Women & our new genomics age

Dr. Joanne Armstrong: Well, I hope technology doesn't convince the population that IVF is a more natural or enjoyable way to build families. I just want to put that out there. Dr. Daniel Kraft: Welcome to Healthy Conversations. I'm Dr. Daniel Kraft. Today, we're in healthy conversations with Dr. Joanne Armstrong. She's the Vice President and Chief Medical Officer for Women's Health and Genomics at CVS Health. Welcome back to Healthy Conversations. We spoke on the prior podcast about your experience as an obstetrician and changes in prenatal and maternal health, but you're also a very involved in the realm of genomics and how that connects to women's health. Can you just refresh us on your background and how you've gotten interested and involved, particularly in this interface of women's health and this new genomics age? Dr. Joanne Armstrong: I'm board certified OBGYN. I have a background in public health and epidemiology and the genetics came a little bit later. Some of it is because of the evolution of genetics as a field itself. Early on when I was training, much of it was focused on prenatal genetics, a bit about cancer genetics, especially breast cancer genetics. I learned on the job, but one caveat, I'm not a geneticist. Dr. Daniel Kraft: But genetics is starting to integrate into all of our lives or can. Dr. Joanne Armstrong: Genetics is really exploding and we can date it probably to the full sequencing of the human genome about 20 years ago. There was genetic knowledge and individual tests before that, but sequencing the genome really started this evolution of genetic information and how that correlates with disease and wellness. More and more of clinical care is linked to genetics. There are about 20,000 genes that have been identified that are correlated with human disease and in fact, 10,000 different conditions. Those pieces of DNA can be combined in different combinations and permutations into tests, and there are now about 80,000 tests that are available on the market or in laboratories around the country. The diagnosis of disease, it can be used to help shape prognosis and then importantly, it's increasingly an important part of treatment decisions. There's another dynamic that's really fascinating, which is the technology platforms that produce this type of genetic information have also evolved. Like that first genome cost a billion dollars to sequence. You can now get a whole genome sequenced for a few hundred dollars and because the market entry is pretty easy, some of those tests that are out there don't even have any clinical wraparounds, counseling or other types of services that would help patients make real decisions based on them. There are a lot of concerns about it. Dr. Daniel Kraft: In your field of obstetrics where prenatal screening used to be through amniocentesis and now is moving to you can sequence the child in utero, can you touch on the arc of what you've seen in your career as a obstetrician? Dr. Joanne Armstrong: Genetic testing used to be invasive tests at 20 weeks which have the risk of disrupting pregnancies. Ideally, testing should be done pre-conceptually, because the information really helps us plan and even prevent disease. There has been a movement to really think about the preconception period and how you optimize that for expecting parents, and then testing that happens within the setting of pregnancy includes what we call carrier screening, which are tests for autosomal recessive disorders, but also now, you can test the mother's blood called cell-free DNA because fetal DNA actually ends up in the maternal system, and then in some settings, we're actually doing whole exome and whole genome sequencing on fetuses. Dr. Daniel Kraft: As we grow older, the role of understanding someone's underlying genetics and risk is getting more and more clinically useful. Where's that BRCA testing at the cutting edge? Preventing disease in those at risk for breast cancer. Dr. Joanne Armstrong: BRCA testing, also called B-R-C-A testing, it's one of the more established tests that are available. BRCA is a genetic mutation that is passed from generation to generation and it increases the risk of some types of inherited cancers including breast cancer, ovarian cancer, pancreatic cancer, prostate cancer. In the case of breast cancer, for example, women and men who are BRCA carriers have a lifetime risk of breast cancer between say 40 and 60%. That's compared to our baseline risk of about one in eight women in their lifetime will develop breast cancer. It really increases the risk pretty significantly for ovarian cancer, it increases the risk to about 40%. Knowing this information in advance is really important. It can be used to actually prevent disease completely, and that can be done in the setting of, say, in vitro fertilization where embryos don't carry these genetic disorders. For individuals who carry the mutations, there are a number of recommended prevention strategies like birth control pills can decrease the risk of ovarian cancer, so that's a relatively