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Detecting Somatic BRCA1/2 Mutations in Ovarian Cancer

Panelists: Bradley J. Monk, MD, FACOG, FACS, University of Arizona; Creighton University School of Medicine; Arizona Oncology; Kathleen N. Moore, MD, University of Oklahoma; Elena S. Ratner, MD, Yale University School of Medicine; Brian M. Slomovitz, MD, Sylvester Comprehensive Cancer Center, University of Miami Health System
Published: Monday, May 20, 2019



Transcript: 

Bradley J. Monk, MD, FACOG, FACS: You’re our NCCN [National Comprehensive Cancer Network] expert today.

Elena S. Ratner, MD: I’m not allowed to say.

Bradley J. Monk, MD, FACOG, FACS: The first controversy was there were only 2 somatic BRCAs in that cohort. We didn’t know whether we were going to get an all-comer germline and somatic indication by the FDA and we did. But the NCCN triaged those with a level 1 for germline but a level 2A for somatic. What do you think about that?

Elena S. Ratner, MD: Level 2A, almost 1. Very close to 1.

Bradley J. Monk, MD, FACOG, FACS: Level 2A and a half.

Elena S. Ratner, MD: What is the difference in germline and somatic? So far we see very similar responses in somatic and germline patients, but we don’t know for sure. Again, the nature of these mutations is a bit different. So I think at this point we don’t know for sure whether somatic mutations will behave exactly the same as germline mutations.

Brian M. Slomovitz, MD: But that’s where the committee is sitting around and they’re coming up, based on the strongest and less strong recommendations…. The bottom line is, if I have a patient in my practice who has a somatic BRCA mutation in the first-line, they’re going to get olaparib.

Kathleen N. Moore, MD: Of course.

Bradley J. Monk, MD, FACOG, FACS: Even if they started on bevacizumab, you’re probably going to stop the bevacizumab, right?

Brian M. Slomovitz, MD: Closest thing is it would be unethical not to.

Kathleen N. Moore, MD: Yes, I agree.

Brian M. Slomovitz, MD: Again, we’re talking about cures in ovarian cancer, which we’ve never done before.

Bradley J. Monk, MD, FACOG, FACS: I agree with you. So, Katie, in the FDA approval on December 19th, there was such a sense of urgency by the FDA that there was no companion diagnostic, at least at that time, and this time for somatic. So how do you recommend that people test for somatic and certainly when? I can answer the when—early. But what’s the best way to test for somatic BRCA?

Kathleen N. Moore, MD: I think that’s the conversation that’s happening right now, which is great. We’re having the conversation. Really, any CLIA [Clinical Laboratory Improvement Amendments]-approved test qualifies. They all have slightly different call coverage and variant classification, but overall, you’re getting the majority of your somatic mutations. You’re going to get your germline and your somatic—most of them, not all of your germline—with really any of the next-generation panels that are CLIA-approved and out there. So I think the controversy right now, and we discussed this at SGO [the Society of Gynecologic Oncology meeting], is: Do you start with a germline test in everybody, which would be the most accurate in finding all of your germlines? And then, if it’s negative, do you do a somatic to find the 7% somatic? Or do you start with a somatic test, which will catch 95% of your germlines and all of your somatics and then reflex the germline?

Bradley J. Monk, MD, FACOG, FACS: No, of course not, because it’s not just about BRCA testing. It’s a panel.

Kathleen N. Moore, MD: Absolutely.

Bradley J. Monk, MD, FACOG, FACS: So you have to do germline testing. Don’t give me this thing where you’re going to test the tumor first, and if the tumor is negative, I’m going to forget about germline. We have to really make that go away.

Kathleen N. Moore, MD: I’m not arguing for that. I’m just saying....

Brian M. Slomovitz, MD: Excuse me, but I’m not so sure.

Bradley J. Monk, MD, FACOG, FACS: Tell me.

