BRCA Testing in Ovarian Cancer

Transcript:Bradley J. Monk, MD: Hello, and thank you for joining us today for this OncLive® Peer Exchange panel discussion, “Advanced Ovarian Cancer: Recent Advances and Unmet Needs.” Despite recent progress in developing novel therapies for advanced malignancies of the ovaries, fallopian tubes, and peritoneum, this heterogeneous group of diseases remains fatal in most cases, and our continued understanding of the underlying biology of these clinically challenging disease states will facilitate development of personalized approaches to systemic therapy. In addition, we’re challenged to delay recurrence and improve clinical outcomes, including patient reported outcomes and quality of life in the clinic, around the world. In this OncLive® Peer Exchange panel discussion, my colleagues and I will discuss the latest research surrounding systemic therapy and surgery for this group of diseases that we call ovarian cancer and the implications for treating our patients.

My name is Brad Monk. I’m a gynecologic oncologist and professor at the University of Arizona and Creighton University, both in Phoenix, Arizona. I’m joined by 4 of my esteemed colleagues. Thank you very much, this is an exciting time. I’ll begin by introducing Dr. Robert Coleman, vice chairman and director of research at MD Anderson Cancer Center. Welcome Rob.

Robert L. Coleman, MD: Thank you Brad.

Bradley J. Monk, MD: Dr. Matthew Powell, thank you for joining us, from Washington University in St. Louis. Dr. Powell is an associate professor and the director of gynecologic oncology. Welcome Matt.

Matthew A. Powell, MD: Thanks for having me.

Bradley J. Monk, MD: Dr. Katie Moore. Dr. Katie Moore runs the Cancer Research Clinical Trials Unit Phase One Program, from the University of Oklahoma. Very ambitious. We’re honored to have you. Thank you.

Katie Moore, MD: Thank you.

Bradley J. Monk, MD: And Dr. Gottfried Konecny, an associate professor within the Department of Medicine from the University of California, Los Angeles. Thank you Gottfried.

Gottfried E. Konecny, MD: Pleasure to be here.

Bradley J. Monk, MD: I’d like to begin by talking about molecular testing in ovarian cancer. We live in a personalized medicine world. We’re very fortunate that we are expanding our understanding of ovarian cancer. I’d like to begin by talking about BRCA. Gottfried, tell us what BRCA1 and BRCA2 genes are?

Gottfried E. Konecny, MD: BRCA1 and BRCA2 genes are critically important for maintaining DNA integrity, and they’re important for double-strand DNA repair. Unfortunately, the BRCA1 and BRCA2 genes are commonly mutated in ovarian cancer, and they lead to dysfunctional double-strand DNA break repair, which is associated with the familial risk for breast and ovarian cancer. But importantly, they now also predict sensitivity to a new class of drugs, the PARP inhibitors.

Bradley J. Monk, MD: What’s that relationship, Rob, between BRCA, double-stranded DNA repair, and PARP?

Robert L. Coleman, MD: PARP, we’ve now come to realize, is a protein that has a lot of functions. And one of those functions is to repair single-strand DNA breaks. And so, to tie in with what Gottfried mentioned, if we’re able to inhibit that process of base excision repair, then there’s a reliance on more high-fidelity and energy-intensive processes, like homologous recombination pathways, which BRCA governs.

Bradley J. Monk, MD: So, poly ADP-ribose polymerase—PARP—repairs single-stranded DNA. And when you give a PARP inhibitor, the inherited BRCA can’t repair the resulting double-stranded break.

Robert L. Coleman, MD: Correct.

Bradley J. Monk, MD: Matt, who should be tested for germline BRCA mutations, and how do you operationalize that in St. Louis?

