BRCA Mutations in Triple-Negative Breast Cancer


Hope S. Rugo, MD, FASCO, discusses how BRCA mutations change the treatment approach for triple-negative breast cancer.


Paolo Tarantino, MD: What if this patient was BRCA mutant from the beginning, from the early setting? Would that have changed anything in our treatments?

Hope S. Rugo, MD, FASCO: That’s an interesting question. If the patient had a germline BRCA mutation, we’d always check germline testing in a patient like this. In fact, once you get to the residual disease even outside the question of the extent of surgery, testing family, and screening for that patient when she had early stage disease, you also want to know about the use of olaparib based on the OlympiAD trial, which improved survival in patients with residual disease. There was a benefit in OlympiAD giving olaparib for a year after finishing treatment in the adjuvant and neoadjuvant settings. Most patients had BRCA1 mutations and triple-negative disease, but there were also a lot of patients with HR [hormone receptor]–positive. Looking at the subset analyses, they seem to benefit.

In triple-negative disease, it’s particularly effective. It’s a nonquestion: if you have a BRCA mutation and residual disease after neoadjuvant therapy, we give the PARP inhibitor. The big question that comes up is what do you do with pembrolizumab? We continue it because we know it’s safe based on previous data in the metastatic setting. If we can continue, we do. Sometimes insurance pushes back a little, but there are some interesting data that we saw at San Antonio Breast Cancer Symposium, from the DORA trial. It’s a little perplexing because fewer than 50 patients were in the trial, and patients got an induction with chemotherapy and then received a checkpoint inhibitor plus olaparib maintenance. The data from that trial are intriguing, but they’re a little hard to interpret until we get more of the translational data. They suggested that some patients who didn’t have a BRCA mutation benefited even from the combination. We need other biomarkers to understand it, but we know the combination is safe.

There is a phase 2 trial, KEYLYNK-009, which looked at this approach with pembrolizumab after induction with pembrolizumab-gemcitabine-carboplatin regardless of PD-L1 expression in the tumor. With that trial, we’ve been waiting for the data on the value of maintenance of combining PARP inhibitor with a checkpoint inhibitor after induction. It’s larger than the DORA trial. I hope we have data by the end of this year. It’s exciting to see the KEYLYNK-009 phase 2 data.

We already have data in the metastatic setting with olaparib and talazoparib, showing that we improve progression-free survival. The suggestion is that it may be better to give the PARP inhibitor earlier. It ends up bringing up a question. If you have a patient who has early relapse, disease in the liver, and abnormal liver enzymes and who is PD-L1 negative, do you give a PARP inhibitor first or do you give an induction with chemotherapy and then the PARP inhibitor. That has to be individualized based on the patient, the extent of the disease, and how worried you are about immediate visceral compromise.

For a patient who has PD-L1–positive disease, I always start with the checkpoint inhibitor, which has survival benefits with chemotherapy. But I’m intrigued about the idea of the PARP inhibitor as maintenance, and I hope we get some encouraging data on subpopulations in the future. KEYLYNK-009 didn’t select based on PD-L1 positivity, so it might be tough. It’s hard to know. These agents are pretty well tolerated, with anemia, nausea, and some headache, but we’re always excited when we have a PARP inhibitor that we can give these patients. It’s interesting to think about that.

Transcript edited for clarity.

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