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Investigating Breast Cancer: Developing Personalized Risk Prediction

Dr. Mark Robson talks to BCRF about how he’s working to help identify the right tests for the right person at the right age
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Most breast cancers are not the result of inherited mutation in cancer causing genes. For families with a high incidence of breast cancer, however, a genetic component may underlie an inherited risk. We know the BRCA genes are the most common of these inherited mutations, but scientists have uncovered many more genes implicated in a risk of breast cancer.

How can researchers provide more precise risk estimates so that individuals with inherited risks can make informed decisions about their health, so that the right women are getting the right tests at the right age?

Dr. Robson is conducting studies that employ advanced technologies that incorporate information from genetic tests to enhance the precision of genetic risk assessment in women with mutations in the BRCA gene.

Dr. Robson has been a BCRF investigator since 2006 and is an associate attending physician of Clinical Genetics and Breast Medicine Service in the Department of Medicine at Memorial Sloan Kettering Cancer Center.

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Read the transcript below:

Intro: Most breast cancers are not the result of inherited mutation in cancer causing genes. For families with a high incidence of breast cancer, however, a genetic component may underlie an inherited risk. We know the BRCA genes are the most common of these inherited mutations, but scientists have uncovered many more genes implicated in a risk of breast cancer.

So how do genes influence breast cancer risk? And can we develop strategies to precisely predict risk on an individual level? In other words, how can researchers provide more precise risk estimates so that individuals with inherited risks can make informed decisions about their health, determining the level of risk for enhanced screening so that the right women are getting the risk tests at the right age?

Dr. Mark Robson is one to ask. With Dr. Kenneth Offit, Dr. Robson – among other activities – is conducting studies that employ advanced technologies that incorporate information from genetic tests to enhance the precision of genetic risk assessment in women with mutations in the BRCA gene.

Why does he do it? What motivates him? You’ll want to hear Dr. Robson’s thoughtful response about the breast cancer community that included references to James Madison, Virgil, and the that that, as Dr. Robson says: “Life is full of nuances,” and that “everyone experiences” the disease “in a different way.”

Some background: Dr. Robson is an Associate Attending Physician of the Clinical Genetics and Breast Medicine Service in the Department of Medicine at Memorial Sloan Kettering Cancer Center. He is currently the Clinic Director of the Clinical Genetics Service and the chair of the Cancer Genetics Subcommittee of the American Society of Clinical Oncology. He has been a BCRF Investigator since 2006.

Chris Riback: Dr. Robson, thanks for joining me. I appreciate your time.

Dr. Mark Robson: Thank you for having me. Glad to be here.

Chris Riback: I'd like to start with your helping differentiate between two paths to breast cancer, those that result from inherited mutation and cancer causing genes and those that don't. Do the types of breast cancers that result from these paths differ and which path is more common?

Dr. Mark Robson: Yes. So, the vast majority of breast cancer is not due to mutations or the term now is pathogenic variants, which is a little bit more fancy but precise. The vast majority of breast cancer is not caused by those genetic changes. They arise because of alterations that occur in the DNA and it's just acquired through life. But there are a fraction of women who develop breast cancer because of a specific inherited mutation.

And they're in general have the same outcomes as women who don't have mutations. And with one exception, the breast cancer is generally seem to resemble those of women who don't have mutations. The one exception is for women who have mutations in BRCA 1, which is linked to an increased risk of a triple negative breast cancer, which is a particular subtype.

The reasons for looking for these mutations are that ... There's a couple of different ones. One is that women who have mutations, for instance in BRCA 1 or BRCA 2 may be an increased risk for other types of cancer, either second breast cancers in the other breast or ovarian cancer. And that risk means that we should do different things to follow them up.

Also, their family members may be at increased risk if they share the mutation and benefit from specific surveillance approaches and potentially even preventive surgeries. And lastly, women who have metastatic breast cancer with mutations in some genes, although not all genes may benefit from treatment with a specific class of drugs called PARP inhibitors.

Chris Riback: And that's what I just wanted to ask you about. When we talk about inherited risk or pathogenic variants perhaps and genes and breast cancer, most often we hear about what you just raised, BRCA 1 and 2. But those aren't the only genes implicated in a risk of breast cancer, are they?

