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Understanding the Options in Multi-Gene Panels

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: Thursday, Jun 16, 2016


Transcript:

Adam M. Brufsky, MD, PhD:
The ones, at least the most commonly used commercial panels, that I’m familiar with and I tend to kind of consider using in my practice are the Invitae panel, Myriad’s My Risk panel, and Gene DX’s panel. And they’re all somewhat different in a few of the genes that they cover and in the turnaround time that they give. The real difference is what each individual company’s annotation of their genes are. What I mean by that is, for example, Invitae may have a different annotation for their deleterious mutations than Myriad may have. And so for that reason, I think it’s important when someone looks at these panels that they ask, what is your percentage, for example, of variants of unknown significance? The key here is that we’re going to find a lot of variants. For a lot of them, we have no idea what they are. Maybe if you had some experience in molecular biology and kind-of guessed as to what that mutation is… But a lot of us don’t have that experience. So, you really have to trust what each individual company has done in terms of the annotation of their variants of unknown significance. And I think that’s probably the biggest thing that separates a lot of these companies, aside from turnaround times and cost. That to me I think is really the big one.

Harold J. Burstein, MD, PhD: When they’re putting together panels for genetic testing, they typically include genes that have different roles right now in our understanding of hereditary breast cancer. Obviously, there’s BRCA1 and BRCA2, highly penetrant genes where specific mutations have been identified that predispose to cancer and where we have a lot of background information. Then there are these rare genetic syndromes beyond BRCA1 and BRCA2, we’ve mentioned them briefly—Li-Fraumeni syndrome, hereditary diffuse gastric cancer, and lobular breast cancer—where we have a specific gene in mind. And if you find an abnormality there that tracks with a family history, you have a good insight.

The next wave of genes includes a variety of tumor suppressor genes and other genes that have identified large numbers of cases. PALB2, and CHEK2, and ataxia-telangiectasia-mutated genes do clearly seem to have a role in the development of breast cancer, but the penetrance is a lot lower and may be affected by other background genetic information that isn’t fully testable or known at this time. So, instead of an 80% lifetime risk for breast cancer, some of these will have a much lower lifetime risk, say 30%. Well, that would still be twice the average, but it doesn’t mean that you’re necessarily destined to develop breast cancer. The first thing to say is that when you start adding lower penetrant genes, it makes the decision making afterwards more complicated because it’s harder to tell the patient what she should really expect in terms of what her risk is.

The second is that mutations in these genes often come scattered through the genes. Some of them are clearly pathological mutations, and some of these are these variants of unknown significance. Again, with BRCA1 and BRCA2, and some of the other hereditary syndromes, we have a pretty good idea of which the significant mutations are. For these other lesser penetrant genes, it’s not immediately so obvious where the mutations that are problematic lie.

The third is, how would you manage such patients? Would you do prophylactic surgery? Would you do surveillance? And, again, we have a lot less information for some of these less penetrant, less frequent gene mutations. So, that’s where I think charting the information becomes really helpful. And patients are going to have to learn to adapt to a situation where you’re going to acquire information and more meaning for that information, more for that genetic data will emerge over time as we continue to build these.

In terms of the actual platforms, there are a bunch of companies that are developing several of these panels. For the most part, the quality of all of these has been excellent and the actual genetic testing is something of a commodity. It’s not technically that hard, if you run a genetics lab, to do this. What really features into it is putting the right panel together for a specific patient because there are patients where you want to look at one set of genes versus another. There should, in theory, in a free market be some price competition between these, and that may affect the choice that people make. And then finally, some of the companies have done a really good job of building up a repository of the genetic information to help actually explain what the mutations mean, and that’s another value-added product that some of the panels come with.

Claudine Isaacs, MD: When we’re faced with all these choices of different companies for testing, it’s complex decision making. I think for me this speaks again to the concept of having genetic specialists involved. Honestly, as a clinician, that’s not something that we have a lot of experience with and a lot of background in. The companies differ in terms of some of the techniques that they use. Some of the things that we really want to be aware of is, what do they do if they find a variant? How robust is their system for identifying whether that variant is truly a deleterious mutation or if it’s a variant that is inconsequential, a benign polymorphism, or if it’s a variant of uncertain significance? And if it’s a variant of uncertain significance, what are the techniques and how do they manage things in terms of reclassifying that variant? How would they approach that?

If a deleterious mutation is found, if the company is doing next-generation sequencing. Most multigene panels are done by doing next-generation sequencing. Typically the company should then use a second methodology, often Sanger sequencing, to confirm that mutation. So, those are some of the other things that go into it. Again for me, as I mentioned previously, this is one of the reasons why I rely so much on our genetic counselors to help us figure out which companies are really the reputable companies that have the depth of experience in this and who really use stringent techniques for assessing the findings from the testing.