Brian M. Slomovitz, MD: The difference in somatic testing and germline testing, and I agree with Katie’s numbers about you’ll get the 7% here or you’ll miss out on the 5%, but the difference is compliance. If we could test the patients and we have their tumor, we can get them tested. Different institutions have different policies as far as germline testing. With some institutions, you have to go see a genetic counselor.

Bradley J. Monk, MD, FACOG, FACS: I’m sorry for that. That’s the best way to not get a germline test: To send them to the genetic counselor. Every patient needs to be counseled, but it’s the site of contact. Don’t send them away and hope it works out.

Brian M. Slomovitz, MD: But my compliance rate with somatic testing is 100%.

Kathleen N. Moore, MD: Because you control it.

Brian M. Slomovitz, MD: I control it, right.

Elena S. Ratner, MD: But it’s also cost. It’s much more expensive to do somatic testing than it is to do germline testing.

Bradley J. Monk, MD, FACOG, FACS: So actually it’s not that complicated either. There are vendors that do germline testing that, at the same time and for the same cost, will do cell-free DNA, liquid biopsy. Same cost, same test. I’m not going to tell you who the vendor is, but you guys can figure it out. And if you like to use a vendor that doesn’t have cell-free DNA, then you can order the cell-free DNA. But I think the easiest way to get somatic, and I’m trying to be very practical here, is cell-free DNA. It’s a CLIA-approved lab. It will give you the somatic information. It’s not 100% from the somatic because they have to wrestle the DNA away from the pathologist, but I can have her in my office and I can draw the same needle in her arm and I can get germline and somatic with cell-free DNA. What do you think of that?

Kathleen N. Moore, MD: We’ll have to look at cost, and I don’t think that has quite been validated in comparison. So I think that has to be proven. But that being said, I agree with the sentiment of what Brian said.

Bradley J. Monk, MD, FACOG, FACS: I do too.

Kathleen N. Moore, MD: We are so bad right now in the United States with all of our resources at actually testing our patients. SOLO-1 is amazing, number 1. But the number 2 good thing about SOLO-1 is it’s going to make people demand to be tested. Patients are not going to stand to not be tested, and people will get in trouble if they don’t understand that. If we do somatic testing on 100% or germline on 100% and we get to that point, then we can sort out the nuances of the 5% and 7% once we’re there. But we have a long way to go. I do like your ideas that there are individual hospitals and then there are large healthcare systems that are going to make algorithm decisions right now.

Bradley J. Monk, MD, FACOG, FACS: I agree.

Brian M. Slomovitz, MD: Right.

Kathleen N. Moore, MD: And so, while I agree with the sentiment, I think we’re going to have to come up with what we think is the best plan right now, or it’s going to be inbred in several very large healthcare systems, which is great because they’re going to test a lot of patients, but we want to do the right tests.

Brian M. Slomovitz, MD: But now’s the time we have to work with our payers regardless of how you do it. Brad, you described a blood test. My patients, germline, spit in a cup. Somatic, they take tumor. So there’s no blood test.

Bradley J. Monk, MD, FACOG, FACS: They don’t get a CA-125 [cancer antigen 125 test]? That’s blood, brother. There’s no saliva CA-125.

Brian M. Slomovitz, MD: But the bottom line is, we’ve got to work with our payers. We have to work with our payers, and now’s the time we have to get our patients tested.

Bradley J. Monk, MD, FACOG, FACS: I agree. Elena, in your practice, you can’t use olaparib in the frontline maintenance unless you do a BRCA test and it’s positive. What are the techniques and tricks that you’ve learned to maximize testing rates?

Elena S. Ratner, MD: I think anybody who does not test their patients in the primary setting is practicing mismanagement. Right now, thanks to Dr Moore’s study, I think it’s such an incredible advance that we have. Anything less than that is just wrong. We do a combination; we do both germline and somatic. But I also have to mention that the FDA, if you read carefully, says anybody who you believe has a BRCA mutation, and I believe a lot of my people have BRCA mutations.

