Advanced Ovarian Cancer: Role of Non-BRCA Mutations

Transcript: Michael Birrer, MD: Let me first describe what HRD is. That’s homologous recombination deficiency. This deficiency is found in a large percentage of ovarian cancers. It reflects the fact that these tumors cannot repair their DNA effectively. And we think that that’s critical to the actual development of the tumor. So because these cells cannot repair the DNA, they undergo a lot of mutation DNA shifts. And that, over a period of time, causes the cancer to develop. It’s also important to recognize now—with the discovery and FDA approval of PARP inhibitors—that identifying those tumors that have HRD is very, very critical because these are the tumors that will respond most effectively to PARP inhibition.

The timing of testing for HRD has undergone a lot of debate, and the reason is that historically the initial treatment of ovarian cancer has been pretty prescribed: surgery, chemotherapy. And so many investigators have taken their time to test for HRD with the understanding that it would not be relevant to the treatment of the patient. That has changed with the approval of PARP inhibitors. So now the use of a PARP inhibitor, or PARP inhibitors, in the first remission necessitates that HRD testing occur very early. In my practice, I will obtain testing either in the germline on the patient in the initial month or 2 or on the tumor that’s removed at primary debulking, which again is at the beginning of therapy.

This area of genetic testing for ovarian cancer patients has really undergone a lot of evolution. We’ve known for years that the patients who have a family history of ovarian cancer, or ovarian and breast cancer, have mutations in BRCA1 and BRCA2. We now know that there’s an additional 8% to maybe 10% of patients who have no family history but who will have germline mutations of BRCA1 and BRCA2. So it’s very important that all ovarian cancer patients get tested. And then, too, we also now know that there are other genes within the Fanconi DNA-repair pathway that serve as BRCA1 and BRCA2 surrogates. And mutations in these, such as ATM/ATR, P53, CHEK2, PALB2—just to name a few—are important to identify and discover because they might identify a patient who would benefit from a PARP inhibitor. And more importantly, these could be passed on to both sons and daughters. And so the genetic risk is real and substantial.

Transcript Edited for Clarity