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BRCA1/2 Status and Homologous Repair Deficiency in TNBC

Panelists: Adam M. Brufsky, MD, PhD, University of Pittsburgh School of Medicine; Mark E. Robson, MD, Memorial Sloan Kettering Cancer Center; Aditya Bardia, MD, MPH, Massachusetts General Hospital Cancer Center; Kimberly L. Blackwell, MD, Duke Cancer Institute
Published: Thursday, Mar 23, 2017



Transcript:

Adam M. Brufsky, MD, PhD:
Let’s move on to the last topic, which I think is a good one. I think the management of triple-negative breast cancer is tough. I think we all would agree to that. It’s a real challenge. We’ve got great drugs that give us decent responses and decent progression-free survivals with the HER2, as well as with the estrogen receptor-positive subsets of breast cancer. But we’re left with triple negative, which I guess we’re learning over the last couple of years is really probably a collection of multiple different diseases. The first part of it is that piece of disease, that piece of the triple-negative pie that’s BRCA1-mutated. Do you want to talk about that? I guess my first question for you before you even get into BROCADE and some of these other studies is, what would drive you? Someone walks in the door with triple-negative breast cancer, will you just go by the strict genomic criteria to decide whether to test her for BRCA or will you just test her out of hand?

Mark E. Robson, MD: The NCCN criteria are anybody under age 60, which is pretty reasonable. I think an Ashkenazi Jewish woman you could potentially even go up even older than that, although you still have a relatively rare pickup even in that subset. We’re extremely liberal about testing people at this point, both somatically and in germline.

Adam M. Brufsky, MD, PhD: So, a 65-year-old woman walks in with metastatic triple-negative breast cancer and has no real family history, will that drive you to test her?

Mark E. Robson, MD: Not necessarily. Because if she’s Jewish, you can test her, but if she’s not Jewish and on Medicare, you probably won’t be able to do it.

Adam M. Brufsky, MD, PhD: Right, even though that may help? Let’s talk about BROCADE. Let’s talk about some of these trials. Can you describe BROCADE to people first?

Mark E. Robson, MD: So, BROCADE was a randomized phase II trial. It was actually a 3-arm trial in individuals who had germline deleterious or likely deleterious BRCA mutations. And they were randomized to get either carboplatin (Taxol) with veliparib, which is a modestly potent PARP inhibitor, or placebo. Then, the third arm was temozolomide plus veliparib, which was an open-label combination. The temozolomide/veliparib arm had about 30% clinical benefit rate, which is more than we had seen with temozolomide alone in the past. And whether that’s due to the predictive preclinical interaction or whether that’s just single agent PARP inhibitor activity, it’s hard to say. But, in the randomized component, which was the subject of the report, there was a numerical difference—it wasn’t statistically significant—in progression-free survival. And there was a better response rate in the women who got the investigational drug, but it didn’t translate into anything from the clinical perspective. In other words, there wasn’t a significant progression-free survival advantage.

From the surprising standpoint, there wasn’t really an increment in toxicity either because combinations with PARP inhibitors have been a little tricky, particularly for chemotherapy plus PARP, because of myelosuppression. But, in this case, there didn’t appear to be a substantial difference. In one sense, it was a little bit disappointing. In another sense, it’s not really a test of potential benefit of PARP inhibitors in that setting, which is as single-agent therapy rather than as chemotherapy-sensitizers.

Adam M. Brufsky, MD, PhD: But these patients weren’t selected though for BRCA.

Mark E. Robson, MD: In this study, they were.

Adam M. Brufsky, MD, PhD: They were? I thought they were not.

Mark E. Robson, MD: In BROCADE, they were. There’s a neoadjuvant trial, which was triple-negative disease. There’s an I-SPY component, which was triple-negative disease where they weren’t selected, and that was the second study you described.

Adam M. Brufsky, MD, PhD: I’d like to hear about it because I was fascinated by that, that potentially you have potential multigene panels that could select who would benefit from this therapy or not. Could you describe that?

Mark E. Robson, MD: So, there has been this whole idea that cells that lack functional BRCA have issues with repairing double-stand DNA breaks, and you can identify those through a particular signature of genomic damage, genomic scars, and it’s referred to as “BRCAness.” The hope is that cancers in some patients arising without BRCA mutations will have similar defects that will allow them to be sensitive to either PARP inhibition or platinum-based therapy. And there are a reasonable amount of data in ovarian cancer that that’s the case for a meaningful proportion of patients with ovarian cancer. Whether or not that’s the case for breast cancer isn’t clear, and so a number of people have been trying to identify biomarkers of what they are assuming is this DNA damage repair defect, but is actually a readout for sensitivity in different kinds of therapy. So, this arm of I-SPY was a combination of veliparib with a standard chemotherapy backbone, and they were searching for predictors. They had this PARP7 gene signature, which they thought was predictive. That obviously needs to be validated in another setting, and whether that translates into anything meaningful in the clinical setting is not clear because other attempts to look at this, like Andy Tutt’s TNT study, were kind of disappointing. Using commercially available HR assays and other more investigational things, like BRCA1 methylation or mRNA silencing, weren’t able to identify, in the somatic setting, predictors of sensitivity to platinum therapy, which is very similar to sensitivity to PARP.

