Next-Generation Sequencing in Breast Cancer

Transcript:Harold J. Burstein, MD, PhD: We are entering the era of personalized medicine, and genetic and genomic testing is really at the forefront of that. I can only imagine what it was like 100 years ago when they started the era of biochemical medicine and all of a sudden people had to learn what does it mean to have a sodium level that’s abnormal, or to have a creatinine measurement of kidney function, and how do you interpret this information. It’s no different. It’s just the current effort to find—with more detail—the explanation for human health and disease. There’s nothing magical here that’s going on. We’re generating data based on testing, a lot of which we understand and a little bit of which is still a little opaque.

So, for community doctors, the important thing is that you do a family history and you begin to think about which genetic test is going to make the most sense. For many people, that will be BRCA1 or BRCA2 testing based on the specifics of the family history, breast and ovarian cancer, male breast cancer—known mutations, and the ethnicity of the patient. And for other situations where there isn’t something to guide you like that, you’re going to reach earlier for a multi-gene panel to test a wider net of genes and collect the information.

In situations where there’s a strong family history but there is no BRCA1 or BRCA2 mutation, the chance of you finding something is 5% to 15% when you do that kind of multi-gene testing. What we do with that information is advise women, we talk about surveillance for women, and we talk about whether they warrant prophylactic surgery—and the recommendations there are going to depend on the specific identified gene and the family history. And that’s where I think clinicians in the community are going to find themselves on the least firm ground, because there isn’t a lot known about the penetrance and the need for surveillance or prophylaxis with mutations for many of these genes. In the rare instances where you’re finding actual mutations, you might want to get some input from specialty centers that deal with women who have these problems.

Having said that, I think for the vast majority of women, the information from either narrow-panel or broader-panel testing is tremendously powerful and, for most women, provides remarkable reassurance that neither they nor their family harbors hereditary breast cancer. And that information is every bit as powerful as the actual finding of a mutation, in terms of bringing good decision making and peace of mind to the patients.

Adam M. Brufsky, MD, PhD: There’s many ways that we look at next-generation sequencing analysis. So, there are, again, germline mutations where we’re trying to assess risk, and there are somatic mutations in the tumor where we’re trying to determine therapy. Precision medicine tumor boards can do both. I think in the analysis of genetic risk—say someone does a multi-gene panel—they can really help analyze those variants of unknown significance.

So, in a precision medicine tumor board, optimally, you’ll have scientists with expertise in genomics; you’ll have scientists with expertise in protein structure. These are people who study this in the lab. You’ll have physicians who are experts in either screening or managing risk of patients with high-risk disease, as well as physicians who actually treat metastatic cancers in various forms. It’s really a nice group that you have together that can try to make these decisions. And, again, it’s very, very important in these precision medicine tumor boards, either when you get a multi-gene panel from a tumor, a somatic mutation panel, or a multi-gene panel for germline mutations. This can really be very helpful.

And I think that what a lot of us are going for, in our comprehensive cancer centers, are trying to do these virtually for people because it’s very hard with everybody’s very, very busy schedule to get everybody in a room and do this live. I think that a lot of us are trying to develop services where someone can post a question to a genomics group—at my institution or another institution—what does this mutation mean? And then we can circulate that and develop some information for that person, that oncologist in the community to help out with. I think that we’re really going toward these virtual precision medicine tumor boards as opposed to live ones. A lot of us have live ones, have very formal ones. But I think that that may not work for the average or the typical medical oncologist or hematologist/oncologist who is trying to decide what to do with, specifically, these variants of unknown significance.

Claudine Isaacs, MD: One of the issues that’s coming up these days is that we are sometimes finding mutations that are suggestive of germline mutations when we send tumors off for profiling. We’re sending tumors off for profiling increasingly these days, and the reason we’re doing it is mainly to help us guide decision making often for patients with advanced cancer. So, we’re trying to find a somatic mutation, something that might be a driver or something that might be a target for new therapies. But, when you do that, there’s actually a possibility that you will turn up what looks like a germline mutation. The DNA in the tumor is, in large part, very similar to somebody’s DNA elsewhere. It’s representative of their germline DNA. If you’re looking at tumor profiling, you’re looking at all the genes that are expressed in the tumor or series of genes. Those often include some of these genes that may be germline mutations that may confer increased risk for cancer. So, we have to be prepared that when we send a tumor off for tumor profiling, that in a patient where you didn’t necessarily suspect it, you might find a deleterious mutation, and that’s called either a secondary finding or an incidental finding at the time of tumor profiling.

And the question is, what do you do when that happens, and how do you approach that clinically? There are guidelines out there that help us address what we should be doing in that situation. ASCO has guidelines, the American College of Medical Genetics has guidelines, and the guidelines are quite clear. They say that if you find a germline mutation in an actionable gene, most of those, or many of those, are cancer-related genes. But honestly, some of them are genes that increase the risk for heart disease or for various arrhythmias or other things, and those are clinically important for the patient and potentially very clinically important for other family members. So, we have to be prepared for that.

How do we prepare for that? The most gold standard way to do it would be to do genetic counseling before somebody has tumor profiling sent off. I’ll spend a lot of time talking about all of these genes that might be found and prepare the patient for that, and that’s obviously a very difficult thing to do. And ASCO has come out with a much, I think, more clinically reasonable way to think about this, and that is that we should tell our patients before we send the tumor off for profiling that we could find a change that is suggestive of a germline mutation and ask them if we found that, would they want to know that. They should be given the opportunity to say, “No thanks. I just want to know things that might impact my treatment decisions now,” and often those patients have advanced cancer and have a lot of other things that they’re grappling with. But they should be fully explained of the range of things that could be found.

If something is, in fact, found—and sometimes it’s something very surprising in a cancer patient that you wouldn’t expect that they’d have a germline mutation in BRCA1, BRCA2 or Lynch syndrome gene…You could find a mutation in one of those genes that comes up on tumor profiling. Typically, what you want to do in those cases is if you identify that, obviously discuss it with the patient, and then refer them for standard genetic counseling and testing. You then want to verify that result typically at a company that has expertise in that, and that is a CLIA (Clinical Laboratory Improvement Amendments)-certified lab to do that type of testing. Many of the companies that do tumor profiling are not the same ones that do germline testing, and so you’d want to confirm that, and you’d want to offer the patient genetic counseling and testing for that specific mutation that was found at the time of tumor profile.

Transcript Edited for Clarity