Unraveling the Mysteries of Inherited Gene Mutations with Dr. Ephrat Levy-Lahad
By BCRF | September 2, 2021
By BCRF | September 2, 2021
Because certain genetic mutations are linked to a significantly higher risk of breast cancer, developments in screening have both highlighted high-risk groups and added to the broader medical understanding of inherited risk factors.
How can testing data encourage prevention and agency without amplifying personal fear? What can research reveal about genetic markers of risk and predisposition? Or, put differently, how can understanding one’s inherited risk improve approaches to precision prevention?
Dr. Ephrat Levy-Lahad is on the forefront of this research, focusing on breast cancer–associated genetic mutations among various populations, including Arab and Ashkenazi Jewish women. She is a professor of internal medicine and medical genetics at Hebrew University and director of the Medical Genetics Institute at Shaare Zedek Medical Center in Jerusalem.
Chris Riback: Dr. Levy-Lahad, thank you for joining. I appreciate your time.
Dr. Ephrat Levy-Lahad: Thank you for having me.
Chris Riback: Before we get into the specifics and the various studies that you've released, particularly one last year , I've read a line of yours that I really think sets the stage for this conversation. Actually, two lines. One I read where you said, "Knowing your inherited risk is about precision prevention." You've also said you meant it in the context of breast cancer and breast cancer prevention, "Knowledge is power." What did you mean by those two statements?
Dr. Ephrat Levy-Lahad: So the first statement about precision prevention is really a spinoff I would say, or a take-off from precision medicine. We hear a lot about precision medicine, and mostly in the realm of oncology in general and breast cancer in particular, where you're looking for a therapy that's tailored to the patient and to the patient's tumor. And that's usually done using genetic and genomic tools by looking at the genetics and genomics of the tumor. What's really powerful about genetics, and that's where the knowledge is power, is if you know about the genetic risk before you ever get cancer, what you can really do is precision prevention. So prevention that's tailored to the fact that you're at high risk because of a genetic inherited mutation.
And by knowledge is power, what I mean is that there are now very effective means of prevention. So if you have a woman who's at very high risk of getting breast cancer, there are things she can do to substantially reduce her risk. But if she only finds out about it after she has cancer, it's not too late, but it's one cancer too late. And so that's what these two statements are about.
Chris Riback: Yes. And in terms of that precision, really customizing some of that prevention per the individual. I know that various types of prevention can be that specific down to the actual person. And yes, in terms of some of that data on what that prevention can do, or what that knowledge can do in terms of creating outcomes, I know that some of that was part of what you reported in your study last year. But maybe we could start with genetic testing. How do people react when you talk with them about the importance of genetic testing? Who should be thinking about doing it, everyone, or select groups, or individuals? How do you kind of give broad guidance around the thinking about genetic testing?
Dr. Ephrat Levy-Lahad: I think it's a moving target. When genetics of cancer started out in the realm of breast cancer—we're really talking about the mid-90s when BRCA1 and BRCA2 were identified—people were thinking about those tests, mostly in the context of women who have had both breast cancer or ovarian cancer themselves, and had a strong history of these cancers, or people with a very strong family history. Over the years, what we've seen happening is that it's really moved into the realm of the patients. So once a person has cancer or genomic testing of the person and of the tumor, becomes part of their care and management. But where I'm really at in terms of the precision prevention is really trying to get people who are at high genetic risk to be tested before they ever have cancer.
Now, that is also I would say complex. So there are populations where we know that there are very high rates of mutations. So a population I've worked on a lot is the Ashkenazi Jewish mutation, these are Jews of European ancestry, and we know that among Ashkenazi Jews, about one in 40 is a carrier of a mutation either in BRCA1 or in BRCA2. And we've also shown—[and] all of this work has been supported by BCRF—that approximately half of carriers don't have any significant family history for various reasons I can explain later. But the bottom line is that if you only went by family history, you would identify only about half of carriers, even though they're at high risk.
So there are populations, like the Ashkenazi Jewish populations, where I think our studies have shown that it actually makes sense to test everybody. I don't think we're quite there yet for populations where the background risk is lower, but I would hazard a guess that five years from now, I think this is going to become universal. One of the reasons it might become universal also has nothing necessarily to do with breast cancer, it's just that as we understand more and more about our genomes and genetics, I think it's going to become part of routine medical care in general, is to know what diseases you are at risk for and what you can do about preventing them.
