Final Insight: PARPs and gBRCA in Breast Cancer

Transcript:

Joyce O’Shaughnessy, MD: What’s going on, Tiffany, with the PARP inhibitors, that you’re aware of, in the curative setting?

Tiffany Traina, MD: The OlympiA study, building on OlympiAD, is an early-stage trial of a randomization to adjuvant olaparib versus observation or standard of care—radiation therapy and/or endocrine therapy, if appropriate. This is a global trial. It is still accruing, and I think it’s a really important trial for women with early-stage germline BRCA mutations. In the setting of triple-negative breast cancer, if those women did receive neoadjuvant therapy, they need to fail a pathologic complete response to be able to be a candidate for this trial. I think that this trial is a very compelling and important one. It will be worth keeping an eye on. In terms of other areas of interest, we’ve alluded to how important it is to figure out some of these other germline mutations, to see whether there may be a role for PARP inhibition there, as well as for somatic non-BRCA mutations.

Joyce O’Shaughnessy, MD: There is some work going on in the neoadjuvant setting too. What trials come to mind?

Nadine Tung, MD: At the ASCO annual meeting, we’re likely going to hear about monotherapy talazoparib in the neoadjuvant setting. Jennifer Litton from the MD Anderson Cancer Center has completed enrollment to that trial. So I think we’re going to hear about that. Other PARP inhibitors, alone or with immune therapy, are moving into the neoadjuvant setting. So I think there are going to be more data on this. You’re absolutely right—if there’s a study and it looks like there are some exciting results, the need to not miss a germline right from the beginning is going to become paramount.

Joyce O’Shaughnessy, MD: It will be huge, yes. That will be interesting. That’s going to be our first data on preoperative talazoparib, as a single agent, in germline BRCA patients?

Nadine Tung, MD: Yes.

Joyce O’Shaughnessy, MD: For both triple-negative and ER-positive disease?

Nadine Tung, MD: I don’t know the answer to that. I’m not sure.

Joyce O’Shaughnessy, MD: It is tempting to think about olaparib and, hopefully soon, talazoparib, as well, for the germline mutations that are similar to BRCA1 and BRCA2. We think about PALB2. What do we know from other malignancies? We don’t have any data in breast cancer yet, do we?

Nadine Tung, MD: No. The TBCRC [Translational Breast Cancer Research Consortium] just opened a study looking at this question in breast cancer. They are looking at either germline or somatic mutations in other DNA repair genes, or just somatic BRCA mutations, to see whether olaparib will work. In prostate cancer, the results of the Mateo study (published in the New England Journal of Medicine) really showed some success with olaparib in either germline or somatic mutations. And, for example, with ATM. This was a cohort in which they gave all the patients with metastatic prostate cancer with castrate-resistant prostate cancer olaparib, and they looked at who responded. Of the 16 patients who either had both copies of a gene mutated or both lost (one of these DNA repair genes), 14 of the 16 responded to olaparib. So again, this may be another way to get to these patients who don’t have a germline BRCA mutation (who may have the same defect in this homologous recombination pathway), who have a different mutation in this pathway, either in the tumor or germline….

Joyce O’Shaughnessy, MD: It was both somatic and germline?

Nadine Tung, MD: Yes. When they saw, for example, ATM mutations in the tumor, or BRCA2, only half of them were germline. Some of them were just somatic in the tumor. So that’s promising.

Joyce O’Shaughnessy, MD: That is promising. They thought that you might need to have both copies of the gene gone….

Nadine Tung, MD: Absolutely.

Joyce O’Shaughnessy, MD: Obviously, it still has to be worked out. You still may have enough gene function there that you’re not going to get good results. So we have to be careful. Now, when we send our tissues, because we’re looking for clinical trials for patients (they had standard therapies), we’re looking for mutations that might qualify for the clinical trials. We consider next-generation sequencing, and it comes up with the BRCA2 mutation, somatically. We don’t know now whether that’s really functional.

Nadine Tung, MD: Right.

Joyce O’Shaughnessy, MD: It’s not reporting out. Is it both copies down or biallelic loss? So we would have to call up and find out. But your point, though, Nadine, is you would say to just go ahead and do the germline?

Nadine Tung, MD: In the studies, post hoc, there will be a lot of analysis about who responded and who didn’t. I don’t think there’s a way, in real time, at this point. Obviously, if it’s a germline mutation and the cancer is a signature one, breast or ovarian, there’s a presumption. Actually, many have shown that there’s loss of heterozygosity for that. There is loss of that wild-type BRCA allele in the vast majority of the cancers—as high as 90%. I think we have that assumption. If it’s a somatic mutation, only in the tumor, how do we know that both copies are really nonfunctional? We won’t know in real time. We’ll have to look at that.

Joyce O’Shaughnessy, MD: Thank you so much. This has been a really thorough, deep discussion. I just want to give you the opportunity to leave us with one or a couple of take-home messages, for all of us who are just kind of getting used to these data.

Nadine Tung, MD: In metastatic breast cancer, don’t forget to think about finding a germline mutation. We have new therapy. It’s not just about preventive surgery and the prevention of new cancers in the future. This is about treating this cancer. You have to think about how to test for it.

Tiffany Traina, MD: I would echo that.

Joyce O’Shaughnessy, MD: That’s going to help us, I think, as we focus more and more on the metastatic setting. It’s going to raise the consciousness, in general. It will probably spill over to the patients we’re seeing in follow-up. It will be part of our algorithm that we go through with these other germline mutations that are out there. I find myself redoing the family history, etcetera. But it will probably raise the consciousness, in general, for the whole area and will spill over into the curative setting. So it’s just the beginning.

Well, thank you so much. I think this has been an excellent discussion. We hope that you found the information to be very valuable for your clinical practice. Thank you for watching OncLive News Network^®.

Transcript Edited for Clarity