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Clinical Experience with Multi-Gene Panel Use in Breast Cancer

Insights From:Adam M. Brufsky, MD, University of Pittsburgh Cancer Institute; Claudine J. Isaacs, MD, Lombardi Comprehensive Cancer Center; Harold J. Burstein, MD, PhD, Harvard Medical School
Published: Wednesday, Jul 06, 2016


Transcript:

Claudine Isaacs, MD:
There are a number of companies that offer these multi-gene panels, and there are slight differences between them. One of the companies, Invitae, one of the things that’s nice about them is they have a number of different customizable panels, and they let you choose which genes you want to put on and add—do a whole 29-gene panel or even a greater number gene panel. And often what I find particularly useful is, if you have a family where you think BRCA1 and BRCA2 is the likeliest thing, to first of all get BRCA1 and BRCA2. And if that’s negative, to think about adding genes or just focusing on the higher-penetrance genes. So, 6 genes, or maybe you’re also thinking that this might be a Lynch syndrome family, so throw in the Lynch genes. It’s the customizability of some of the panels, and Invitae is one of the companies that has a really nice customizable panel. There are other companies that offer those types of things, as well, and it is very helpful to be able to adjust things based on the characteristics of the family history and the patient’s individual personal history.

Harold J. Burstein, MD, PhD: The important thing about genetic testing, as we enter an era when there’s going to be a lot more genetic testing, is that there isn’t one test that covers everybody under every circumstance that you’re always going to reach for any more than in most things in medicine. So, when we talk about managing patients with our genetics counselors and our specialists in hereditary breast cancer, the first thing we want to think about is, what exactly are we looking for? If you’re talking to a patient whose mother had BRCA1 and she wants to know what her risk of hereditary cancer is, all you have to do is a narrow window test for BRCA1, and if it’s negative, you have the information you need. Then there are other families where there might be a different cluster of genes, and, again, you can tailor the evaluation for them based on the family history, the kinds of cancers that are arising in that family, and what other genetic information is already known. More and more, as more women get tested, there is circulating information in the family record about where these mutations might be and that can obviously guide it.

Now, there are still situations where you think there is a strong family history of cancer, but you don’t know where the mutation lies. And, in those instances, we’re going to be doing these multi-gene panels. They typically have about two dozen genes on them. There are several commercially available ones, and different health plans cover different insurances. Different genetics teams have better working relationships with one product line than with another, such that they get faster turnaround on them. The technical quality for most of these seems to be actually very similar, and so what mostly matters is to make sure that you have access to high quality testing, that the team can work quickly with the genetics company to get the information back, and that the information is delivered in a way that everybody understands the technical details about what’s being reported upon and what isn’t.

Adam M. Brufsky, MD, PhD: I think one of the big things for treatment-related decisions that we’ve seen, at least in my practice, is women with PALB2 mutations. A number of women with CHEK mutations, that I found, would not have been found if we had just been doing standard single-gene or double-gene BRCA1, BRCA2 testing. And I think that this has changed—at least offered to these women—certain screenings they would not have had before. I had a woman who elected to have a bilateral mastectomy with a PALB2 mutation, and we explained to her the risks—especially a New England Journal of Medicine paper that came out a few years ago—and she chose to have a bilateral mastectomy, which was her choice. So, clinical decisions are being made now with these multi-gene panels. And, again, I think that if we’re going to make a clinical decision with these panels, we need to be as sure as we can be that the mutation is actually something that’s pathogenetic and is potentially actionable.

Harold J. Burstein, MD, PhD: The advice for community-based physicians on which test to start with really begins with the history of the woman or the patient who you’re talking with at that time. If there is a family history that is already known, if there is a specific mutation that’s already identified within the family, then you start with that work. So, you might start with BRCA1 or BRCA2. If the families are of Ashkenazi Jewish ancestry or Eastern European ancestry, and there’s a much greater likelihood of having a BRCA1 or BRCA2 mutation, again, that’s where you would begin. If the patient has a family history and is already known to be BRCA1- or BRCA2-negative, or if there isn’t reason to imagine that it’s part of that syndrome, then you’re going to cast a wider net right away. And that’s when people begin reaching for the multi-gene panels out of the box. And that’s been a very efficient way to guide the genetic testing.

