Taking Action to Individualize Ovarian Cancer Care: Effect of BRCA on Treatment

In this first episode of OncChats: Taking Action to Individualize Ovarian Cancer Care, John Nakayama, MD, of the Division of Gynecologic Oncology, Allegheny Health Network, and assistant professor of OBGYN at Drexel University, and Christopher B. Morse, MD, gynecologic oncologist, Allegheny Health Network, discuss how BRCA mutational status affects treatment decisions for patients with ovarian cancer.

Nakayama: We are focusing today on gynecologic malignancies, particularly in ovarian cancer. The goal of this video blog and its subsequent episodes are to review important [updates] in cancer treatment and how Allegheny Health Network is able to treat cancer. I'm joined today by Dr Christopher Morse. He's one of the gynecologic oncologists at Allegheny Health Network.

Chris, I have been thinking about this a lot, and I feel like ovarian cancer treatment has totally changed. Can you talk to me about how you think about BRCA and how that affects your treatment of your [patients with] ovarian cancer?

Morse: Yes, and I agree with you. The landscape and the treatment paradigms that we use for treating ovarian cancer in the past decade have really changed dramatically. A lot of what has led to that change is the testing of patients who carry a mutation, such as BRCA1 or BRCA2, which not only puts them at increased risk for developing ovarian or breast cancers, but also leads to defects in the way that their DNA is repaired through something called homologous recombination deficiency (HRD), which we will review shortly.

What is really interesting about these defects is that we can target [them] with new therapeutics called PARP inhibitors, which have really revolutionized the way that we think about treating patients—not only after their initial surgery and chemotherapy with maintenance therapy...but also possibly during later lines of treatment, as well. As such, I think [this has] really shifted the paradigm of how we treat ovarian cancer, and it has greatly improved the quality of life for our patients, as well as progression-free survival.

Nakayama: I could not agree with you more, and I really loved what you said about the repair mechanisms. I am just going to show my inner nerd right now. I think that the most important thing is to really understand how your drugs work. As you alluded to, I am going take the attempt to show everybody what we are talking about.

Overall, HRD is a repair of double-stranded DNA, right? So, let's make both of the helixes here. What happens when you have cancer is that occasionally you will have a break; you will have a bit of DNA off, which, obviously, you know. Then, you have homologous recombination, like you mentioned. Because homologous recombination is a high-fidelity repair mechanism, you will get your DNA—and let me just highlight that bit that got repaired—and you have a very high-fidelity repair, which is wonderful. What is important, though, as you alluded to, is BRCA.

BRCA is absolutely critical to homologous recombination. If you knock out BRCA, you lose your homologous recombination, as you mentioned before. Now, if you lose that, what people will default to is generally single-stranded DNA repair. The most common one that people talk about is base excision repair. Please excuse my terrible doctor handwriting.

Of course, Dr Morse knows all of this already, but what happens is people will default to this base excision repair. Now, you have a situation with BRCA carriers who already have the HRD loss. If you take out the base excision repair, [suddenly], you have a problem. That is exactly what PARP inhibitors do; they take out that base excision repair and then you cannot repair your DNA, [which] leads to cell death or fancy word would be apoptosis.

Check back next Wednesday to view the next segment in this series.