Kimberly L. Blackwell, MD: And I just would put in a plug because there is a phase III study that will look at the addition of that PARP inhibitor. But there are lots of PARP inhibitors out there for BRCA mutation carriers. And what I’m seeing in my referral patterns is people, when they have a triple-negative, in particular BRCA, there’s a rush to putting them on a platinum chemotherapy and then sending them to a place for trial. I’m really trying to encourage referring physicians to think twice in the BRCA mutation carriers and try to get them on a study before they utilize a platinum-based agent because for the most part, I’d say in over half of the BRCA mutation randomized studies, you can’t have received a platinum. So, just to be a little bit more thoughtful. And all of these studies actually support the mutational testing, at least the ones we have open. And so, you ask if we would test a 65-year-old with first-line triple-negative. I probably would in the context of a screening for a clinical trial. I don’t think there’s any harm to doing that. Just be a little cautious about jumping on that platinum bandwagon in these BRCA mutation carriers without at least a clinicaltrials.gov search.

Adam M. Brufsky, MD, PhD: But, if there isn’t a clinical trial, do you believe the TNT data? Would you say that if someone is BRCA-mutated, you would prefer a platinum if a trial wasn’t available?

Kimberly L. Blackwell, MD: I believe the data, yes. And, at least in my BRCA mutation carriers, platinums are very active, but they’re going to be there second-line and third-line and really trying to get them. I think the data are quite supportive of the PARP inhibitors in this very unique population of patients.

Adam M. Brufsky, MD, PhD: Do you have anything to add about the MGH (Massachusetts General Hospital) version? Do you do BRCA testing on people with triple-negative that come in the door?

Aditya Bardia, MD, MPH: We do if there’s a reason to do BRCA testing in terms of either a clinical trial or you’re worried that the patient has high-risk for triple-negative and is in their 40s. So, I think if there’s a clinical indication to do BRCA testing or indication in terms of a clinical trial, we would consider that. But we don’t do it for everyone with triple-negative breast cancer.

Transcript Edited for Clarity

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Transcript:

Adam M. Brufsky, MD, PhD:
Let’s move on to the last topic, which I think is a good one. I think the management of triple-negative breast cancer is tough. I think we all would agree to that. It’s a real challenge. We’ve got great drugs that give us decent responses and decent progression-free survivals with the HER2, as well as with the estrogen receptor-positive subsets of breast cancer. But we’re left with triple negative, which I guess we’re learning over the last couple of years is really probably a collection of multiple different diseases. The first part of it is that piece of disease, that piece of the triple-negative pie that’s BRCA1-mutated. Do you want to talk about that? I guess my first question for you before you even get into BROCADE and some of these other studies is, what would drive you? Someone walks in the door with triple-negative breast cancer, will you just go by the strict genomic criteria to decide whether to test her for BRCA or will you just test her out of hand?

Mark E. Robson, MD: The NCCN criteria are anybody under age 60, which is pretty reasonable. I think an Ashkenazi Jewish woman you could potentially even go up even older than that, although you still have a relatively rare pickup even in that subset. We’re extremely liberal about testing people at this point, both somatically and in germline.

Adam M. Brufsky, MD, PhD: So, a 65-year-old woman walks in with metastatic triple-negative breast cancer and has no real family history, will that drive you to test her?

Mark E. Robson, MD: Not necessarily. Because if she’s Jewish, you can test her, but if she’s not Jewish and on Medicare, you probably won’t be able to do it.

Adam M. Brufsky, MD, PhD: Right, even though that may help? Let’s talk about BROCADE. Let’s talk about some of these trials. Can you describe BROCADE to people first?

Mark E. Robson, MD: So, BROCADE was a randomized phase II trial. It was actually a 3-arm trial in individuals who had germline deleterious or likely deleterious BRCA mutations. And they were randomized to get either carboplatin (Taxol) with veliparib, which is a modestly potent PARP inhibitor, or placebo. Then, the third arm was temozolomide plus veliparib, which was an open-label combination. The temozolomide/veliparib arm had about 30% clinical benefit rate, which is more than we had seen with temozolomide alone in the past. And whether that’s due to the predictive preclinical interaction or whether that’s just single agent PARP inhibitor activity, it’s hard to say. But, in the randomized component, which was the subject of the report, there was a numerical difference—it wasn’t statistically significant—in progression-free survival. And there was a better response rate in the women who got the investigational drug, but it didn’t translate into anything from the clinical perspective. In other words, there wasn’t a significant progression-free survival advantage.

