20 Years Since BRCA2: Where Are We Now in Cancer Screening?

; Nazneen Rahman, MD, PhD


April 13, 2015

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Music and Medicine

Eric J. Topol, MD: Hello. I'm Eric Topol, editor-in-chief for Medscape. Joining me today is Dr Nazneen Rahman from the United Kingdom. She heads up the Institute for Cancer Research at the Royal Marsden Hospital and is a very unique individual, because she not only is a medical geneticist (focusing on cancer, biology, and predisposition genes), but she is also a singer and songwriter.

At our Future of Genomic Medicine conference, you not only gave a talk about predisposition genes for cancer, but you also sang original music from your album that came out last year.

Nazneen Rahman, MD, PhD: That's right—Can't Clip My Wings.

Dr Topol: That is symbolic of you. You are a free spirit, and you have a lot of talent in two diverse areas. How did you get into music and songwriting as well as genetics?

Dr Rahman: I don't find them so different. Creativity is at the heart of both of them. Scientific endeavors are very creative. You have to be thinking of new ways to do things, thinking outside of the box. For me, science is the creative end of medicine. As a medical doctor, you want to follow protocols, so getting into genetics gave me a creative outlet from medicine.

The singing is something I have always done. Music is important to so many people. I have met many people at the conference here who say, "Oh, yes, I'm going to pick up my sax," or "Music is the lifeblood for so many," and I'm one of those people.

Dr Topol: Did you ever have a point when you had to choose—when you weren't able to follow both paths?

Dr Rahman: No; I have never thought of being a professional musician in that sense. Music is my outlet, but to be a successful musician involves aspects that I'm not talented in—going out there and publicizing your music, and doing those things. It's tough being a professional musician. I just like being able to make music that I like. If other people like it, that's great.

It Started With BRCA2

Dr Topol: I had not met you in person until your visit here to La Jolla, but I found about you through your incredible review paper in Nature.[1] I see you as the leading authority in predisposition genes to cancer—the germline of the cancer story. Can you give us a sense of where we are today in terms of familial cancers, and how much we have learned?

Dr Rahman: It's a very exciting time, but it also has a very long history. It was 20 years ago this year that the BRCA2 gene was identified. We have been working on this field for a long time. I was Mike Stratton's PhD student when he was cloning BRCA2, so that's how I got started in the area. It's one of those pioneering areas for predisposition genetics, and it has pioneered many different aspects of that.

The changes in genomic technologies that have taken place over the past few years are now giving us opportunities to make an impact on a massive scale from helping hundreds of people, to thousands and millions of people. That is what we are able to do at the moment. We need to capitalize on making use of these technologies so that we can deliver a greater impact and help more people.

Dr Topol: You alluded to the work on BRCA for breast cancer, and you have told us about an ovarian cancer program. Can you summarize what that is about?

Dr Rahman: People know that the BRCA genes are involved in breast cancer because of the breast cancer genes, and it's also known that they lead to an increased risk for ovarian cancer. What is not so well known is that the proportion of ovarian cancer due to BRCA is much higher than that of breast cancer. About 15% of ovarian cancer is related to BRCA mutations, compared with 3%-4% of breast cancers. In terms of ovarian cancer, it is very important because ovarian cancer still is a very serious disease. Often, people present late, and the outcomes are not as good as we would hope.

After women have had their families, removing the ovaries by keyholes can be very effective in preventing ovarian cancer. Identifying women with ovarian cancer who have the BRCA mutations allows us to give them the best possible treatment. We can tailor treatments, particularly for BRCA mutations, with poly ADP ribose polymerase (PARP) inhibitors. It also allows us to help out the wider family and prevent the ovarian cancer and potentially breast cancers in the relatives before they have developed cancer. It's a wonderful example of genomic medicine.

Like Writing a Book

Dr Topol: It amplifies the potential by getting to all the family members. You had a fantastic way of explaining interpretation and analysis. Can you give us a run-through? I know you can't do it graphically.

Dr Rahman: One of the things that we have been struggling to communicate is genetic testing. We know that sequencing is much cheaper, so why is it taking longer than we might hope to get it into the clinic? The sequencing part—getting those letters—is just one part of the process of a genetic test.

We found the analogy of a book to be very helpful. When you make a book, you need all of the letters, but you can't just have them in a random order. Getting the letters is the sequencing, but then you have to put them into words and into sentences, and get the punctuation right. That's the analysis.

It's only when you have done those other things that you can read the book and understand its meaning, and then do something about it. That last part is the interpretation. You need all three of those components to do a genetic test that is going to make a difference for the patient.

Dr Topol: You mentioned that much of what we get now when we do sequencing and interpretation are variants of unknown significance (VUS).

Dr Rahman: "VUS" can also stand for "very unhelpful statement." I am called all the time when someone has received a report that basically says "VUS," and they ask, "What do I do with that?" That's an entirely reasonable question.