simple intervention worthy of knowing that information. For other things, it's preventive mastectomies or preventive oophorectomy, and that's meaning removal of the ovaries to prevent the risk of ovarian cancer. It's life altering, but it's also life-saving, so when you think about decisions like that, how important it is that you've got clinically grounded testing and you have the confidence that you've brought all the information you can to bear. I'd like to share work that we did here at Aetna to bring it to life. We worked with an academic research group to understand how BRCA tests are used for women who have a new diagnosis of breast cancer, and we asked a very simple question. What is the timing of the result relative to the surgery that women had? So an important thing to note about BRCA in breast cancer is that women who have that mutation have an increased likelihood of having bilateral disease. Instead of treating one breast, one might want to treat both breasts and inversely, people who do not have a mutation may decide that they don't want a bilateral mastectomy, so what we've found was only 54% of women with a new diagnosis of breast cancer who had BRCA testing within a year of this diagnosis had the testing and the results back before the surgery. The data wasn't even back in time. Clearly, there's an opportunity, and I bring this up because it is one of the longest established tests, so that was actually one of the motivators for us to think about how do we move this solution that we developed called guided genetic health into an oncology setting? Dr. Daniel Kraft: Perfect. Even in the prenatal setting, many of the children growing up today will be sequenced at birth and it'll be part of their medical record, which might mean there's proactive steps to prevent their risk of breast or ovarian cancer, even if they are BRCA positive. Dr. Joanne Armstrong: With children, the guidelines don't recommend testing beforehand because one of the other precepts in genetic testing is you shouldn't just get random amounts of data and information if they're not actionable because some of what you find is really devastating and there's nothing you can do about it. It's recommended for BRCA that you wait until somebody's old enough to even consent to be tested for it, but you're touching on a very interesting area of ethics and genetic testing. Dr. Daniel Kraft: I totally agree. You want actionable insights. If you have the gene for Huntington's chorea, you may or may not want to know about that if there's nothing to do, but increasingly, as we have more folks sequenced and we combine that with other omics, we'll have earlier signs when we can intervene. How do you think about who gets tested? How do you frame what's appropriate testing today and what kind of testing can they get? Dr. Joanne Armstrong: I think that it's really important for people to understand that genetic testing, it's not a yes/no decision. You're really just sequencing what the letters look like, and it's the literature and researchers that tell us what each of these sequences mean, and that is constantly evolving. When you get results back, you can get what are called variants of unknown significance. It's not normal, but it's not what they call deleterious or disease-causing. It's somewhere in the gray matter and we don't quite know what to do with it. That's one area to think about because people can leave with a belief that, for example, they're not at risk for cancer. That's not true. If you're BRCA negative, it just means you're negative for the mutations that we know to be deleterious. We still have other risk factors, family history, that's not BRCA related. Another worry is is there any guidance in how these test results are really interpreted? There can be false positives, there can be false negatives. What does the test actually mean? There are a lot of unintended consequences that can come out of this. It has implications for your sisters and your children. Have you just included them in a medical journey that perhaps they didn't want to be a part of? Because genetics is a family affair and the more appropriate person for testing may not be you. It may actually be your mother. I think because of the market dynamics that it's moving into a low cost, easy to obtain environment, some of these concerns are being left on the side and it does represent quality problems for patients. Dr. Daniel Kraft: Another challenge as we have in this explosion of omics information is how do you translate that and communicate that to the clinician? Dr. Joanne Armstrong: Can you possibly imagine that you know how to interpret 80,000 different genetic tests of varying clinical utilities? The literature is constantly evolving, so the answer is it's really difficult, but that does not always stop people from just ordering tests without knowing what to do with them. It's really a problem for patients in many areas. One of the points that I make when I talk to folks is just because it exists doesn't mean that you should order it or use it. If you are really unsure what