Transcript Edited for Clarity
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Transcript:

Adam M. Brufsky, MD, PhD:
The ones, at least the most commonly used commercial panels, that I’m familiar with and I tend to kind of consider using in my practice are the Invitae panel, Myriad’s My Risk panel, and Gene DX’s panel. And they’re all somewhat different in a few of the genes that they cover and in the turnaround time that they give. The real difference is what each individual company’s annotation of their genes are. What I mean by that is, for example, Invitae may have a different annotation for their deleterious mutations than Myriad may have. And so for that reason, I think it’s important when someone looks at these panels that they ask, what is your percentage, for example, of variants of unknown significance? The key here is that we’re going to find a lot of variants. For a lot of them, we have no idea what they are. Maybe if you had some experience in molecular biology and kind-of guessed as to what that mutation is… But a lot of us don’t have that experience. So, you really have to trust what each individual company has done in terms of the annotation of their variants of unknown significance. And I think that’s probably the biggest thing that separates a lot of these companies, aside from turnaround times and cost. That to me I think is really the big one.

Harold J. Burstein, MD, PhD: When they’re putting together panels for genetic testing, they typically include genes that have different roles right now in our understanding of hereditary breast cancer. Obviously, there’s BRCA1 and BRCA2, highly penetrant genes where specific mutations have been identified that predispose to cancer and where we have a lot of background information. Then there are these rare genetic syndromes beyond BRCA1 and BRCA2, we’ve mentioned them briefly—Li-Fraumeni syndrome, hereditary diffuse gastric cancer, and lobular breast cancer—where we have a specific gene in mind. And if you find an abnormality there that tracks with a family history, you have a good insight.

The next wave of genes includes a variety of tumor suppressor genes and other genes that have identified large numbers of cases. PALB2, and CHEK2, and ataxia-telangiectasia-mutated genes do clearly seem to have a role in the development of breast cancer, but the penetrance is a lot lower and may be affected by other background genetic information that isn’t fully testable or known at this time. So, instead of an 80% lifetime risk for breast cancer, some of these will have a much lower lifetime risk, say 30%. Well, that would still be twice the average, but it doesn’t mean that you’re necessarily destined to develop breast cancer. The first thing to say is that when you start adding lower penetrant genes, it makes the decision making afterwards more complicated because it’s harder to tell the patient what she should really expect in terms of what her risk is.

The second is that mutations in these genes often come scattered through the genes. Some of them are clearly pathological mutations, and some of these are these variants of unknown significance. Again, with BRCA1 and BRCA2, and some of the other hereditary syndromes, we have a pretty good idea of which the significant mutations are. For these other lesser penetrant genes, it’s not immediately so obvious where the mutations that are problematic lie.

The third is, how would you manage such patients? Would you do prophylactic surgery? Would you do surveillance? And, again, we have a lot less information for some of these less penetrant, less frequent gene mutations. So, that’s where I think charting the information becomes really helpful. And patients are going to have to learn to adapt to a situation where you’re going to acquire information and more meaning for that information, more for that genetic data will emerge over time as we continue to build these.

In terms of the actual platforms, there are a bunch of companies that are developing several of these panels. For the most part, the quality of all of these has been excellent and the actual genetic testing is something of a commodity. It’s not technically that hard, if you run a genetics lab, to do this. What really features into it is putting the right panel together for a specific patient because there are patients where you want to look at one set of genes versus another. There should, in theory, in a free market be some price competition between these, and that may affect the choice that people make. And then finally, some of the companies have done a really good job of building up a repository of the genetic information to help actually explain what the mutations mean, and that’s another value-added product that some of the panels come with.

Claudine Isaacs, MD: When we’re faced with all these choices of different companies for testing, it’s complex decision making. I think for me this speaks again to the concept of having genetic specialists involved. Honestly, as a clinician, that’s not something that we have a lot of experience with and a lot of background in. The companies differ in terms of some of the techniques that they use. Some of the things that we really want to be aware of is, what do they do if they find a variant? How robust is their system for identifying whether that variant is truly a deleterious mutation or if it’s a variant that is inconsequential, a benign polymorphism, or if it’s a variant of uncertain significance? And if it’s a variant of uncertain significance, what are the techniques and how do they manage things in terms of reclassifying that variant? How would they approach that?

If a deleterious mutation is found, if the company is doing next-generation sequencing. Most multigene panels are done by doing next-generation sequencing. Typically the company should then use a second methodology, often Sanger sequencing, to confirm that mutation. So, those are some of the other things that go into it. Again for me, as I mentioned previously, this is one of the reasons why I rely so much on our genetic counselors to help us figure out which companies are really the reputable companies that have the depth of experience in this and who really use stringent techniques for assessing the findings from the testing.


Transcript Edited for Clarity
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