Dr. Mark Robson: No. Indeed not. When a new type of technology called next generation sequencing became available a number of years ago, it became possible to test individuals for many different genes at the same time. And once that became possible, so-called panel testing came into the clinic.

And we discovered that a significant number of women have pathogenic variants or mutations in genes other than BRCA 1 and BRCA 2. And while BRCA 1 and BRCA 2 are still the most common identified inherited risk factors, there are a range of others that in aggregate are equally calm.

Chris Riback: There was a quote I saw recently from Larry Norton of Memorial Sloan Kettering, but also obviously BCRF, where he said, "We know from our data at Memorial Sloan Kettering that if you only test people with strong family histories, you miss half the cases." And I know this is a key question. If we know inherited risk is a thing but we don't necessarily know which genes drive the risk, how can individuals with inherited risks make informed decisions about their health?

Dr. Mark Robson: Well, I think that that's a topic that we're having a lot of discussions about right now. So, I think what Larry was referring to was that even among women who have BRCA 1 and BRCA 2 mutations... Sorry about the phone. Even among women who have BRCA 1 and BRCA 2 mutations, half of the women with mutations aren't found until they themselves develop a cancer and would not have been tested based upon what their family history is until they themselves develop a cancer.

That's one component of the unidentified risk. The other component is that the genes other than BRCA 1 and BRCA 2 are actually much less strongly predisposing than BRCA 1 and BRCA 2. So, they may move through families without actually causing cancer. And so, can be hidden, if you will, until perhaps someone is unlucky enough to develop the disease and get tested.

Chris Riback: Let's talk about your work and some of your goals. Because among your goals, as I understand it, is to determine not only how we can make more precise risk estimates but how we can precisely predict risk on an individual level. Take me through that process. How are you trying to do that? And perhaps relatedly, what are single-nucleotide polymorphisms?

Dr. Mark Robson: Right. Should we call SNPs because there's so much easier to say?

Chris Riback: Thank you. We will call them SNPs.

Dr. Mark Robson: Yes. SNPs. So, what we've been talking about so far are so-called rare variants. In other words, everybody has the BRCA 1 or BRCA 2 gene but very... Because they perform normal functions in our bodies. But very, very few people actually have mutations or pathogenic variants in those genes. In the general population, it's probably only around one in 400, maybe one in 500 people have a mutation. Although in certain populations that we'll talk about later, it may be more common.

These rare variants are predisposed to cancer but not everybody who has a mutation in one of these genes gets cancer. So, for instance, for BRCA 1, it's probably about 65 to 75% of women get breast cancer and 40 to 60% get ovarian cancer depending on the study. For BRCA 2, the numbers are perhaps a little bit lower. It's maybe two thirds get cancer and 15% or so get ovarian cancer.

And for genes like those other so-called moderate penetrance genes, those other genes that we talked about a little bit earlier, one such gene is called CHEK2. And for those women, the lifetime risk of breast cancer is maybe about 25%. So, the question becomes what's different about the women who do get breast cancer and don't get breast cancer when they have a mutation in one of those genes? And there's a number of things that play into that.

But one thing is genetic background. And we have millions and millions of places throughout our DNA where we're subtly different from other people. These are so called common variants or SNPs. And it turns out that some of those SNPs are associated with greater or lesser risks of disease. And this isn't just breast cancer, this is all kinds of diseases, diabetes, cardiovascular disease, et cetera, et cetera.

And they're not mutations in the sense that they don't cause problems with genes but they're just part of us, part of our background. And we can now through genetic testing in research settings, identify the pattern of common variation that a person has. And what we found is that certain patterns of common variation, so-called polygenic risk scores are associated with greater or lesser risks of disease both in the general population and in people who have mutations in genes like BRCA 1, BRCA 2 or CHEK2.

So, one of the things that we're trying to do is measure this background variation in individuals, predict how that might affect the risk that's associated with say a mutation in BRCA 1 or BRCA 2 and see whether if we give that information to women, the differences are sufficient to influence their decision making about things like preventative surgery.

Chris Riback: Almost focusing the light on the amount of risk based much more on an individual reading it seems than on the readings that we have had to date.

Dr. Mark Robson: Correct. Because right now when a woman goes in for a genetic counseling, for a BRCA mutation, she is often given a fairly wide range of potential risks. Say, "Your risk may be anywhere from 65 to 95%." And what we're exploring is whether it is helpful to those individuals to become a little bit more precise. There's still going to be some range but the question is can we narrow that range in a way that it's helpful?

