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BRCA Testing for Ovarian Cancer

Panelists: Bradley J. Monk, MD, University of Arizona and Creighton University School of Medicine at St. Joseph’s Hospital; Robert L. Coleman, MD, MD Anderson Cancer Center; Thomas Herzog, MD, University of Cincinnati; Kathleen N. Moore, MD, Stephenson Cancer Center; Angeles Alvarez Secord, MD, Duke University School of Medicine
Published: Tuesday, Jan 24, 2017


Transcript:

Bradley J. Monk, MD:
So, Angeles, I think that was very helpful, and I appreciate that. Let’s define some of these terms because they’re so important. BRCA repairs double-stranded DNA breaks, and other genes involved in that create difficulty in repairing double-stranded DNA breaks. That’s called homologous recombination repair deficiency (HRD). Tom, we haven’t gotten you involved yet. How do we test patients for BRCA or HRD? What’s the current state-of-the-art in molecular testing in epithelial ovarian cancer?

Thomas Herzog, MD: Well, there are a lot of ways of approaching. Currently, it’s recommended that all epithelial ovarian cancers are tested, and that’s with a blood test. That would be germline testing that goes on.

Bradley J. Monk, MD: Test for what now?

Thomas Herzog, MD: Testing for BRCA. Now, there are also others who are raising the hypothesis that perhaps we should be testing the tumor as well and then reflexing. So, there are a lot of different things out there, but I think the important take-home message here is that we recommend that all women who have an epithelial ovarian cancer get tested, and there are several implications from that. Obviously, it has prognostic implications in terms of how the patient is going to do; they’re going to do better. And now we have drugs that are available, either approved or on clinical trial for treatment. Of course, you have the concern of what this means for the family at large, so there is cascade testing for other members of the family in terms of carriers for BRCA, which has significant implications in terms of risk reduction strategies.

Bradley J. Monk, MD: I’m always struck when I see a patient in consultation that’s had epithelial ovarian cancer for a long time and she has never been BRCA tested, even though there’s ASCO, Society of Gynecologic Oncology, and NCCN level 1 evidence for testing. The idea of testing the tumor is new. Those are certainly somatic mutations, but also germline mutations. If a woman has a germline mutation, obviously the tumor has it, too. But the opposite is not true. So, you could have a tumor mutation, but have it not be germline. Tell us about somatic or tumor testing. Are you doing that yet, Katie?

Kathleen N. Moore, MD: Actually, there was a test that was just approved on December 5th. We can now test for homologous recombination deficiency through sending a sample of tissue or tumor in, and they’ll run this homologous recombination deficiency test and give you a score that your patient is positive or negative. So, it won’t tell you a specific somatic mutation, but if you have a somatic BRCA mutation or another important somatic mutation in the DNA repair pathway, you’re going to show up in that homologous recombination–positive group. And that could someday potentially reflex you to a germline test. I don’t think we’re there yet, but that’s one test that’s now available to do.

Bradley J. Monk, MD: So, I know what to do with a germline mutation. The genetic counselor is involved, and we deal with their kindred and risk-reducing surgery. I tell her that her prognosis is better if she’s germline-mutated, and I try to get her in a clinical trial. What do I do with an HRD test? I get that it exists. What do I do with that now?

Robert L. Coleman, MD: I think a key point that was brought up here is that it’s probably more important right now to just understand that the machinery is messed up, so that the ability of a cancer cell to fix itself…

Bradley J. Monk, MD: There are double-stranded DNA breaks.

Robert L. Coleman, MD: Right. That then becomes a vulnerability you could take advantage of if you can promote that in the cancer cell. So, that’s the idea of the whole synthetic lethality that we talk about in the context of the PARP inhibitors. But it applies across other things. Anything that can cause DNA damage with an imperfect repair mechanism can lead to lethality. And so, that’s why we see some better outcomes, prognostically and predictively, about using drugs that have direct DNA damaging, like platinum, liposomal doxorubicin, and other DNA-damaging agents that actually produce better outcomes than expected in the same patient population.

Bradley J. Monk, MD: So, Angeles, what’s the connection then to PARP and BRCA or HRD?