any of this means, you leave it to folks who can do that, which really is the realm of genetic counseling and medical geneticists. Dr. Daniel Kraft: So maybe this segues into a bit about the inspiration for Aetna's guided genetic health solution. Dr. Joanne Armstrong: So guided genetic health is a solution that we created trying to improve access to medically grounded, high quality genetic services where it makes sense for patients. We focused this on what we call carrier screening or preconception and pregnancy-related testing, inherited cancers like BRCA for breast and ovarian or colorectal cancer syndrome like in Lynch syndrome, and then some preventive cardiology. Think about what access to good quality evidence-based care is and marry that with the benefits of what a direct-to-consumer experience feels like, meaning easily accessible, convenient, low cost, private, personalized to your needs and leaving some of the worst of direct-to-consumer to the side. That is no guidance, uncertain about the validity and the quality of the lab, junk genetic tests that are out there, and then also no sharing of the data, no selling it to third parties so the patient can control where the genetic consult and the genetic testing goes to their physician, and it starts with basically a series of questions that get at levels of family or personal risk, all online and based on that, a referral into a telephonic based genetic counseling experience, just as you would get if you went to a clinician's office for the things you noted and for the things that you didn't note. For patients that are appropriate for testing, they are then rooted into a high quality genetic testing lab CAP, CLIA certified, high grade clinical lab, the same as what you would get if your physician ordered these tests. If patients are recommended for testing and they go through with that, they will actually get a test kit at home and post-test counseling either through the telephonic genetic counseling service or through the laboratory, and then the patient decides where that information is sent. The genetic counselor also puts together a wellness strategy that's attached to that information, so it's not just like, "Hey, here it is." It's what do you do with that? Then the important thing from a cost perspective, it's done for a flat fee, so the value proposition of all these technology advancements that are out in the world that really are bringing the cost of sequencing down, but in many cases, the patient doesn't always experience that. Where we're heading this year is to expand or scale guided genetic health into two different clinical programs. One of those is the enhanced maternity program, both in the preconception period and through pregnancy, and the other one is transform oncology, which is for patients who have cancer. What I'm really excited about in both cases in the broader country, patients who are appropriate and getting breast cancer surgery don't have this in time to do it. So by embedding this into oncology, we're able to actually start thinking about prevention, and then in the maternity space, we have the opportunity now to start these conversations before pregnancy takes place, and then importantly, for carrier screening, their patients are tested for the same fee, marrying the best of clinical grade genetic experience with some of the convenience and the best part of direct-to-consumer. Dr. Daniel Kraft: Everyone always asks the question about privacy. Dr. Joanne Armstrong: The test results are shared only with the genetic counselor. The laboratory of course knows that and the patient. If the patient wants his or her physician to have access to those results, then that can be done automatically as well, but it does not come back to us. Aetna and CVS Health has been very clear that we don't request and require or require genetic testing as a requirement for coverage or anything else like that. Dr. Daniel Kraft: You mentioned the price of sequencing might be less expensive to get a full genome test than a x-ray or complete blood count, let's say by 2030. Where do you see this entire field moving? Dr. Joanne Armstrong: Will there be 280,000 tests out there? Probably. One challenge we have to figure out is at what point do we say this is just a piece of information, but it has no clinical relevance. We need more and more filters to understand that. The development of filters will be a technology solution, so technology will come in there to better rationalize what's appropriate and what's not. There will certainly be more of this, more testing, more clinical conditions, and then how we use it, so it's not just information utility, but it actually changes the course of disease. Dr. Daniel Kraft: Many diseases are going to get subsetted genetically and otherwise, which would mean we have different ways of preventing and managing them in a much more precise personalized way. Dr. Joanne Armstrong: Oncology is moving very quickly into that molecular pathology defined disease states. I'm an obstetrician, and I think often that we really know so little