From the surprising standpoint, there wasn’t really an increment in toxicity either because combinations with PARP inhibitors have been a little tricky, particularly for chemotherapy plus PARP, because of myelosuppression. But, in this case, there didn’t appear to be a substantial difference. In one sense, it was a little bit disappointing. In another sense, it’s not really a test of potential benefit of PARP inhibitors in that setting, which is as single-agent therapy rather than as chemotherapy-sensitizers.

Adam M. Brufsky, MD, PhD: But these patients weren’t selected though for BRCA.

Mark E. Robson, MD: In this study, they were.

Adam M. Brufsky, MD, PhD: They were? I thought they were not.

Mark E. Robson, MD: In BROCADE, they were. There’s a neoadjuvant trial, which was triple-negative disease. There’s an I-SPY component, which was triple-negative disease where they weren’t selected, and that was the second study you described.

Adam M. Brufsky, MD, PhD: I’d like to hear about it because I was fascinated by that, that potentially you have potential multigene panels that could select who would benefit from this therapy or not. Could you describe that?

Mark E. Robson, MD: So, there has been this whole idea that cells that lack functional BRCA have issues with repairing double-stand DNA breaks, and you can identify those through a particular signature of genomic damage, genomic scars, and it’s referred to as “BRCAness.” The hope is that cancers in some patients arising without BRCA mutations will have similar defects that will allow them to be sensitive to either PARP inhibition or platinum-based therapy. And there are a reasonable amount of data in ovarian cancer that that’s the case for a meaningful proportion of patients with ovarian cancer. Whether or not that’s the case for breast cancer isn’t clear, and so a number of people have been trying to identify biomarkers of what they are assuming is this DNA damage repair defect, but is actually a readout for sensitivity in different kinds of therapy. So, this arm of I-SPY was a combination of veliparib with a standard chemotherapy backbone, and they were searching for predictors. They had this PARP7 gene signature, which they thought was predictive. That obviously needs to be validated in another setting, and whether that translates into anything meaningful in the clinical setting is not clear because other attempts to look at this, like Andy Tutt’s TNT study, were kind of disappointing. Using commercially available HR assays and other more investigational things, like BRCA1 methylation or mRNA silencing, weren’t able to identify, in the somatic setting, predictors of sensitivity to platinum therapy, which is very similar to sensitivity to PARP.

Kimberly L. Blackwell, MD: And I just would put in a plug because there is a phase III study that will look at the addition of that PARP inhibitor. But there are lots of PARP inhibitors out there for BRCA mutation carriers. And what I’m seeing in my referral patterns is people, when they have a triple-negative, in particular BRCA, there’s a rush to putting them on a platinum chemotherapy and then sending them to a place for trial. I’m really trying to encourage referring physicians to think twice in the BRCA mutation carriers and try to get them on a study before they utilize a platinum-based agent because for the most part, I’d say in over half of the BRCA mutation randomized studies, you can’t have received a platinum. So, just to be a little bit more thoughtful. And all of these studies actually support the mutational testing, at least the ones we have open. And so, you ask if we would test a 65-year-old with first-line triple-negative. I probably would in the context of a screening for a clinical trial. I don’t think there’s any harm to doing that. Just be a little cautious about jumping on that platinum bandwagon in these BRCA mutation carriers without at least a clinicaltrials.gov search.

Adam M. Brufsky, MD, PhD: But, if there isn’t a clinical trial, do you believe the TNT data? Would you say that if someone is BRCA-mutated, you would prefer a platinum if a trial wasn’t available?

Kimberly L. Blackwell, MD: I believe the data, yes. And, at least in my BRCA mutation carriers, platinums are very active, but they’re going to be there second-line and third-line and really trying to get them. I think the data are quite supportive of the PARP inhibitors in this very unique population of patients.

Adam M. Brufsky, MD, PhD: Do you have anything to add about the MGH (Massachusetts General Hospital) version? Do you do BRCA testing on people with triple-negative that come in the door?

Aditya Bardia, MD, MPH: We do if there’s a reason to do BRCA testing in terms of either a clinical trial or you’re worried that the patient has high-risk for triple-negative and is in their 40s. So, I think if there’s a clinical indication to do BRCA testing or indication in terms of a clinical trial, we would consider that. But we don’t do it for everyone with triple-negative breast cancer.

Transcript Edited for Clarity
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