Germline BRCA Mutations in TNBC


Joyce A. O’Shaughnessy, MD: Thank you for that general overview. Let’s transition to the PARP inhibitors because we really now have some new information, some new therapeutics to grapple with. How common do we see that in triple-negative? And should we be testing for BRCA1 and BRCA2 on every metastatic triple-negative, do you think?

Claudine Isaacs, MD: I think these days we should start thinking about it, certainly in the adjuvant or neoadjuvant setting. The current guidelines suggest that we should be referring any of our patients who are under 60 years of age who have a triple-negative breast cancer, we should be referring them for genetic risk assessment and likely for genetic testing. The likelihood of detecting a BRCA1 or BRCA2 mutation in those people, it depends on the studies, but even in less than 60 years of age with no other significant family history, it was about 10% to 12%. And these are things that if you don’t test for them, you’ll never find that 10% to 12%. So, I’m perpetually telling the patients that I am referring that on the backside when we’re seeing them in genetic counseling and testing, that it is unlikely that they actually harbor a predisposition to breast cancer but a subset of them will. So, I do think it is something that we really need to think about, and the studies in general show that somewhere overall, between 10% to 15% or a little bit higher than that, have a BRCA1 or BRCA2 mutation.

Joyce A. O’Shaughnessy, MD: So, not uncommon, basically. Claudine, what about some of the newer data that have come out with olaparib leading to very recent FDA approval within the last week or 2 and also the EMBRACA data with talazoparib? Could you just tell us a little bit about those data?

Claudine Isaacs, MD: Sure. So, those were both trials done specifically in women who had been identified to have a mutation in BRCA1 or BRCA2so a deleterious mutation, one of those genes, germline again. And in breast cancer, we’re really focusing just on the germline mutation so it’s going to be of interest eventually looking at individuals who might have a somatic mutation. But these are germline BRCA1 or BRCA2 mutations. Both of the trials were similar in that they could have had some prior therapy. In OlympiAD, it was up to 2 prior lines of chemotherapy, and the randomization schemes on both of these trials was very similar. It was basically to PARP inhibitor or to treatment of physician choice. And the treatment of physician choice was any one of the number of chemotherapies that we think would be appropriate for breast cancer for metastatic disease. It included not just triple-negative. It also included hormone receptor-positive, HER2-negative. So, the main thing is that these were both trials in HER2-negative populations of patients.

So, OlympiAD was a randomization to olaparib versus treatment of physician choice, and what it showed was that in the group of women who got olaparib, there was a significant improvement in progression-free survival on the order of about 3 months. The objective response rate was very good. It was about 60% or so, but the duration of response or the median progression-free survival was about 7 months with the olaparib and about 4 months with treatment of physician choice. Patients were allowed to have received prior platinum, and the numbers were a little bit different in the 2 studies in terms of the parentages, but both had similar design that way.

The EMBRACA trial was, again, germline BRCA1/2 mutation, less than 3 prior lines of chemotherapy, and the randomization to the PARP inhibitor as single-agent therapy versus treatment of physician choice. Again, the treatment of physician choice was a little bit different, but these were drugs that I think we would all pull out of our back pocket as something to give. So, it was eribulin, capecitabine, vinorelbine, and one of them also included gemcitabine. And, again, there was about a 3-month prolongation in progression-free survival, so very similar findings favoring the use of a very targeted therapy, right, favoring the use of the PARP inhibitor in this group of patients.

Joyce A. O’Shaughnessy, MD: It’s really interesting because olaparib is now available, and we probably would have predicted talazoparib will not be far behind. Now we have these therapeutics, so now we have to find the germline patients and secondly, we’ve got to figure out where in the order of the options for the patients do we treat them with PARP inhibitors. What do you think about both of those, Tiffany?

Tiffany Traina, MD: I think we need to readdress the conversations with our patients, as you’ve already mentioned. There’s a pool of patients who we may have mentioned genetic counseling to who didn’t pursue that, and now this is actionable for their treatment and not just risk assessment. So, we need to make sure we’re not missing potential candidates for this therapy. Beyond that, we need to be sure we’re focusing on what are known to be deleterious mutations and perhaps not overusing olaparib in a setting that didn’t apply to these clinical trials. Because, in that case, we may be disappointed with the results, so deleterious germline BRCA mutation.

I think that an important distinction to be aware of is the platinum exposure story. The patients who were eligible for these trials may have had prior platinum, but they could not progress on a platinum in the metastatic setting, and they may have received their platinum in the adjuvant or neoadjuvant setting. But anywhere between 6 months to a year needed to elapse before coming on to a PARP inhibitor. So, I think keeping that in mind will help set expectations, to have an oral regimen that is well tolerated, sort of a kinder, gentler platinum. Notice in both of these trial designs, platinum is missing from the treatment of physician’s choice control arm. But in oral therapy that had improved progression-free survival, higher responses, a very favorable toxicity profile, and comparable time to response—so quick response with oral therapy—I think favors using this perhaps early on in metastatic disease for the appropriate patient.

Transcript Edited for Clarity

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