And it may be that for the very strongly predisposing genes, the precision may be helpful. We may narrow the range but the range may still be so high that it doesn't change decision making. But for this other group of genes that we have been talking about, the moderate penetrance genes, it may matter.

Because if your average risk is 25 to 30% but there's some group of women that are in the 15% range and some group of women that are in the 40% range, that may well have an influence on what they decide to do. So, we're also as a next step looking at polygenic modification of moderate penetrance.

Chris Riback: And is this the Prospective Registry Of Multiplex Testing, PROMPT? So, we had SNP earlier and now we have PROMPT. First, is this the group that you are doing this work with? And then two, how would you characterize where you are on the work? How far along would you say you are?

Dr. Mark Robson: So, PROMPT is actually a little different. PROMPT is when multigene panel testing became available, it is the thing about which we have very little evidence to understand how people are receiving the information, how the information is being communicated to them and what they are choosing to do with the information.

This was something that multigene panel testing was rolled out commercially, not as a research test, with very broad adoption very quickly but with still a lot of questions about how best to use the information. So, we created PROMPT as a voluntary internet based registry for people who had been found to have mutations on multigene panel testing to share their experiences, to tell us what they had because that in and of itself was something that was interesting. What were the diseases that they had, et cetera.

But also, what were they doing subsequently in terms of screening or surgery? And what was their understanding of these alterations? What had they been told? What had they received? And now, we're following these... Largely women, not exclusively but largely women serially over time to try to understand longitudinally what they're doing.

So, that's an observational project that I think is very important because it's giving us a view of what's happening in the real world with multigene panel testing. With regard to the risk modifier work, we were facing some challenges getting a clear based... Which is a laboratory approved assay done that we could share with people that we had enough confidence would be accurate.

We've now circumvented that hurdle through a relationship with a vendor, have achieved the appropriate regulatory approvals and are now moving it into the clinic to start offering the testing to women who have had newly identified BRCA mutations so that we can give them this information and essentially measure what it is that they choose to do with it.

Chris Riback: And the point that you were just making, I'm sure it's a question that any person would have first of all around genetic testing and understanding one's own risk and modifying one's own risk as much as possible. But in particular, individuals at risk of carrying BRCA 1 or 2 mutation, this becomes even more powerful for them.

You wrote in a recent editorial in the journal of the American Medical Association with a colleague, you wrote a little bit about this. And one of your lines was, "Identification of individuals at risk of carrying a BRCA 1 or 2 mutation can be lifesaving and should be a part of routine medical care."

Now, that may have been geared towards a particular population but I thought that might be something to get some guidance on or some insight on from you because it's an area obviously that so many people would be curious about.

Dr. Mark Robson: Right. So, we have reasonably strong observational evidence. That if you identify a woman who's having a BRCA mutation and then prevent her from getting ovarian cancer by doing a preventive surgery to remove her fallopian tubes and ovaries, that that will improve the survival of the population because screening for ovarian cancer is inadequate and it's a tough disease that frequently presents an advanced stage.

There is also some potential benefit from women who choose to undergo preventive mastectomy, although whether that has much of a survival advantage is not clear. But prophylactic oophorectomy is something that we believe does save lives. So, finding women who have BRCA mutations, that's not something that you want to do lightly, certainly not in younger women because premature menopause is quite a significant impairment to quality of life and potentially to longterm health.

Dr. Mark Robson: So, finding the women who've got mutations is important. The way that we have done that to this point has been by using things like family history to try to predict who is more likely to have a mutation. Remember as I said earlier, it's only about one in 400 to one in 500 in the general population. So, creating a system of testing, everybody becomes challenging.

The thought is perhaps to start this process by concentrating on groups who have higher risks of carrying a mutation. So, for instance, the population of the Ashkenazi Jewish individuals. So, individuals of Eastern or Central European Jewish descent have about a one in 40 chance of carrying one of three specific BRCA 1 or BRCA 2 mutations.

So, nearly 10 times higher. And there has been thought now that perhaps everyone who is of Ashkenazi Jewish descent... And defining that becomes a little bit of an issue. But everybody who's of Ashkenazi Jewish descent should at least be offered or have a discussion about the possibility of undergoing BRCA testing, at least for those three common mutations.