Bradley J. Monk, MD, FACOG, FACS: That’s funny.

Kathleen N. Moore, MD: That’s a good one.

Transcript Edited for Clarity

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Transcript: 

Bradley J. Monk, MD, FACOG, FACS: You’re our NCCN [National Comprehensive Cancer Network] expert today.

Elena S. Ratner, MD: I’m not allowed to say.

Bradley J. Monk, MD, FACOG, FACS: The first controversy was there were only 2 somatic BRCAs in that cohort. We didn’t know whether we were going to get an all-comer germline and somatic indication by the FDA and we did. But the NCCN triaged those with a level 1 for germline but a level 2A for somatic. What do you think about that?

Elena S. Ratner, MD: Level 2A, almost 1. Very close to 1.

Bradley J. Monk, MD, FACOG, FACS: Level 2A and a half.

Elena S. Ratner, MD: What is the difference in germline and somatic? So far we see very similar responses in somatic and germline patients, but we don’t know for sure. Again, the nature of these mutations is a bit different. So I think at this point we don’t know for sure whether somatic mutations will behave exactly the same as germline mutations.

Brian M. Slomovitz, MD: But that’s where the committee is sitting around and they’re coming up, based on the strongest and less strong recommendations…. The bottom line is, if I have a patient in my practice who has a somatic BRCA mutation in the first-line, they’re going to get olaparib.

Kathleen N. Moore, MD: Of course.

Bradley J. Monk, MD, FACOG, FACS: Even if they started on bevacizumab, you’re probably going to stop the bevacizumab, right?

Brian M. Slomovitz, MD: Closest thing is it would be unethical not to.

Kathleen N. Moore, MD: Yes, I agree.

Brian M. Slomovitz, MD: Again, we’re talking about cures in ovarian cancer, which we’ve never done before.

Bradley J. Monk, MD, FACOG, FACS: I agree with you. So, Katie, in the FDA approval on December 19th, there was such a sense of urgency by the FDA that there was no companion diagnostic, at least at that time, and this time for somatic. So how do you recommend that people test for somatic and certainly when? I can answer the when—early. But what’s the best way to test for somatic BRCA?

Kathleen N. Moore, MD: I think that’s the conversation that’s happening right now, which is great. We’re having the conversation. Really, any CLIA [Clinical Laboratory Improvement Amendments]-approved test qualifies. They all have slightly different call coverage and variant classification, but overall, you’re getting the majority of your somatic mutations. You’re going to get your germline and your somatic—most of them, not all of your germline—with really any of the next-generation panels that are CLIA-approved and out there. So I think the controversy right now, and we discussed this at SGO [the Society of Gynecologic Oncology meeting], is: Do you start with a germline test in everybody, which would be the most accurate in finding all of your germlines? And then, if it’s negative, do you do a somatic to find the 7% somatic? Or do you start with a somatic test, which will catch 95% of your germlines and all of your somatics and then reflex the germline?

Bradley J. Monk, MD, FACOG, FACS: No, of course not, because it’s not just about BRCA testing. It’s a panel.

Kathleen N. Moore, MD: Absolutely.

Bradley J. Monk, MD, FACOG, FACS: So you have to do germline testing. Don’t give me this thing where you’re going to test the tumor first, and if the tumor is negative, I’m going to forget about germline. We have to really make that go away.

Kathleen N. Moore, MD: I’m not arguing for that. I’m just saying....

Brian M. Slomovitz, MD: Excuse me, but I’m not so sure.

Bradley J. Monk, MD, FACOG, FACS: Tell me.

Brian M. Slomovitz, MD: The difference in somatic testing and germline testing, and I agree with Katie’s numbers about you’ll get the 7% here or you’ll miss out on the 5%, but the difference is compliance. If we could test the patients and we have their tumor, we can get them tested. Different institutions have different policies as far as germline testing. With some institutions, you have to go see a genetic counselor.