We need to make sure that the reports that are going back to patients and clinicians have gone one step further and have answered that question to the best of our knowledge with the amount of information that we have today. That is what we try to do—give clear information about the relevance with the information that we have today, and also make sure that we keep these variants in an initiative process, so if new information becomes known that might change the significance of those VUSs, we can go back and give that information to them.

Context Matters

Dr Topol: You draw a distinction between a person who has a disease or condition and genetics are being applied, vs a person who is unaffected or asymptomatic and may only have a risk for that disease. The threshold has to be markedly different when you are potentially taking out a body part (ovary, breast, colon). That is a very important distinction that we need to zoom in on.

Dr Rahman: That is the most important message for genomic medicine that will make a difference. Most people think of all genetic testing as all the same, but the context of that testing makes a difference. If somebody has a disease, whether it's cancer or heart disease, and you are doing genetic testing along with MRI and other tests, that is just normal medicine. It's part of the information you are trying to gather to make that person better.

All societies embrace the fact that you try to make ill people better, and we should be trying make it as easy as possible to get all that information so that can be done. Quite often, a genetic diagnosis can be clinically recognized and that would be routinely done.

With predictive testing, the person is well, and you trying to give them a window into the future. That is quite complicated, both for individuals and for societies. Do we want that information? When do we want that information? What are we going to do with that information? That requires careful consideration and thinking about, but because people think of testing all in one way, they think you have to have all of that counseling when you are doing a straightforward medical test. We are trying to think more about that separation—when you need that detailed kind of information as part of all of the other tests you are doing to help the patient get a better treatment, then of course you should have that test. We find that patients have pretty straightforward decision-making. Give me the test.

Sequencing at Birth?

Dr Topol: I love the way you take these complex issues and translate them to make them simple, practical, and understandable.

I want to fast-forward with you. Mary-Claire King said recently that all women should have BRCA testing, but now millions of people are being sequenced. We understand a bigger landscape of the genes predisposing for, or at least in the germline, for cancer. Do you foresee a time when at birth, or at some early point in life, each person would have screening for the likelihood of developing any cancers over the course of their lives?

Dr Rahman: I can potentially see that coming to pass, but there is a lot of information that we don't have at the current time. The problem at the moment is that people think it's a fixed risk. If you have a mutation, you have a fixed risk of developing cancer, but in fact, those mutations are just one of the many different factors that can influence whether a person develops cancer.

We know that the exact same mutation in the BRCA gene may confer a risk of 80% in one context if you have a strong family history, but a much lower risk (for example, 40%) if you don't. We don't know all of the other factors that are making these very big differences in risk, and levels of change of risk that are affecting behavior, because people are potentially doing very significant things, such as having surgery to have parts of their bodes removed. Until we have better information, we need to be cautious, because otherwise, we may very easily enter into an era of genetics over diagnosis.

It's a little bit like what we have seen with prostate-specific antigen (PSA) screening. Years down the road, we might say, "Well, actually, your risk wasn't that high," but it will be difficult to know that for a long time, because if you have surgery, your risk will be reduced. You may have done that because you thought your risk was much higher than it is.

Dr Topol: Your point is an excellent one, but it may be even more complex than identifying modifier genes and protective alleles, because it may not be just be a sequence story. It could be the microbiome.

It could be a long time before we can sort all this out, but perhaps someday we will be smarter about the studies in which people are already affected with cancer, to try to help all their descendants. Hopefully, we can intervene at a much earlier stage.

Dr Rahman: I am a practical individual. I do find these issues interesting and I think they are important, but at the same time there are ways today, for many different diseases, that we could potentially do prevention, and we should be trying to do that. At the same time, there are precision medicine initiatives in the United States, the United Kingdom, and elsewhere; we should procure information that will inform, but we should be cautious about going too far down the line before we have the correct information. People take information obtained in one context and extrapolate it to a completely different context, often inappropriately. We have to be cautious that we are doing that correctly.

The Angelina Effect

Dr Topol: I couldn't agree with you more.

The last question is about the "Angelina Jolie effect." What do you make of the whole thing? Is this just a short-term thing, or will it have a durable impact?

Dr Rahman: It did make quite an impact. It made people more aware. It made people think about the prospect of being at risk for cancer, yet being empowered to make an informed decision about it. I think that's great.

In this particular context, there are many things that one could do, from surveillance to surgery. There are options. You can give information so that people can make a more informed decision.

In the background, it was about people knowing a lot more about genetics, DNA, and genomics. I'm constantly amazed by the patients I meet—how engaged and informed they are. That's a general change. It's wonderful.

Dr Topol: It's great. It's no surprise, having had a chance to talk with you and listen to you sing, that you were recognized by the BBC as one of the most influential and most powerful women in the United Kingdom. We are going to be seeing a lot more about you and from you in the future. Thanks so much for joining us on this segment of Medscape One-on-One.


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