Chris Riback: So, it's a bit of a shifting of the thinking around who might want to do it. And I'm sure that there's still much discussion and increasing the number of the amount of testing carries... “controversy” is the wrong word, but one wants to manage – and you were saying this – and handle testing appropriately.

As I'm talking to you, so much of it seems what you think about, what you have worked on in your career, what you've dedicated yourself to is around the genetic component and about the considering and the managing of risk. I found myself thinking about you almost as a medical actuary doing, thinking... So, why? What interests you about that? And have you ever thought of yourself as a bit of a medical actuary?

Dr. Mark Robson: No. I never thought of myself as a medical actuary. Because why am I interested in it? That's a fascinating question that I've really never deeply thought about. My perception is that life is full of nuance. And what I enjoy about this area is trying to communicate with people about uncertainty and help them navigate that in a way that is concordant with their values and how they want to approach managing potential threats to their health.

I mean, not everybody who has a BRCA mutation gets cancer. And certainly, not everybody with a moderate penetrance mutation gets cancer. And yet when they have a test result, many people seem to internalize that as a diagnosis, essentially pre-cancer. And the question is how can we help them navigate that and just recognize that this is something that is a risk that you know about. Perhaps there are others that you don't. And that's what I enjoy about it.

Chris Riback: And does that lead in some way to your clinical work? I mean, it wasn't lost on me that my understanding of the clinical side for you, you'll correct me if I have this wrong, is that your practices weighted toward the management of young women with breast cancer, especially hereditary breast cancer. I recently had a discussion with Doctor Ann Partridge, who runs the young and strong program for young women with breast cancer. The disease is different for young women, isn't it?

Dr. Mark Robson: I think that the disease is different for everybody, right?

Chris Riback: Yes.

Dr. Mark Robson: I mean, everybody experiences it in a different way and it has a different impact. I do work a lot with younger women just because I work a lot with inherited risk and that overlaps. But also take care of people who are older as well. And it's the same concept. I mean, if you think about after a diagnosis and treatment of breast cancer, once again, people are living with a pretty fair degree of uncertainty.

About at least for a while, "Is this going to come back? How am I going to integrate this into my life? " And again, it becomes a conversation about moving forward in the face of uncertainty. And uncertainty with a possibility of something not good happening, right? And I think that from the humanist perspective of Madison that being a little bit of a Virgil in that setting, is a privilege. And I enjoy doing that.

Chris Riback: Was it always medicine for you? Was science always the direction that you were going to go? You mentioned Virgil. Were there other areas of interest for you growing up?

Dr. Mark Robson: I've always been interested in the arts and humanities. But mainly as a way of, again, informing perspectives on life. Gosh, I'm getting all philosophical here on a Thursday afternoon. But no. I mean, I've been joking with my daughter who's now in 10th grade and I remember actually starting thinking about doing medicine when I was in 10th grade biology class.

So, yes. I mean, it pretty much has always been medicine for me but for different reasons. When I was younger, it was because it was tough and it was hard and I felt like it was intellectually challenging, which has a certain arrogance to it. And then, as I got older, it became much more because it was a life of connection. And connection not only to your patients but connection to your colleagues and connection to the broader world. And I think that's a very nourishing thing.

Chris Riback: Yes. It's not a bad way to go through. And to close out, I'd be remiss if I didn't ask you, doing the amounts of research that you do and that other researchers, scientists, doctors do can be challenging at times, what role has BCRF played in your research?

Dr. Mark Robson: Well, BCRF has been an incredible financial supporter. The model is very unique. And the idea that you have funding to explore ideas that would be difficult to get funded through other mechanisms because of the novelty, because of the newness of what you're trying to do. So, there's that component to it.

The other component goes back to what we were just talking about is that it's a phenomenal community of both researchers but also... And perhaps more importantly, patients, family members, supporters, who are energizing through their dedication to the course and their energy for the course.

And so, I think we all talk about the research support that's critically important. But the community writ large is in my mind equally important and perhaps even more so.

Chris Riback: Well, thank you. I'm certain that they're grateful to have you part of that community. And yes, it's a remarkable community to say the least. Dr Robson, thank you for taking the time. And of course, thank you for the work that you do.

Dr. Mark Robson: Thanks very much. Appreciate it.

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