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Chemotherapy in gBRCA1/2+ Metastatic Breast Cancer

Panelists:Joyce OShaugnessy, MD, Baylor University Medical Center; Tiffany A. Traina, MD, Memorial Sloan Kettering Cancer Center; Nadine M. Tung, MD, Harvard Medical School
Published: Tuesday, Apr 24, 2018



Transcript: 

Joyce O’Shaughnessy, MD: Let’s go on to the topic of the most recent FDA approval of olaparib in BRCA-mutant metastatic patients. I guess it comes into the context of how we’ve been treating these women anyway. We’ve been treating them. We’ve known that they have BRCA mutations. They were in the metastatic setting. What kind of approaches have you been using? We’ll also discuss the preoperative, which is a bit of a conundrum with regard to BRCA. But in the metastatic setting, what kind of data do we have with regard to chemotherapy?

Nadine Tung, MD: For chemotherapy, I think what Tiffany was alluding to was that we do get some sense of different responses to chemotherapy. The TNT trial is probably the one to talk about. The TNT trial was a randomized phase III trial for patients with triple-negative breast cancer but also for those with a germline BRCA mutation.

In that study, there were 43 BRCA carriers. Most of them had triple-negative disease. There were a few BRCA-positives, but there were 43 BRCA carriers. The study randomized patients, in the first-line metastatic setting, to either platinum or to docetaxel, carboplatin. At progression, there was a crossover. There was always a preplanned analysis by BRCA status. So the take-home message in that study was that overall, there was no advantage. There was no difference in response rate of progression-free survival between the platinum or the docetaxel, except for the germline BRCA carriers. They had a significantly better response rate and a bit better progression-free survival.

This confirmed older, smaller studies that showed that platinum seemed to be more active among the triple-negative population, in those who had a germline BRCA mutation. It was better than docetaxel and better for those who didn’t have a BRCA mutation. So platinum is an active agent. There’s no doubt about that. I think the question then becomes, Is platinum better than standard chemotherapy? Is it better than the anthracycline (AC)–based regimens? We don’t have a direct comparison to answer that question. The only other data that speak to it, in some perspective way, are studies like GeparSixto. This was a study, in the neoadjuvant setting, for triple-negative breast cancer. The investigators used a little bit of a different regimen—a weekly anthracycline, weekly taxane—asking how much of a benefit was seen if you added the platinum. Do you get a better pathologic complete response? Is there better disease-free survival?

Interestingly, if you look at using the standard therapy, if you look at the BRCA carriers (there were 50 of them) versus those without the mutation, the pathologic complete response was much higher in those with the BRCA mutation standard therapy—a 68% versus 33% pathologic complete response. So standard therapy is very sensitive in the BRCA carriers.

If you asked whether the platinum added anything, it only added for the wild-type patients—those without the BRCA mutation. So one interpretation of all of this is that BRCA-associated breast cancer is more chemo-sensitive. Platinum is active. Standard therapy is active. Until you compare, head-to-head, you don’t really know which is better. We’re actually conducting a study like that in the neoadjuvant setting—comparing cisplatin with AC. I think that will provide some data, even in the ER-positive BRCA-associated breast cancers, for which there are no platinum data at all. So I think chemo-sensitive tumors is what I would say, at this point.

Joyce O’Shaughnessy, MD: That’s really interesting. We don’t have a whole ton of data in the metastatic setting with regard to chemotherapy. The TNT trial with carboplatin showed nice level 1 evidence. Albeit, this was a small subset, but it is really interesting, regarding the GeparSixto—no additional benefit from the addition of the carboplatin in pathologic complete response or disease-free survival in that population.

How about in the metastatic setting with the BRCA patients? Before olaparib came along, for example, did you prefer to start with a platinum?

Tiffany Traina, MD: I think that it’s been somewhat evolving. These patients, often in the early-stage setting, would have received an anthracycline, a taxane. They may have received a platinum. In the time of CREATE-X, they also may have received post-neoadjuvant therapy with capecitabine, if they failed to have a pathologic complete response. So a lot of this is the art of medicine. It depends on what they’ve previously seen. How long of a disease-free interval did that patient have? But I think that taxane/platinums remained as a first-line option. Personally, I found that I was moving eribulin up sooner in the metastatic disease course, for these patients, as well.