about preterm birth, 12, 11% of all deliveries, the leading cause of morbidity and mortality for infants. It's a clinical problem that is asking to apply some of this knowledge to it. There's just a whole range of areas that we haven't even scratched the surface on. Dr. Daniel Kraft: Another interesting piece now that more folks are getting fully sequenced is this realm of what's often called polygenic risk scores. As we know, most women who develop breast cancer aren't BRCA positive. Dr. Joanne Armstrong: I see that as another piece of the evolution of understanding how genetics play in clinical decision making. There's often not a one-to-one relationship. You've got this genetic marker and therefore, this thing will happen to you. What does it not mean? It doesn't mean you don't have risk for breast cancer. There's a lot of other inputs into breast cancer, including other genetic things that are not BRCA and environmental issues and things we haven't even characterized yet, as in like preterm birth. Polygenic risk scores are just a start to figure out what is it about it, using genetic information to say what is the likelihood of recurrence? In the past, all early stage breast cancer was treated the same; lumpectomy, radiation therapy, five years of tamoxifen. That was done to prevent 5 year and 10 year recurrences, even though the likelihood of recurrence for someone with early stage breast cancer was really small, but we couldn't find the needle in the haystack. Everybody gets the same treatment for the 5% of people for whom they might recur. Now, it's common to look at genetic markers on the tumor itself to ask what is it about this tumor that increases the likelihood? Dr. Daniel Kraft: The early pioneer that was a company I think called Genomic Health where they would look at more common stage one breast cancer and should you go on to advanced chemo and radiation and adjuvants or are you going to be at normal or low risk? That's probably going to happen across many other cancers and many other diseases. Dr. Joanne Armstrong: Exactly, and it gets to this earlier point you made that we are evolving to understanding cancer as a disease of genetic dysregulation. If we understand what those signals are, then it shows you a new treatment pathway and we're getting there. Dr. Daniel Kraft: Let's go back to sometimes a controversial area. We're now what? 40 years into IVF? What's the slippery slope? We've seen a couple of years ago, the first CRISPR baby done in an unethical way. What are some of the dystopian elements we need to be aware of and what are some of the bright positive realms? Dr. Joanne Armstrong: Well, I hope technology doesn't convince the population that IVF is a more natural or enjoyable way to build families, so I just want to put that out there. It's very common to have, let's call them genetic misfires in embryos. I used to tell patients that I love to garden and every year, I plant 10 or 100 pea plants and 40% will take. I change the soil. I do X, Y, and Z, but there's a certain amount of genetic failure. In IVF, the ones that are abnormal can be put to the side, and the ones that appear to be genetically normal are the ones that are transferred back. That's the application of genetics and IVF. Most of it, what I just described is called pre-implantation genetic testing. It is also a really important technology for families who have very devastating genetic disorders that can be transferred to fetuses. Think about Tay-Sachs disease. Different families will use the information differently. Some families may decide, "I don't want to have children. I'm going to adopt." Wonderful. What's important is that you go into this with all the information you need. Dr. Daniel Kraft: This is a small example. A family friend had a child with Fanconi's anemia who, in order to hopefully have a better chance of a long, healthy life, needed a transplant and there were no matches, so they ended up conceiving their next child by IVF and selecting for an embryo that did not carry Fanconi's and was able to be the cord blood transplant donor, and both siblings are now doing great. Speaking directly to our audience of clinicians, physicians, health care providers, any parting words on genetic health, updates in women's health or other general advice and clinical innovation that you'd like to touch on? Dr. Joanne Armstrong: We know that we are in a genomics age. It's just getting bigger and bigger and more and more complex. I would advocate for all of us to recognize what our limits are and ask for help as we do for everything else, for cardiology, for diabetes. Look to see what other services and support are available and to use them. For patients, I would say be cautious. Not everything that can be tested should be tested. Ask questions, turn to the professionals where you need them. That's what I'd advise. Dr. Daniel Kraft: 100%. It's a team sport. Well, thank you so much, Dr. Joanne Armstrong, for being back with us on Healthy Conversations, and we look forward to learning more about genomic and genetic health going forward.