Chris Riback: Yes. I hope to get to ask you just a little bit about biogenetic ethics as well, which I know is an area of interest of yours. And yes, I am curious, the ubiquity of genetic testing today surely is changing some of those dynamics, not only the ethical dynamics, but also in the knowledge. Right now, I would believe very initial knowledge that laypeople like myself might be gaining around genetic testing, but as it becomes more part of the dialogue and the conversation, it would make sense to me as an outsider why your view of five years, as opposed to 10, might be possible. How do you help individuals balance the fear of results versus that power of knowledge, and the power of knowing genetic testing results early?
Dr. Ephrat Levy-Lahad: I think the balance is obviously difficult sometimes, but the balance I usually talk to my patients about is what, in a way, how you would weigh the so-called bad outcomes, and what weight would you give to them. So one bad outcome is you're going to know that you have a mutation, and that is definitely going to cause some anxiety. And there is quite a bit of data that once a woman finds out she's a carrier, there's an uptick in anxiety, that actually usually goes down over time. The other bad outcome is finding a cancer late, that you may have prevented. I'll give the example of ovarian cancer, which is very easily preventable because you did not want to know that you were at risk. And if you look at these two outcomes and you weigh them, you have to decide what works better for you.
One of the big issues we have is that often men and women will find out they're carriers, will tell only very few of their relatives. So maybe a brother and a sister, sometimes not their mother and not their children. And many times, not their cousins, for example. And I've had patients who are carriers tell me, once I told them, "Listen, you need to call your cousin Ruth and tell her that there's a mutation in the family." I say, "You don't have to say you're a carrier, but somebody, we can do it, or you can do it, needs to tell her." And she says, "Well, what do you expect me to do? Call her on Jewish New Year's or Passover? And say, 'I forgot to tell you that we have this mutation in the family.'"
And when I started out over 20 years ago doing this, I would sympathize with that conflict. But over the years, because I practice in Israel, which is a small place, and I often see those cousins in the end in my clinic, I said, "If next time you call her for Jewish New Year's and she tells you that she has a cancer that you could have prevented, how are you going to feel about that?" Once you sort of put it in that light, people realize how important it is.
It's like going for a mammogram. When you go for a mammogram, you're afraid to go for the mammogram because you don't want them to find anything and you're afraid, but on the other hand, what will you do? Not get a mammogram? So I think it's a battle between your assertive rational self and your fears. And that's something we confront all the time.
Chris Riback: And maybe some of the data help as well. You published a study last year in JAMA Oncology. Tell me about the differences in life expectancy and the need for chemotherapy for women who found out they were genetic carriers.
Dr. Ephrat Levy-Lahad: So what we did in the JAMA Oncology paper was really ask ourselves that knowledge is power question. Meaning what happens if you know that you're a carrier before you developed breast cancer, and then you have the opportunity to take whatever preventative measures you want to take, versus if you find out you're a carrier only once you've developed breast cancer. And we even narrowed it down to women who knew they were carriers, but chose not to have a risk-reduction surgery. So as I'm sure many of you know, one of the possibilities for prevention of breast cancer for women who are carriers is to have a [preventative] double mastectomy. And this is something that seems to have great variability worldwide. And in Israel only a minority, maybe about 15 percent of carriers, choose to have bilateral mastectomy. So we wondered whether if they just have surveillance, what is that going to look like, compared to women who find out they're carriers only after they were diagnosed with breast cancer. And we found that overall mortality was significantly lower in those who had just surveillance.
Chris Riback: Even with just surveillance. So you don't even have to do the bilateral.
Dr. Ephrat Levy-Lahad: Even with just surveillance, right. So, there was 94 percent survival over five years compared to 78 percent survival. That means 22 percent of deaths for women who found out they were carriers only after they had breast cancer. And the early detection in carriers, who knew they were carriers and were being followed, led to the fact that if they did develop cancer, it was very early stage. And so, most of them, 55 percent, did not need any chemotherapy compared to 80 percent who needed the chemotherapy in the group that found out they were carriers only after they were diagnosed with cancer. So even women who elect not to have double mastectomy really gain by knowing that they’re carriers ahead of time.
Chris Riback: And what has this done in Israel in terms of genetic testing? And maybe you can talk about what is known as the Israeli Health Basket, and the type of testing that's available just as part of the healthcare system there.
