BCC 2021 | The latest treatment options for BRCA-mutated breast cancer

We have all accepted the tumors that are driven by BRCA1 and 2, and increasingly PALB2, that the tumors themselves have deficiencies in their repair of errors in the DNA, and this makes them vulnerable to chemotherapy. And whereas we thought that perhaps platinum would be a particularly useful agent because of the way it works in tumors that have deficiencies in these genes because of their inherited mutations, so errors in double strand break repair in the DNA. And because there are trials where the addition of platinum has been helpful. One of the trials this year, the INFORM study that was presented by Dr Tung at ASCO last year, compared single-agent cisplatin to standard AC chemotherapy in the neoadjuvant setting, and there was no group that benefited from platinum more than AC, AC was superior in every group.

That does not mean platinum has no role in the treatment of breast cancer, but rather that as a single agent in neoadjuvant disease, this really is not the drug to use. The addition of platinum or the substitution of platinum in the treatment of patients, people who’ve had a previous primary with their anthracycline or potentially the addition of platinum may be helpful. But fortunately, these tumors are sensitive to chemotherapy. People have now used PARP inhibitors in the neoadjuvant setting, as well as in the advanced disease setting, and they have activity. Whether they should be used alone, in combination with immunotherapy, or otherwise has not yet been established, but their activity we’ll learn more about when the OlympiA trial is presented, hopefully at ASCO this year.

Perhaps areas where there have been more progress has been in advanced disease in mutation carriers. And originally this was BRCA1 and 2, and even limited to triple negative disease in BRCA1 primarily, a little bit of BRCA2. Certainly, those were tumors where chemotherapy was used more often. But the data certainly shows that tumors in individuals with mutations in BRCA1, BRCA2, and now PALB2, which are often ER-positive, and even in tumors that have had CDK4/6 inhibitors, PARP inhibitors may still be active and often are quite active.

So there have been now many trials that have shown improved disease-free survival, none that have shown improved overall survival for mutation carriers in the metastatic setting with BRCA1 and 2 mutations. And then this past year at San Antonio, we presented the TBCRC 048 Olaparib Expanded, which was the use of a PARP inhibitor, this time olaparib, in patients who either had a germline mutation in a breast cancer susceptibility gene, other than BRCA1 or 2, or patients who had acquired a mutation in their tumor in BRCA1 or 2 primarily, or any of these other DNA repair genes. And very clearly, the data showed that PALB2-related tumors in the germline space, almost all responded to PARP inhibitor, and they were almost all ER-positive and almost all had had a CDK4/6 inhibitor.

In the acquired mutations, those who had acquired a BRCA1 or 2 mutation. So they weren’t in the original tumor in general, they were not in the germline, but the mutation had been acquired by the tumor, these tumors also were responsive to treatment with PARP inhibitors. Disappointingly, the ones that were not were the more common mutations like CHEK2 and ATM in this dataset. That does not mean it’s true across the board. The question is going to be, do we have to test each gene one at a time to figure out which ones PARP inhibitors and other related DNA repair drugs work in, or will this be broader?

In prostate cancer, they’ve taken the broad approach. We didn’t do that in this study. We’ll see what happens in other studies because there certainly are other confirmatory studies already in progress, including our own expansion, to try and sort out these mutations individually more thoroughly.