Angeles Alvarez Secord, MD: Well, we’re going to a whole next step, but this is a great conversation and a great question. What happens here, and Rob alluded to this, is something called “synthetic lethality.” If somebody has that BRCA mutation, whether it’s germline or somatic, or they have another defect that’s causing this loss of homologous recombination, then the cells can’t repair themselves once they’re subjected to a DNA-damaging event. That’s where the PARP inhibitor comes in. So, you have the cell that can’t repair itself because of this HRD, then you add the PARP inhibitor and you block another mechanism of DNA repair and are much more likely to shuttle that cell toward an apoptotic or death pathway.

Bradley J. Monk, MD: So, PARP inhibitors inhibit single-stranded breaks. If you can’t repair single-stranded breaks, you get a double-stranded break. And if you have BRCA or a BRCA-like gene, you can’t repair the double-stranded break, the cell dies, and that concept is synthetic lethality.

Robert L. Coleman, MD: I think that’s the general cartoon that we all have in our mind; it’s the easiest thing to understand. But I think it would be minimizing the science if we didn’t say that there were multiple other mechanisms involved with that. And so, one that I find quite interesting is that PARP actually regulates a poor fidelity pathway of DNA repair called nonhomologous end-joining. When you inhibit PARP, it actually takes the brakes off of that, and so that there’s preferentially a line of development that goes down into that nonhomologous end-joining pathway, where more mistakes can be made. So, there are other options.

Thomas Herzog, MD: I think there are 2 things to emphasize here. We talk about DNA damage and how many times the cell has to address this. The modeling I’ve seen is amazing in terms of the number of times in a day that you have to address this.

Bradley J. Monk, MD: It depends on how much alcohol you drink. Does that constitute any damage?

Thomas Herzog, MD: That certainly could be related. A number of environmental issues could certainly be related. To Rob’s point, the repair takes place. It’s just that you shift from a high-fidelity to a lower-fidelity system with the nonhomologous end-joining, for example. But there are other pathways as well.

Bradley J. Monk, MD: And I’m struck by the idea that in these HRD cells, because the fidelity is not high, there may be more neoantigens, and it may be an opportunity for immunotherapy.

Thomas Herzog, MD: That’s right.

Transcript Edited for Clarity
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Transcript:

Bradley J. Monk, MD:
So, Angeles, I think that was very helpful, and I appreciate that. Let’s define some of these terms because they’re so important. BRCA repairs double-stranded DNA breaks, and other genes involved in that create difficulty in repairing double-stranded DNA breaks. That’s called homologous recombination repair deficiency (HRD). Tom, we haven’t gotten you involved yet. How do we test patients for BRCA or HRD? What’s the current state-of-the-art in molecular testing in epithelial ovarian cancer?

Thomas Herzog, MD: Well, there are a lot of ways of approaching. Currently, it’s recommended that all epithelial ovarian cancers are tested, and that’s with a blood test. That would be germline testing that goes on.

Bradley J. Monk, MD: Test for what now?

Thomas Herzog, MD: Testing for BRCA. Now, there are also others who are raising the hypothesis that perhaps we should be testing the tumor as well and then reflexing. So, there are a lot of different things out there, but I think the important take-home message here is that we recommend that all women who have an epithelial ovarian cancer get tested, and there are several implications from that. Obviously, it has prognostic implications in terms of how the patient is going to do; they’re going to do better. And now we have drugs that are available, either approved or on clinical trial for treatment. Of course, you have the concern of what this means for the family at large, so there is cascade testing for other members of the family in terms of carriers for BRCA, which has significant implications in terms of risk reduction strategies.

Bradley J. Monk, MD: I’m always struck when I see a patient in consultation that’s had epithelial ovarian cancer for a long time and she has never been BRCA tested, even though there’s ASCO, Society of Gynecologic Oncology, and NCCN level 1 evidence for testing. The idea of testing the tumor is new. Those are certainly somatic mutations, but also germline mutations. If a woman has a germline mutation, obviously the tumor has it, too. But the opposite is not true. So, you could have a tumor mutation, but have it not be germline. Tell us about somatic or tumor testing. Are you doing that yet, Katie?

