Pedram Razavi, MD, PhD: For germline testing, I—and this is the approach that we are trying to promote here at MS—we are going for wider, earlier, genomic-germline testing for the patients. We are not there yet, to offer universal testing, but I think that's where we're going soon: offering universal germline testing to our patients. And it has implications even in first-line setting. And this is mainly coming from the research, but there is going to be some implications in clinical practice, hopefully soon, as well. And we're finding the interactions between these germline alterations and the somatic alterations, the ones that are unique to the tumor. And with some of these germline alterations actually alter the mutational profile of the tumor [and] make them more or less likely to respond to certain therapies. For example, more recently reported on BRCA alterations, specifically BRCA2, germline alterations resulting in CDK4/6 inhibition resistance. And we have identified the mechanism for that as well. So, I think this becomes a good point for us to have an eye on it. So, if we have a germline BRCA2 patient, I have a closer eye on that patient when I put the patient on CDK4/6 inhibitor. Not that I change my first-line treatment, but I have a closer eye. And then I have PARP inhibitor as my second-line setting, second-line treatment whenever this patient has evidence of progression.

Joyce O'Shaughnessy, MD: Awesome. Great. That was super, guys. Thank you so, so much. And I'm going to—I have lots of questions but—I'm going to go ahead because we have other good topics here. We talked a little bit about germline testing and I'll just put something out here and see what you guys think. It's so important now with the PARP inhibitors to not miss germline BRCA. There's lots of good reasons not to miss germline mutations but from a therapeutic standpoint, we got BRCA1/2, even germline PALB2 that we can offer patients PARP inhibitors. But it was a bottleneck at genetic counseling, upfront genetic counseling, so we started doing more of it at point of service in the clinic and then referring patients who have deleterious alterations or even variants or what have you, or people who want to go, but really not miss those patients. I'm just curious at Memorial, Pedram, what's happening there?

Pedram Razavi, MD, PhD: That's what we do here, as well. So, actually, we have simplified the process. We have a [INAUDIBLE] genomic protocol here, so the patients watch a 15-minute video, educate them on benefits and some caveats with the germline testing. They make an informed decision to go ahead with the germline testing. And then, again, as you just mentioned, not to overwhelm our clinical genetic service, only the patients who have a pathogenic alteration or the patients who have a VUS [variant of uncertain significance]—those are important—some of these VUSs, when they go on the database and they have a consultation, they may decide that this might be deleterious next year or might become completely benign next year. So, we send those patients also to the clinical genetic service to have a consultation. And there is a small subset of patients; the ones that have very strong family history, something else going on, but the germline testing that comes back negative, are still those patients who meet the criteria, it's better to send them to the experts so that they can look at the data, look at the type of analysis that have been done, and maybe sometimes even enroll them in certain studies that we have to understand some of the unknown germline alterations associated with the risk of cancer. So, I think for that reason, strong family history is still a good reason to send them even if the patient has a negative testing marker. That has been a way for us not to overwhelm the system, but at the same time, offer the germline testing to almost all of our patients at the point of contact.

Joyce O'Shaughnessy, MD: Thank you. Komal, anything you want to add about germline testing in your practice?

Komal Jhaveri, MD, FACP: No. I think early stage, I think I want to say that wherever we want to apply the approval of a PARP inhibitor in early stage is where we think, certainly we don't want to forget about germline testing. So, as Pedram was saying, you want to try and offer it to all in the metastatic setting because we have approval for drugs in the early stage of these based on the OlympiA [NCT02032823] trial. All the triple-negative breast cancer patients and ER-positive breast cancer patients would have met the eligibility criteria for that study. We certainly don't want to forget that as an option because clearly that is where we've seen a dramatic disease-free survival benefit with this class of drugs in early-stage disease. So, I think this has been something that we want to do and we do in clinic.

Joyce O'Shaughnessy, MD: Yeah, very important. Lifesaving therapy right there in the adjuvant setting with olaparib for the germline BRCA1/2 patients.

Transcript is AI-generated and edited for clarity and readability.