Invitae is working on—is to work with government and regulators to create policies and tools that find the right balance.
We can’t continue to make progress without having those safeguards in place. This past century is rife with examples of misuse of people’s data and information. We can’t make those mistakes again. We have to find a way to go forward, but in a way that ensures balance, and understanding, and control.
How did you first get involved in life sciences and eventually precision medicine?
I started off in the lab as a scientist. I guess it was the early days of precision medicine, working on VEGF. We were targeting flt and KDR which are receptors of VEGF. It wasn’t genomic precision medicine, but it was the first time in cancer they were targeting something other than broad spectrum chemotherapies. It gave me a little taste of hitting a target and seeing a result. I think by starting with the vasculature to the tumor you can see the tumor shrink pretty quickly,
It has been an evolution. At the time, we were measuring with response rate and people would get excited if you saw a 17% or 20% response rate for patients. With VEGF, and if I fast forward to something like Herceptin because I was at Genentech, all of a sudden you are seeing 70, 80 90% response rates. Now people aren’t talking about response rates, they are talking instead about duration of response and overall survival because you are actually going to be able to make a difference.
For me, that evolution over 20 years was fascinating to see in oncology. Fast forward to today, and I feel fortunate to be at a company like Foundation Medicine. I’ve been on the other side with the therapeutics and recognizing that we weren’t seeing as many people tested as we’d like. Having people in my own family with cancer, in particular, most recently with my mom, I’m a believer. People need to get tested for the best possible therapy and the best possible outcome, and Foundation Medicine has a testing portfolio with tissue, liquid, and monitoring. It is a very exciting time.
Using today as the starting point and the trajectory of the filed, what do you see as the real promise of precision medicine?
Lung cancer was an excellent starting place. Once we identified genes and targeted them, we changed overall survival rates by three to five times—if you think about EGFR, ALK, KRAS…to me that was a proving ground for precision medicine. Now it is broader, and we are looking at breast cancer, prostate cancer, ovarian cancer, colorectal cancer—across the board.
As we identify these mutations, we are able to unpack the biology a little more. At Foundation Medicine we’ve been able to look at a couple of things. One is the socioeconomic impact of precision medicine. We have a collaboration with Flatiron Health and we often can use clinical and genomic data to support dossiers for reimbursement. Now, if a patient is getting a targeted therapy, there is a much higher chance they will respond to it. We aren’t just throwing spaghetti at the wall. That means the overall health system is not paying for things in the same way—not knowing if you are going to get a response.
We know today that only 40% of the patients will have an identifiable mutation that you can match to. I remember when that was 20%. My hope is that in the next five years we can get to 60 or 70%.
The second thing I’m excited about is the monitoring space. That is pretty new. Having the Foundation One Liquid product allows us to do monitoring but it is also quite costly—you are paying for a full comprehensive panel. We are now working with a company called Natera where we take our F1 CDx assay for the baseline and then we find the top six to 12 mutational drivers for a monitoring test for that patient. You can tell very quickly if a patient is not responding.
The benefit of that is you are not exposing patients to radiological CT scans and things like that; you are able to monitor them in a very economical way though their blood. The promise is we are able to find more therapies and match more patients to clinical trials, but also that we use these technologies as a way to monitor disease progression.
Payer issues loom large in precision medicine. What can a company like Foundation Medicine do to ensure health providers large and small understand the reimbursement landscape?
Today, 40% of patients are still getting single gene tests. We’re at about 18% of patients that are getting comprehensive genomic profiling. Because when you use the tissue on a single gene, you’ve lost the tissue.
So we are educating on comprehensive genomic profiling and why it is important to do that as a baseline for any cancer patient in the metastatic setting—and perhaps in the early setting if we can move there. Educating them on the fact that CMS reimburses for the test. One of the pieces is outcomes based on a treatment. That is something we can measure with the Flatiron database. That information is interesting to biopharma and also to payers.
The number of cancer patients getting any kind of molecular test remains low. What needs to happen to improve this?
We have a single goal at Foundation Medicine this year and it is to increase comprehensive genomic profile testing by 25%. It doesn’t have to be our test. It is about education for the community on why to do this. That is our job.
With our direct-to-consumer advertising, it is a way to meet the masses. So if the physician is asking for it, now the patients are asking for the testing. More of that has to happen across the ecosystem. Also, instead of working the sales rep to the physicians’ level we are working at the community practice level. One thing we have focused on the last two years is how do we publish more with the community than with academic centers. How do we get to these community centers—we know they are seeing 80% of the patients— to use testing and provide a really good experience there?
Overall, what kind of impact do you, and Foundation Medicine, want to make in precision medicine?
When I first arrived, I asked our management team: “Are we a testing company or are we an insights company?” Half of the room raised their hand and said we are testing company. They were the team that works in the lab. The other half of the people in the room ,who do all the backend genomics, said we are an insights company.
So how do we move to being an insights company? If you think about it with that lens, what are the questions that need answering for an oncologist to make a therapeutic decision? What are the data we need to provide? Hence the acquisition of (liquid biopsy company) Lexent Bio.
Clinico-Genomic Database? Very critical. You can look up a patient that looks very similar to the patient in front of you, figure out what others have treated with, figure out what the outcomes were, and make a decision off of that. We have moved into that decision insights view of the world. We know the insights come from our tests, so these need to be cutting edge and at the front of innovation. That is how we have been thinking about it. Staying ahead of that clinical decision-making curve is critical.
Looking ahead three to five years, as a company, where do you want to be?
We recognize there is a lot of excitement around early detection and early screening. You see GRAIL and you see Thrive and a number of other players in that space. We are really focused on once you have developed something that is cancer, or will be cancer, how can we grab that patient to really understand their cancer, get the genomics or multi-omics and get them the right therapy to get cured. GRAIL had some great data but it is still in stage 3 and stage 4 cancer. They haven’t gotten to the earlier phases yet, but I think that is going to happen in the next two to five years.