Adam M. Brufsky, MD, PhD: My own personal bias is to start with a bigger panel because, again, you never know what’s going to happen 5 years from now and at least you have the genetic data there. The data’s the data; once you do a genetic panel on somebody—especially in the germline—it doesn’t change. And you have that data. When new information comes out, you can always go back to that. Of course, you want to deal with a company that stores the data and that will also potentially contact you, or you can contact them when new variants and new mutations are discovered. I think my advice to community oncologists is to not use these lightly. These are very powerful tools. I think that, if possible—either through a virtual consult or a direct consult—use these with someone with genetics expertise, especially in trying to interpret the variants of unknown significance. I think that that’s very, very important. We don’t want to make a clinical decision based on a variant that we really don’t know causes disease; we just don’t know.

There’s a lot that’s unknown with these tests, and I think that, again, my advice to community oncologists is the data’s the data, and more data is always better than less—most of the time. But if you don’t have the expertise, really, to interpret the actual mutations, it’s very, very important to try to get either a virtual consult or an actual consult with either a genetic counselor or someone who understands the genetics. And those are always available. I think that if they can’t consult in person, I think most organizations have people that are available to discuss these mutations with.

There are many support services for physicians and for patients, both from the actual companies that provide the testing, as well as national organizations. ASCO has a variety of resources online, both for patients and physicians. The American Society of Human Genetics has a lot of Web-based resources, both for physicians and for patients. But I wouldn’t discount your local or your regional academic oncology facility. Most places in the country do have a comprehensive cancer center that’s fairly close by. The vast majority of these comprehensive cancer centers do have genetics expertise that could be available for a lot of the bigger practices even; bigger non-comprehensive cancer centers around the country do have resources. But, again, I think it’s very important, both for the patient and the physician—if they don’t have the expertise in trying to analyze some of these variants—to really involve these resources early on in the decision.

Transcript Edited for Clarity
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Transcript:

Claudine Isaacs, MD:
There are a number of companies that offer these multi-gene panels, and there are slight differences between them. One of the companies, Invitae, one of the things that’s nice about them is they have a number of different customizable panels, and they let you choose which genes you want to put on and add—do a whole 29-gene panel or even a greater number gene panel. And often what I find particularly useful is, if you have a family where you think BRCA1 and BRCA2 is the likeliest thing, to first of all get BRCA1 and BRCA2. And if that’s negative, to think about adding genes or just focusing on the higher-penetrance genes. So, 6 genes, or maybe you’re also thinking that this might be a Lynch syndrome family, so throw in the Lynch genes. It’s the customizability of some of the panels, and Invitae is one of the companies that has a really nice customizable panel. There are other companies that offer those types of things, as well, and it is very helpful to be able to adjust things based on the characteristics of the family history and the patient’s individual personal history.

Harold J. Burstein, MD, PhD: The important thing about genetic testing, as we enter an era when there’s going to be a lot more genetic testing, is that there isn’t one test that covers everybody under every circumstance that you’re always going to reach for any more than in most things in medicine. So, when we talk about managing patients with our genetics counselors and our specialists in hereditary breast cancer, the first thing we want to think about is, what exactly are we looking for? If you’re talking to a patient whose mother had BRCA1 and she wants to know what her risk of hereditary cancer is, all you have to do is a narrow window test for BRCA1, and if it’s negative, you have the information you need. Then there are other families where there might be a different cluster of genes, and, again, you can tailor the evaluation for them based on the family history, the kinds of cancers that are arising in that family, and what other genetic information is already known. More and more, as more women get tested, there is circulating information in the family record about where these mutations might be and that can obviously guide it.