Transcript Edited for Clarity
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Transcript: 

Joyce O’Shaughnessy, MD: Let’s go on to the topic of the most recent FDA approval of olaparib in BRCA-mutant metastatic patients. I guess it comes into the context of how we’ve been treating these women anyway. We’ve been treating them. We’ve known that they have BRCA mutations. They were in the metastatic setting. What kind of approaches have you been using? We’ll also discuss the preoperative, which is a bit of a conundrum with regard to BRCA. But in the metastatic setting, what kind of data do we have with regard to chemotherapy?

Nadine Tung, MD: For chemotherapy, I think what Tiffany was alluding to was that we do get some sense of different responses to chemotherapy. The TNT trial is probably the one to talk about. The TNT trial was a randomized phase III trial for patients with triple-negative breast cancer but also for those with a germline BRCA mutation.

In that study, there were 43 BRCA carriers. Most of them had triple-negative disease. There were a few BRCA-positives, but there were 43 BRCA carriers. The study randomized patients, in the first-line metastatic setting, to either platinum or to docetaxel, carboplatin. At progression, there was a crossover. There was always a preplanned analysis by BRCA status. So the take-home message in that study was that overall, there was no advantage. There was no difference in response rate of progression-free survival between the platinum or the docetaxel, except for the germline BRCA carriers. They had a significantly better response rate and a bit better progression-free survival.

This confirmed older, smaller studies that showed that platinum seemed to be more active among the triple-negative population, in those who had a germline BRCA mutation. It was better than docetaxel and better for those who didn’t have a BRCA mutation. So platinum is an active agent. There’s no doubt about that. I think the question then becomes, Is platinum better than standard chemotherapy? Is it better than the anthracycline (AC)–based regimens? We don’t have a direct comparison to answer that question. The only other data that speak to it, in some perspective way, are studies like GeparSixto. This was a study, in the neoadjuvant setting, for triple-negative breast cancer. The investigators used a little bit of a different regimen—a weekly anthracycline, weekly taxane—asking how much of a benefit was seen if you added the platinum. Do you get a better pathologic complete response? Is there better disease-free survival?

Interestingly, if you look at using the standard therapy, if you look at the BRCA carriers (there were 50 of them) versus those without the mutation, the pathologic complete response was much higher in those with the BRCA mutation standard therapy—a 68% versus 33% pathologic complete response. So standard therapy is very sensitive in the BRCA carriers.

If you asked whether the platinum added anything, it only added for the wild-type patients—those without the BRCA mutation. So one interpretation of all of this is that BRCA-associated breast cancer is more chemo-sensitive. Platinum is active. Standard therapy is active. Until you compare, head-to-head, you don’t really know which is better. We’re actually conducting a study like that in the neoadjuvant setting—comparing cisplatin with AC. I think that will provide some data, even in the ER-positive BRCA-associated breast cancers, for which there are no platinum data at all. So I think chemo-sensitive tumors is what I would say, at this point.

Joyce O’Shaughnessy, MD: That’s really interesting. We don’t have a whole ton of data in the metastatic setting with regard to chemotherapy. The TNT trial with carboplatin showed nice level 1 evidence. Albeit, this was a small subset, but it is really interesting, regarding the GeparSixto—no additional benefit from the addition of the carboplatin in pathologic complete response or disease-free survival in that population.

How about in the metastatic setting with the BRCA patients? Before olaparib came along, for example, did you prefer to start with a platinum?

Tiffany Traina, MD: I think that it’s been somewhat evolving. These patients, often in the early-stage setting, would have received an anthracycline, a taxane. They may have received a platinum. In the time of CREATE-X, they also may have received post-neoadjuvant therapy with capecitabine, if they failed to have a pathologic complete response. So a lot of this is the art of medicine. It depends on what they’ve previously seen. How long of a disease-free interval did that patient have? But I think that taxane/platinums remained as a first-line option. Personally, I found that I was moving eribulin up sooner in the metastatic disease course, for these patients, as well.

Transcript Edited for Clarity
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