Bradley J. Monk, MD, FACOG, FACS: I’m sorry for that. That’s the best way to not get a germline test: To send them to the genetic counselor. Every patient needs to be counseled, but it’s the site of contact. Don’t send them away and hope it works out.

Brian M. Slomovitz, MD: But my compliance rate with somatic testing is 100%.

Kathleen N. Moore, MD: Because you control it.

Brian M. Slomovitz, MD: I control it, right.

Elena S. Ratner, MD: But it’s also cost. It’s much more expensive to do somatic testing than it is to do germline testing.

Bradley J. Monk, MD, FACOG, FACS: So actually it’s not that complicated either. There are vendors that do germline testing that, at the same time and for the same cost, will do cell-free DNA, liquid biopsy. Same cost, same test. I’m not going to tell you who the vendor is, but you guys can figure it out. And if you like to use a vendor that doesn’t have cell-free DNA, then you can order the cell-free DNA. But I think the easiest way to get somatic, and I’m trying to be very practical here, is cell-free DNA. It’s a CLIA-approved lab. It will give you the somatic information. It’s not 100% from the somatic because they have to wrestle the DNA away from the pathologist, but I can have her in my office and I can draw the same needle in her arm and I can get germline and somatic with cell-free DNA. What do you think of that?

Kathleen N. Moore, MD: We’ll have to look at cost, and I don’t think that has quite been validated in comparison. So I think that has to be proven. But that being said, I agree with the sentiment of what Brian said.

Bradley J. Monk, MD, FACOG, FACS: I do too.

Kathleen N. Moore, MD: We are so bad right now in the United States with all of our resources at actually testing our patients. SOLO-1 is amazing, number 1. But the number 2 good thing about SOLO-1 is it’s going to make people demand to be tested. Patients are not going to stand to not be tested, and people will get in trouble if they don’t understand that. If we do somatic testing on 100% or germline on 100% and we get to that point, then we can sort out the nuances of the 5% and 7% once we’re there. But we have a long way to go. I do like your ideas that there are individual hospitals and then there are large healthcare systems that are going to make algorithm decisions right now.

Bradley J. Monk, MD, FACOG, FACS: I agree.

Brian M. Slomovitz, MD: Right.

Kathleen N. Moore, MD: And so, while I agree with the sentiment, I think we’re going to have to come up with what we think is the best plan right now, or it’s going to be inbred in several very large healthcare systems, which is great because they’re going to test a lot of patients, but we want to do the right tests.

Brian M. Slomovitz, MD: But now’s the time we have to work with our payers regardless of how you do it. Brad, you described a blood test. My patients, germline, spit in a cup. Somatic, they take tumor. So there’s no blood test.

Bradley J. Monk, MD, FACOG, FACS: They don’t get a CA-125 [cancer antigen 125 test]? That’s blood, brother. There’s no saliva CA-125.

Brian M. Slomovitz, MD: But the bottom line is, we’ve got to work with our payers. We have to work with our payers, and now’s the time we have to get our patients tested.

Bradley J. Monk, MD, FACOG, FACS: I agree. Elena, in your practice, you can’t use olaparib in the frontline maintenance unless you do a BRCA test and it’s positive. What are the techniques and tricks that you’ve learned to maximize testing rates?

Elena S. Ratner, MD: I think anybody who does not test their patients in the primary setting is practicing mismanagement. Right now, thanks to Dr Moore’s study, I think it’s such an incredible advance that we have. Anything less than that is just wrong. We do a combination; we do both germline and somatic. But I also have to mention that the FDA, if you read carefully, says anybody who you believe has a BRCA mutation, and I believe a lot of my people have BRCA mutations.

Bradley J. Monk, MD, FACOG, FACS: That’s funny.

Kathleen N. Moore, MD: That’s a good one.

Transcript Edited for Clarity
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