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Behind the Breakthroughs: Harnessing Genetic Testing for Precision Prevention
BCRF investigator Dr. Ephrat Levy-Lahad discusses inherited gene mutations and how identifying high-risk individuals changes outcomes in surprising ways
We know that when a woman finds out she has an inherited gene mutation, such as BRCA1 or 2, she can significantly reduce her risk of breast cancer if she undergoes a preventative mastectomy.
According to a recent study published by Dr. Ephrat Levy-Lahad and her team at Shaare Zedek Medical Center in Jerusalem, Israel, even carriers who opt not to undergo preventative procedures benefit from of knowing their status before diagnosis. They experienced better outcomes and required less chemotherapy overall.
BCRF spoke with Dr. Levy-Lahad about her research and what she thinks the future holds for genetic screening.
Tell us about your research.
I’m a medical geneticist and clinician. My interest in cancer genetics began in the mid-1990s after I met Dr. Mary-Claire King, another BCRF grantee. In Israel, there is a particularly high frequency of women with inherited mutations in [breast cancer] genes, because about half of the population is Ashkenazi Jewish. This offered a paradigm for studying hereditary breast cancer and starting large population studies, which we’ve been able to do thanks to BCRF funding.
How does the rate of incidence a BRCA mutation among Ashkenazi Jews compare to a non-Ashkenazi population? What’s driving these differences?
Among Ashkenazi Jews, about one and 40 men or women carry one of three common mutations. If you look at the rate in other populations, the estimates are around one in 160, or one in 200, so about four to five times lower. The reason for this particularly high frequency in Ashkenazi Jews has to do with genetic history. As we know, there are a number of diseases that are more common in the Ashkenazi populations that have nothing to do with breast cancer, like Tay-Sachs. That’s because of they were a more limited tribe of individuals. That’s true for other groups and countries, too. For example, in Iceland, there is also a BRCA2 founder mutation. This high frequency matters for the kinds of studies you can do, but it doesn’t matter for the generalizability of the results or their applications to other populations.
Your work has focused a lot on genetic testing to identify people at high risk. Why is this important?
If you look at inherited breast cancer, you can view it in the sense of fear [that you will have] the disease, which is a very common and understandable way to look at it. But it’s also very empowering to know if you’re at high risk, because then you can really do something about it before you ever develop the disease. The focus of that has been on risk reduction surgeries. But we hope that in future there will also be medications and other ways to reduce risk or to prevent cancer in people [with these mutations].
Our work has recently shown that even if women know in advance that they’re carriers and don’t choose to have double mastectomies (still the most effective way of reducing breast cancer risk), they still reap very tangible benefits. We showed that women with breast cancer who knew ahead of time that they were carriers had better survival rates than women who found out only after they were diagnosed with cancer. They were diagnosed at earlier stages and required less chemotherapy. So, it’s really lifesaving to know ahead of time that you have a mutation.
The guidelines around genetic screening are really determined by a variety of risk factors—the most prominent one being family history. But your research has shown that family history may not be a really fair predictor of whether or not someone could potentially be a carrier. Could you tell us a little bit more about that work?
We did a very large population study in Israel where we tested more than 8,000 healthy men in order to identify families with BRCA mutations that weren’t based on their family history. What we found out—and what has since been found repeatedly by other researchers—is that about half of women who are carriers, in fact, do not have significant family history.
Why would this happen? So theoretically, you could say, well, maybe the risk is not as high as we thought it was. But we actually looked at it, and we see that the risk is still high. But the reason that people don’t have family history has to do with both history and biology. The history part of it is that your family might be small, or there might be many men in the family. Or you might have what we call Mendelian luck, meaning we know that even within a family with BRCA mutations, about half of relatives are going to have the mutation and half are not. If that half just happen to be all men, for example, then you’re just not going to see [high rates of] cancer.
We also know that the same environmental factors that increase risk for breast cancer in the general populations—having earlier menstruation, having children at older ages, not breastfeeding—also acts upon carriers. Carriers born in previous generations were at less risk than carriers who are young women today. You might have less family history, because of the effects of these non-genetic factors.
What do you envision for the future of genetic screening?
I think that in the not too far future, all people are going to be tested for their inherited cancer risk. There are some issues that need to be addressed in places like Israel, where we’ve done our studies, because they are more complex than in other societies. We have to make sure that the mutations we’re identifying are really meaningful. That’s easy to do in the Ashkenazi population, because we have three common mutations that we know for sure are pathogenic, or disease-causing. When you start doing more generalized screening, this issue becomes more complex, because there are variants that we still don’t understand (what we call VUS, or variants of unknown significance). Then you run into this situation where you test a woman and you find out she has something, but you’re not sure whether it’s pathogenic or not. I think that can be circumvented by just making the decision that for screening, we are going to ignore those VUS and at least focus on the variants that we are sure are pathogenic. But that’s obviously going to evolve.
We want to make sure we’re able to offer the kind of screening that’s required for women at high risk after they are identified. If you have a lot of barriers for the kind of surveillance you need, then you haven’t really done much good. In the study I described earlier, where we looked at the women who knew ahead of time, what really made the difference in terms of early diagnosis was the fact that they underwent breast MRI. That’s a relatively expensive surveillance procedure. If breast MRIs are not available, then you’re not going to going to be gaining as much benefit unless you choose to have risk-reduction surgery.
I also think it’s a new paradigm in terms of how we deliver genetic testing. Traditionally, we’ve said that before you have a genetic test of this type, you should receive counseling before and after. This is not really feasible—and I don’t think actually really necessary—at a very large scale. We’ve done studies to show that you can give much more minimal information ahead of time, and then really focus your genetic counseling time and efforts on the women who find out they are at high risk.
All these pieces have to have to come together for this to be possible, but I think they will someday. Knowing your inherited risk is about precision prevention. It’s about [not needing] precision medicine because you don’t develop cancer in the first place.
This interview has been edited and condensed. For more interviews with BCRF researchers, click here.