Angeles Alvarez Secord, MD: I wanted to back up and talk about that, because now we’re in a situation where it’s maintenance treatment in the second-line setting, and how you made that decision to continue going on with the maintenance bevacizumab versus, do you change to another drug if you have just a partial response. And so, as a physician, when I’m considering maintenance treatment in a situation and somebody has a complete response or a partial response, I think it’s very reasonable. If somebody has progressive disease, then you might make a switch to the right chemotherapy option, but now we have another option, which is PARP inhibitors. If somebody has a BRCA1 or BRCA2 mutation, it could be an option that opens up another situation. So, this gets into the whole situation of what’s maintenance? What’s treatment? As a patient, do you feel like that’s difficult to understand or keep those 2 apart?
Michelle Berke: No. They overlap a little bit, too, because, like you said, I’m on a PARP inhibitor now, and it’s treatment but it’s also maintenance for me, right?
Angeles Alvarez Secord, MD: Well, you’re on it for a treatment, but you definitely responded. And so, it is kind of…
Michelle Berke: It’s kind of like treatment now, because I am doing so well on it, so it overlaps a little bit.
Angeles Alvarez Secord, MD: I agree with you 100%. I think it’s hard for some people to leave that out. So, if somebody has a complete response in that situation, and even partial response, some people lump together under the maintenance. Other people will say, “Hey, wait, you have a partial response, you’re treating cancer, and that’s treatment. Or even if you have a complete response, you still have cancer there because we know it’s going to come back so quickly, that’s still treatment.” So, the lines are blurred.
Michelle Berke: It’s very blurred, yes.
Angeles Alvarez Secord, MD: But they’re important distinctions because some of the FDA approvals for PARP inhibitors are treatment approvals and others are maintenance approvals. I like the way you think about it though. I think that’s good. You had a partial response to chemotherapy so we kept on the bevacizumab for quite some time. And you were tolerating that well. You had some issues with your blood pressure.
Michelle Berke: About 6 or 7 months, yes, blood pressure was a little high on that. I think that’s why we stopped it.
Angeles Alvarez Secord, MD: Actually, you progressed, and we actually had to work a little bit to get your blood pressure under control. But we were at a point where it was stable, so we were okay with that.
Michelle Berke: And now, it’s under control. I’m not on blood pressure medications or anything right now.
Angeles Alvarez Secord, MD: Which is probably awesome.
Michelle Berke: Yes, I’m happy.
Angeles Alvarez Secord, MD: Explaining how PARP inhibitors work can be pretty confusing. So, I’ll try my best.
Michelle Berke: Alright, it is.
Angeles Alvarez Secord: So, the BRCA1 and BRCA2 genes are involved in DNA repair pathways, and there are a whole bunch of different DNA repair pathways. They’re involved in the most efficient ones with double-stranded breaks. The PARP inhibitor is involved in single-stranded breaks. So, the whole idea here is if you block off DNA repair, because somebody has a germline mutation in BRCA1 or BRCA2, or they even have a tumor mutation, a somatic mutation, the DNA won’t repair itself as well when it’s subjected to injury from chemotherapy or radiation and so forth. And so, it’s more likely for that cancer cell to die when it’s exposed to that treatment. When you add a PARP inhibitor on top of that BRCA1 or BRCA2 mutation, then it creates a situation where now you lose your other DNA, another DNA pathway repair.
Michelle Berke: Oh, interesting, OK.
Angles Alvarez Secord, MD: So, if you have a single-stranded break and you can’t repair that, then you’re more likely to have these double-stranded breaks. And if you’re BRCA1 and BRCA2 deficient, then it’s more likely to lead a cancer cell to a death pathway, essentially. So, that’s how it works. But it’s much more complicated than that. There’s all these other enzymes and proteins involved in DNA repair. The other way these drugs work is called PARP trapping.
Michelle Berke: Trapping?
Angeles Alvarez Secord, MD: Trapping.
Michelle Berke: OK.
Angeles Alvarez Secord, MD: So, when the DNA is under the process of repair and the PARP enzyme is on the DNA repairing it, if you have a PARP inhibitor, it traps it there on the DNA so that no repair can happen. So, sometimes it’s stronger. The PARP trapping is one of the fastest ways these drugs can be more effective. We haven’t seen that clinically, but that’s another mechanism of repair. And then quite frankly, I think there’s probably another way that this drug works that we don’t fully understand, because we are seeing that benefit in the all-comer population.
Transcript Edited for Clarity