Kathleen N. Moore, MD: Actually, there was a test that was just approved on December 5th. We can now test for homologous recombination deficiency through sending a sample of tissue or tumor in, and they’ll run this homologous recombination deficiency test and give you a score that your patient is positive or negative. So, it won’t tell you a specific somatic mutation, but if you have a somatic BRCA mutation or another important somatic mutation in the DNA repair pathway, you’re going to show up in that homologous recombination–positive group. And that could someday potentially reflex you to a germline test. I don’t think we’re there yet, but that’s one test that’s now available to do.

Bradley J. Monk, MD: So, I know what to do with a germline mutation. The genetic counselor is involved, and we deal with their kindred and risk-reducing surgery. I tell her that her prognosis is better if she’s germline-mutated, and I try to get her in a clinical trial. What do I do with an HRD test? I get that it exists. What do I do with that now?

Robert L. Coleman, MD: I think a key point that was brought up here is that it’s probably more important right now to just understand that the machinery is messed up, so that the ability of a cancer cell to fix itself…

Bradley J. Monk, MD: There are double-stranded DNA breaks.

Robert L. Coleman, MD: Right. That then becomes a vulnerability you could take advantage of if you can promote that in the cancer cell. So, that’s the idea of the whole synthetic lethality that we talk about in the context of the PARP inhibitors. But it applies across other things. Anything that can cause DNA damage with an imperfect repair mechanism can lead to lethality. And so, that’s why we see some better outcomes, prognostically and predictively, about using drugs that have direct DNA damaging, like platinum, liposomal doxorubicin, and other DNA-damaging agents that actually produce better outcomes than expected in the same patient population.

Bradley J. Monk, MD: So, Angeles, what’s the connection then to PARP and BRCA or HRD?

Angeles Alvarez Secord, MD: Well, we’re going to a whole next step, but this is a great conversation and a great question. What happens here, and Rob alluded to this, is something called “synthetic lethality.” If somebody has that BRCA mutation, whether it’s germline or somatic, or they have another defect that’s causing this loss of homologous recombination, then the cells can’t repair themselves once they’re subjected to a DNA-damaging event. That’s where the PARP inhibitor comes in. So, you have the cell that can’t repair itself because of this HRD, then you add the PARP inhibitor and you block another mechanism of DNA repair and are much more likely to shuttle that cell toward an apoptotic or death pathway.

Bradley J. Monk, MD: So, PARP inhibitors inhibit single-stranded breaks. If you can’t repair single-stranded breaks, you get a double-stranded break. And if you have BRCA or a BRCA-like gene, you can’t repair the double-stranded break, the cell dies, and that concept is synthetic lethality.

Robert L. Coleman, MD: I think that’s the general cartoon that we all have in our mind; it’s the easiest thing to understand. But I think it would be minimizing the science if we didn’t say that there were multiple other mechanisms involved with that. And so, one that I find quite interesting is that PARP actually regulates a poor fidelity pathway of DNA repair called nonhomologous end-joining. When you inhibit PARP, it actually takes the brakes off of that, and so that there’s preferentially a line of development that goes down into that nonhomologous end-joining pathway, where more mistakes can be made. So, there are other options.

Thomas Herzog, MD: I think there are 2 things to emphasize here. We talk about DNA damage and how many times the cell has to address this. The modeling I’ve seen is amazing in terms of the number of times in a day that you have to address this.

Bradley J. Monk, MD: It depends on how much alcohol you drink. Does that constitute any damage?

Thomas Herzog, MD: That certainly could be related. A number of environmental issues could certainly be related. To Rob’s point, the repair takes place. It’s just that you shift from a high-fidelity to a lower-fidelity system with the nonhomologous end-joining, for example. But there are other pathways as well.

Bradley J. Monk, MD: And I’m struck by the idea that in these HRD cells, because the fidelity is not high, there may be more neoantigens, and it may be an opportunity for immunotherapy.

Thomas Herzog, MD: That’s right.

Transcript Edited for Clarity
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Online CME Activities
TitleExpiration DateCME Credits
Oncology Best Practice™: Expert Perspectives to Incorporate Evidence on PARP Inhibitors into Practice and Optimize the Medical Management of Ovarian CancerOct 31, 20181.0
Community Practice Connections™: Precision Medicine for Community Oncologists: Assessing the Role of Tumor-Testing Technologies in Cancer CareNov 30, 20181.0
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