Dr. Ephrat Levy-Lahad: So I would say over the years, I've asked myself the question of whether we should really be testing all Ashkenazi Jews. And we sort of took this step-by-step. The original study that we did, which was published in 2014, was we actually try to find carriers who were identified at random, not because they had cancer or because they had a family history of cancer. And the way we did that was by testing over 8,000 Ashkenazi men. So basically, these were unaffected men that some of them, about 10 percent did have a family history of cancer, which is what you would expect in a general population, but they themselves were healthy.
We found the expected rate of carriers, which is about two and a half percent. And then we looked at the women in the families of these carriers, and we found out that they were still at very high risk for breast and ovarian cancer, because at least theoretically, you could think that maybe there are carriers out there who are actually at low risk, but they have other protective factors that we still haven't identified. But we found that even if you just test everybody, those who are carriers are still going to be at very high risk for breast and ovarian cancer.
Once we found that out, we started doing studies to show if it's feasible from, I would say, a psychosocial view, whether women will actually want to get tested, how we can provide such testing, because you really need a different kind of model. If you're testing people who come in because they have a personal or a family history of cancer, you're doing a 45-minute session of genetic counseling, you're explaining all the pros and cons, the types of tests they can do, what the results are going to be. That's something that's not really feasible on a large scale. And there was a question actually of whether it's necessary or not. So we've done studies to show that in the context of a general screen, you can really shorten the pre-test process even to just written information, without compromising psychological outcomes in the end.
And once we did that, we approached what's called the Israeli Health Basket committee. So in Israel, we have universal health insurance. It's provided through four large HMOs, but the government decides what is the minimalist of services, that's called the Health Basket, what's the minimalist of services that these HMOs must provide to every Israeli. And they have a committee that sits every year to decide on new technologies, new drugs that are part of this mandatory list of services. And the first time we applied was in 2018, it was rejected in 2018, rejected in 2019. And in January of 2020, it was approved for the Israeli Health Basket for every Ashkenazi woman to be tested for the common mutations in BRCA1 and BRCA2.
As we all know, there were some other health issues in 2020, namely [COVID-19]. So really it's just getting off the ground now in the middle of 2021. And I hope that in a year or two, we'll have some more information on how that's actually playing out. It's not considered a national screening program. There is no, I would say, active encouragement yet of women to come and be tested, but all Ashkenazi women are offered this test.
I will say what makes this population different is one aspect that I've already mentioned, is that very high background rate, one in 40, that has a mutation. The second difference is that we're not doing full testing of the BRCA1 and BRCA2 genes. We're not testing other genes. We are really testing just specific mutations that are known to cause a high risk for breast and ovarian cancer. And if you look at the genetic tests that are normally done, you're looking at tests that sequence the entire sequence of BRCA1 or BRCA2, or do an entire gene panel. And there are all kinds of issues there about the different types of mutations and the different types of variation that may actually not be disease-causing.
So doing a more expansive genetic test also creates new conundrums in terms of understanding what the variants do. And Ashkenazi Jews were really keeping it simple. We're just testing for those specific mutations. But still, I think it's extremely valuable because it's really a paradigm for the way forward, because ultimately we're going to know a lot more about variants and we're going to know which ones are disease causing and which are not. And this will give us a lot of information about how we can actually take the genetics and bring it to the population level.
Chris Riback: Yes. It's occurring to me as you're talking, what an incredible, and first of all, what an advancement, but additionally, what incredible data you're going to get. I mean, it's just an incredible amount of information that surely will be helpful in all sorts of new ways. Speaking of which, my understanding of some of your current work involves, maybe not exclusively, but two related projects: the Israel Breast Cancer Study and the Middle East Breast Cancer Study, which you're doing with two other BCRF colleagues. Tell me about each of those.
Dr. Ephrat Levy-Lahad: So the Israel Breast Cancer Study started out with Ashkenazi Jews, because that's [who] was possible to test when we started out, and we've now segued into non-Ashkenazi Jews. And the idea there is actually to look at this population, which is really under-studied. A lot of the information we have in genetics is about Europeans and whites, and Ashkenazi Jews, which are very, I would say, well-studied group in general in genetics. But we know that if we want to really understand the genetic underpinnings of disease, we really have to look for much more diverse sources of genetic information. So if you look at, I would say, almost any field in genetics and genomics today, there is a big push to study populations that haven't been studied yet, because they harbor a lot of genetic variation on which we don't have sufficient information and knowledge.