Matthew A. Powell, MD: That’s a great question, Brad. As you mentioned, when we’re talking about ovarian cancer, we also mean primary peritoneal cancer and fallopian tube cancer, and it’s important for all of us to realize that we really offer testing to all of our patients who have those diagnoses. We offer it early, and we have them see a genetic counselor. The testing processes usually involve a lot of education, but we really think getting that information helps us triage that patient, not only for clinical trials but also for cascade testing for their families. So, it can have a very big impact on that—not only the patient, but the family as well.

Bradley J. Monk, MD: So, it’s autosomal dominant. You test everyone. It’s inherited—what I call genetic. But then, there’s a genomic-developing molecular signature. It could still be BRCA, but the patient developed it; they didn’t get it from their parents. When should we test the tumor? Should we test both the germline and the tumor? Because if you’re germline negative, you might have a somatic mutation.

Gottfried E. Konecny, MD: Recent data suggest that approximately 10% to 15% of unselected patients with ovarian cancer have a germline mutation, but then there’s another 5% to 10% who have a somatic mutation, meaning they developed it in the disease process. And recent data show that they also respond well to PARP inhibitors. So, the question is, do you extend your germline testing to somatic tumor testing? I think that’s an ongoing debate.

Bradley J. Monk, MD: I used to think, “Why did I just test the tumor?” Because germline mutations are present in the tumor. But I think you have told me that I need to do a germline panel. I understand, we test for BRCA. What’s the role of panel testing? What are the other germline genes?

Katie Moore, MD: There are panel tests available, and they include a variety of genes. But the ones we think are important right now—and this may change—are, of course, BRCA1 and BRCA2, but also BRIP1, RAD51C, and RAD51D. And PALB2 may become important for ovary cancer treatment. It’s certainly important in breast cancer treatment. So, I think that’s on the list. And so, those are roughly 1% to 2% frequency genes. You don’t find them often, but we increasingly believe that they’re high-penetrance. They import the same risk of developing cancers as BRCA1 or BRCA2, and we’re treating them and doing cascade testing for them, just as we do for BRCA. So, you should treat them very similarly and counsel their families, importantly.

Bradley J. Monk, MD: The NCCN guidelines give some guidance, right, in how to handle the family member who might be positive, regarding mammography and colonoscopy?

Katie Moore, MD: Right.

Gottfried E. Konecny, MD: Would you then just skip testing for BRCA1 and BRCA2? Would you go straight to gene panel testing to cover a bigger group of patients who may potentially benefit or would you wait and see first?

Katie Moore, MD: We’re sending panel testing from the beginning. That’s what our institution does.

Matthew A. Powell, MD: Yes, that’s our process as well.

Robert L. Coleman, MD: We do the same, and this is an evolving field. So, we started out very focused, and now we’re expanding. And as we learn more, more of these will come.

Bradley J. Monk, MD: I hope that a lot of people listen to this. I think we’re all doing panel testing. But the American Society of Clinical Oncology, the National Comprehensive Cancer Network, and the Society of Gynecologic Oncology only say, “Test everyone for BRCA.” Do these groups need to reassess the guidelines and really say that we should test for all ovarian cancers for the panel that you suggested? Wouldn’t it be helpful if we could have some consensus guidelines?

Gottfried E. Konecny, MD: I think they’re coming.

Bradley J. Monk, MD: Are they?

Robert L. Coleman, MD: Yes.

Gottfried E. Konecny, MD: Well, if your look at the association of familial risk, I think there are good data out there to show that they are linked to an increased risk of breast or ovarian cancer. But regarding response to PARP inhibitors, we don’t have very solid data, yet. But for familial risk, yes, it should be standard of care.

Bradley J. Monk, MD: Even Lynch syndrome genes increase your chance of having ovarian cancer. So, again, that’s more the role of panel testing.

Gottfried E. Konecny, MD: I agree.

Robert L. Coleman, MD: I just have one comment, because Katie mentioned highly penetrant genes. There are now, emerging, a number of low-penetrant genes, which also seemed to carry familial risk, and those are starting to be looked at carefully. Like I said, it’s an evolving, dynamic field—very exciting.

Transcript Edited for Clarity