Early Assessment of BRCA Status Key in Ovarian Cancer, Two Experts Agree

Robert Coleman, MD

Early identification of BRCA mutations can significantly help inform future treatment choices for patients with ovarian cancer, with the availability of an ever-growing arsenal of therapies for patients with these alterations, according to interviews with two experts that were conducted at the 2016 ASCO Annual Meeting.

The importance of BRCA testing for treatment selection continues to be enhanced, with the availability of the PARP inhibitor olaparib (Lynparza), which has shown an improvement in overall survival as a maintenance therapy for patients with ovarian cancer. Moreover, in December 2014, olaparib was approved for the treatment of women with BRCA-positive advanced ovarian cancer following treatment with three or more prior lines of chemotherapy.

Outside of treatment selection, the identification of germline BRCA mutations could have broader implications. Identifying this alteration could lead to the prevention of cancer for family members, through screening, testing, and prophylactic measures.

OncLive: What is the importance of early BRCA testing?

For further insight into the importance of BRCA testing, OncLive interviewed Robert Coleman, MD, and Leslie Randall, MD. Coleman is a professor in the department of Gynecologic Oncology and Reproductive Medicine, University of Texas MD Anderson Cancer Center, and Randall is associate professor, gynecology/ oncology, University of California Irvine.Coleman: In the past, it was all about trying to figure out whether or not the patient was a germline carrier, and if they were what that implication would be for their offspring. So with that knowledge, it's much easier to test the family because we know what the mutation is, so the testing is cheaper and more directed. Even if they chose not to get tested, there is still some counseling that can be done in terms of how to lower their individual risk.

Leslie Randall, MD

In the recent years, with the development of PARP inhibitors I think there is a much better understanding about how DNA repair happens. There is this whole homologous recombination deficiency area that's really exploded. That allows us to use these novel drugs, like olaparib, which has already been approved in the BRCA mutation population. Upcoming very soon are going to be multiple different drugs that'll have multiple indications and this will be really relevant.

The way we did it before was to essentially look at family histories, and with very large families, we can get a very good idea about what the individual risk is. The point was that if we felt that there was at least a 10% chance of finding the mutation for germline sequencing, then we would do it. If it were less than that, we would just offer general counseling.

Now we understand that if the families are not that large, we don't have good detailed history, and we have lots of missing information. We found that actually in the lower risk, predicted risk, we missed the majority of patients that would be BRCA positive. Because of those factors, we now recommend to get it done at diagnosis.

Randall: Early BRCA testing is very important for several reasons, the most of which is identifying patients who have specific tumor biology. Patients with BRCA mutations tend to be more platinum-sensitive than patients who don't have those mutations. They're also eligible for different clinical trials than patients who don't have those mutations.

What are the current recommendations for BRCA testing?

In addition to that, identifying these patients will identify them for later on in their treatment line for things like PARP inhibitor therapy, as well as identify those whose family members should maybe be tested for genetic mutations.Coleman: The guidelines say that patients should get it at the diagnosis. What we've learned now is that some of the other histology types have enough of a frequency that it's worth testing as well. Outside mucinous tumors, we've seen germline testing across the board. We believe the high-grade serous guidelines should be expanded.

Randall: BRCA testing is recommended for all of our invasive ovarian cancer patients to include fallopian tube and peritoneal cancer. Those guidelines are endorsed by the NCCN, ASCO, the Society of Gynecologic Oncology, SGO, National Genetic Counselor’s Society, and also the American Congress of Obstetrics and Gynecology. All of these come together in what we called the Genetic Summit to discuss how strongly we recommend BRCA testing in our ovarian cancer patients.

We all strongly recommend it, and are somewhat disenchanted that it hasn't been happening at the rates we would like to see, though I think it was significantly improved within the last year.

What would you say the prevalence of BRCA is in patients with ovarian cancer?

The level of evidence to support it is about a Level B if you look at the Preventative Taskforce Levels of Evidence.Coleman: It's hard to answer. Prevalence means that if I were to sample the population today, how many of the 200,000 women that are alive actually have BRCA mutation? From an incidence standpoint, we know if you combine somatic and the germline, you get around 20% to 25%, but those patients are more likely to be alive at a longer duration of time. While the prevalence of ovarian cancer is around 190,000 cases, the proportion of those patients that are BRCA is probably higher than the 20% to 25% that we quote.

I don't know that we know exactly what that proportion is, but the 5-year survivors are much more likely to have the BRCA mutation or at least an HRD state than the earlier survivors.

What is the difference in terms of germline versus somatic BRCA alterations, and is one more important than the other?

Randall: I always say that the more we test, the more we'll learn that more patients have it. Currently, we think the prevalence of BRCA mutations in ovarian cancer patients is about 20%.Coleman: For BRCA, at least the data that we have, looks very much the same. We don't have as much data on the other non-BRCA germline that might be associated with familial or genetic risk, and what their likelihood is, but that field is expanding and we should have some better clarity as time goes on.

Randall: Germline and somatic mutations are both important. Germline mutations are the ones that are inherited, so you're born with a germline mutation in BRCA1 you can pass that on to your offspring. Somatic mutations happen only in the tumor. Somatic mutations can't be inherited, they can't be passed on to future generations, so that's the very important distinction between germline and somatic mutations.

I think they're both important because they are both associated with responses to BRCA-specific therapies like PARP inhibition.