So I would say in that sense, both the Israel Breast Cancer Study and the sister project, the Middle East Breast Cancer Study, are doing that. The Middle East Breast Cancer Study is in collaboration with Dr. Moien Kanaan from Bethlehem University and the Palestinian Authority, and with Dr. Mary-Claire King, the mother-god of all breast cancer genetics from the University of Washington. And we're really looking at Palestinian women with breast cancer, again, with the aim of capturing that genetic diversity.
An interesting thing is that in that process, in the Middle East, both in Jewish families and in Palestinian families, we often have relatively large families that are in a small geographical area that we can reach. And so we have many families that are so-called “unsolved families” in the sense that there are families with multiple cases of breast cancer, but the genetic cause is not yet known. So part of our efforts are trying to figure out what is the genetic cause in these families. I know it, and it still amazes me every time, is how you can study a specific or a smaller population, and you can still gain insights into questions that are much larger and that affect women worldwide. So, I'll just give an example from the Palestinian Breast Cancer Study.
Chris Riback: Please.
Dr. Ephrat Levy-Lahad: We found out that about 1 percent of all breast cancer families in the Palestinian population have a mutation in a different gene, it's called TP53, and generally mutations in this gene cause a very severe cancer predisposition syndrome that's called Li-Fraumeni syndrome. And that is actually associated with severe tumors in children, often hematological sarcomas. And when we looked at these families in the Palestinian population that have a bonafide mutation in TP53, we really aren't seeing any childhood cancers, but we're seeing breast cancers.
What should we be doing with Palestinian women with these mutations? Do they really need the onerous follow-up and surveillance that Li-Fraumeni children have and adults? And we're talking about having a total body MRI every year and other tests. And it turns out to be a much more general question today. So, when you're doing a gene panel testing, you're not just testing for BRCA1 or BRCA2. You're testing for often dozens of different genes that are associated with cancer. And certainly TP53 is associated with young onset breast cancer.
But now you have these women who are 50, 60, 70 with breast cancer, no family history, and they turn out to have TP53 mutations. So there's actually now a whole need for information on what subset of TP53 mutations actually behave differently, do not cause Li-Fraumeni syndrome. And we've started doing that just in a specific population, but then you can see how it impacts a much more general question in genetic testing today.
Chris Riback: It's the nature of science. Questions generate new answers, which in turn so frequently generate new questions, which is what would keep folks like you going, and going, and going. Do I have this right, is it, the work that you're doing, the largest cohort of Arab women in the world to undergo such testing?
Dr. Ephrat Levy-Lahad: So really the credit for that goes to Moien Kanaan's team in the Palestinian Authority. And really this is the largest Arab cohort. And it's been done under very often difficult circumstances. Both geographically, the Palestinian Authority, the West Bank, Gaza, movement is often difficult. Also, cultural difficulties. Genetic testing really wasn't available before the Middle East Breast Cancer Study started. There was a lot of suspicion and worry about genetic testing in adults in the Palestinian population. So, I think Dr. Kanaan and his team have really made a huge difference there. And the BCRF by supporting this study has actually created a service that wasn't there at all to begin with. And that's been one of the really gratifying aspects of this project.
Chris Riback: Yes, I would assume so. Now, you also are active in bioethical aspects of genetic research, we touched on it earlier, and I realized that you could do an entire lecture series on this topic. But I'm curious what you might see as the primary bioethical aspects today. I mean, we have a ubiquity of home gene testing, as we discussed. We have massive advances in gene editing. We have privacy and knowledge gaps. What areas around this gained your greatest focus?
Dr. Ephrat Levy-Lahad: I'm going to actually start with the privacy end. I think there are some differences between genetic privacies and other types of medical privacies, but I don't think the differences are as big as originally imagined. Personally, I think that the emphasis should be on best efforts to keep information private, and I would say this about a lot of medical information, and also nonmedical information. But I think actually a lot of the weight should actually be moved to the downstream, meaning to abuse, or we're trying to breach that privacy. I think a lot of the effort is made in the safeguards and consent and whatever, and I think a lot more effort should be put into enforcement of any breaches of privacy. I think that's one way to solve this issue.
And I think the reason for the conflict is because it's clear that for biomedical research to fulfill its promise, we need a lot of data from individual people. So individuals have to be willing to give their information for this greater good. And if that doesn't happen, none of us are going to reap the maximum benefits. But it also has to be safeguarded.