Now, there are still situations where you think there is a strong family history of cancer, but you don’t know where the mutation lies. And, in those instances, we’re going to be doing these multi-gene panels. They typically have about two dozen genes on them. There are several commercially available ones, and different health plans cover different insurances. Different genetics teams have better working relationships with one product line than with another, such that they get faster turnaround on them. The technical quality for most of these seems to be actually very similar, and so what mostly matters is to make sure that you have access to high quality testing, that the team can work quickly with the genetics company to get the information back, and that the information is delivered in a way that everybody understands the technical details about what’s being reported upon and what isn’t.

Adam M. Brufsky, MD, PhD: I think one of the big things for treatment-related decisions that we’ve seen, at least in my practice, is women with PALB2 mutations. A number of women with CHEK mutations, that I found, would not have been found if we had just been doing standard single-gene or double-gene BRCA1, BRCA2 testing. And I think that this has changed—at least offered to these women—certain screenings they would not have had before. I had a woman who elected to have a bilateral mastectomy with a PALB2 mutation, and we explained to her the risks—especially a New England Journal of Medicine paper that came out a few years ago—and she chose to have a bilateral mastectomy, which was her choice. So, clinical decisions are being made now with these multi-gene panels. And, again, I think that if we’re going to make a clinical decision with these panels, we need to be as sure as we can be that the mutation is actually something that’s pathogenetic and is potentially actionable.

Harold J. Burstein, MD, PhD: The advice for community-based physicians on which test to start with really begins with the history of the woman or the patient who you’re talking with at that time. If there is a family history that is already known, if there is a specific mutation that’s already identified within the family, then you start with that work. So, you might start with BRCA1 or BRCA2. If the families are of Ashkenazi Jewish ancestry or Eastern European ancestry, and there’s a much greater likelihood of having a BRCA1 or BRCA2 mutation, again, that’s where you would begin. If the patient has a family history and is already known to be BRCA1- or BRCA2-negative, or if there isn’t reason to imagine that it’s part of that syndrome, then you’re going to cast a wider net right away. And that’s when people begin reaching for the multi-gene panels out of the box. And that’s been a very efficient way to guide the genetic testing.

Adam M. Brufsky, MD, PhD: My own personal bias is to start with a bigger panel because, again, you never know what’s going to happen 5 years from now and at least you have the genetic data there. The data’s the data; once you do a genetic panel on somebody—especially in the germline—it doesn’t change. And you have that data. When new information comes out, you can always go back to that. Of course, you want to deal with a company that stores the data and that will also potentially contact you, or you can contact them when new variants and new mutations are discovered. I think my advice to community oncologists is to not use these lightly. These are very powerful tools. I think that, if possible—either through a virtual consult or a direct consult—use these with someone with genetics expertise, especially in trying to interpret the variants of unknown significance. I think that that’s very, very important. We don’t want to make a clinical decision based on a variant that we really don’t know causes disease; we just don’t know.

There’s a lot that’s unknown with these tests, and I think that, again, my advice to community oncologists is the data’s the data, and more data is always better than less—most of the time. But if you don’t have the expertise, really, to interpret the actual mutations, it’s very, very important to try to get either a virtual consult or an actual consult with either a genetic counselor or someone who understands the genetics. And those are always available. I think that if they can’t consult in person, I think most organizations have people that are available to discuss these mutations with.

There are many support services for physicians and for patients, both from the actual companies that provide the testing, as well as national organizations. ASCO has a variety of resources online, both for patients and physicians. The American Society of Human Genetics has a lot of Web-based resources, both for physicians and for patients. But I wouldn’t discount your local or your regional academic oncology facility. Most places in the country do have a comprehensive cancer center that’s fairly close by. The vast majority of these comprehensive cancer centers do have genetics expertise that could be available for a lot of the bigger practices even; bigger non-comprehensive cancer centers around the country do have resources. But, again, I think it’s very important, both for the patient and the physician—if they don’t have the expertise in trying to analyze some of these variants—to really involve these resources early on in the decision.

Transcript Edited for Clarity
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