If I think about the other aspects, I think gene editing is really a big game-changer in that respect. And I had the privilege of being a member of a National Academy of Sciences committee on gene editing a couple of years ago. And the questions, especially around changing our inherited genetics, what's called germline gene editing, I think those are going to be very big questions. The situation right now is that I would say on the technical level, it's not yet safe enough for clinical use. So that gives us time and space to think about what will happen when it actually does become technically safe, because I assume that it will become technically safe. And those are going to be very big questions.
One thing I think in the committee we grappled with a lot and in general I think about, is how do you involve the public in this discussion? And it's not simple. So the whole idea of I would say scientific advances that have big social impacts, and the political impacts, is you don't want only scientists making these decisions, or thinking about these problems. But it's not easy to engage the general public in such questions. And I think things like this podcast, or other discussions, are really important if we want to get to end points that are really maximally beneficial to all of humans.
I think input from the public is extremely important, because the concerns that I might see are going to be very different from concerns that another person is going to have, even in the committee, which was all people who understand gene editing, there were many different viewpoints. That sort of crosstalk is extremely important.
Chris Riback: I'm sure that it would be. Quickly as we start to close the conversation. I'm curious about you. How did you get into this growing up? For you, was it always science? How did you end up in this?
Dr. Ephrat Levy-Lahad: I was always interested in science. In high school, I became really interested in genetics, because I had an amazing biology teacher. Her name was Hannah, and she was just really, really smart. And a lot of my high school classes were really boring, and biology in general and genetics in particular were really interesting. So that was one thing. The other thing I think of all the fields of medicine, genetics relatively has a stronger mathematical component, and I'm a daughter of a mathematician. I could never be a mathematician, but I think that also had some influence.
Chris Riback: Being the daughter of a mathematician might be harder than actually being a mathematician, but that's a whole other conversation.
Dr. Ephrat Levy-Lahad: And the other thing is actually I would say generational. I'm a woman, and I was really worried about ultimately not having a job or a career that could fulfill what I thought was my potential. And my mother, who is in her late 80s, is from a different generation. And she actually started out in science, and for various reasons, she ended up doing other things. And among that, it's because I think if you do a straight science career, at the time was more difficult. And my thinking about this was, "I like people. And if I go into medicine, I can still do science, but if the science part doesn't work out, I will still have a profession that I can work in." I did not honestly see myself as not having a profession.
That wasn't my plan for myself. So, I would say in medical school, I was still interested in genetics. I think Israel is really a genetics laboratory. We have so many different populations with so many different diseases and conditions. And when I went to do my fellowship at the University of Washington, what I was really looking towards was to learn basically research tools that would help me understand disease genetics, and bring those tools back to Israel. And I originally did my residency in internal medicine, and my focus was actually adult disease. And my fellowship actually was more on Alzheimer's disease and I discovered an Alzheimer's disease gene, but I think that's one of the reasons I also went into cancer genetics, is even though at the time genetics was largely a pediatric endeavor, I was an internist and I was interested in adult medicine and these are sort of the major adult diseases.
Like anything else in life, there are many instances of chance along the way. And one of them was that towards the end of my fellowship, Dr. Mary-Claire King, of breast cancer genetics fame, moved from Berkeley, California to the University of Washington. And so here was this world-famous researcher in breast cancer genetics, and I started speaking to her and the rest is history.
Chris Riback: Yes. I would imagine conversations, for those who have the privilege to have those conversations, that's the way it goes with her. And lastly, I know you've mentioned it a couple of times, but what role would you say BCRF has played in your research?
Dr. Ephrat Levy-Lahad: If not for BCRF, none of my breast cancer research would have happened. In Israel, I would say the opportunities for translational research funding are very slim, and that is really what BCRF has provided, I think in general, but also specifically for me. All the studies I have described have all been funded by the BCRF, and would not have been otherwise possible. So it's all BCRF. That's all I can say. And it's an amazing organization.
Chris Riback: Well, and it's just a little bit the researchers like you as well. Dr. Levy-Lahad-
Dr. Ephrat Levy-Lahad: It's all nature and nurture.
Chris Riback: It's all nature and nurture, it sure is.
Dr. Ephrat Levy-Lahad: Well, BCRF is all nurture.
Chris Riback: Good. Well, then great for you to bring I'm sure nurture as well, but bring a good helping of nature along with it. Thank you. Thank you for your time. Thank you for the work that you do.
Dr. Ephrat Levy-Lahad: Thank you.
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