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Andrea Miyahira: Hi everyone. I'm Andrea Miyahira here at the Prostate Cancer Foundation. Joining me today is Dr. Hiba Khan, an associate professor at Fred Hutchinson Cancer Center. Dr. Khan just presented a poster at ASCO on germline genetic associations in a large prostate cancer cohort. Dr. Khan, thanks so much for joining us today.

Hiba Khan: Thank you for having me. I'm so happy to be here.

Andrea Miyahira: Prostate cancer is one of the most heritable types of cancer, with over 50% having a genetic component. Many DNA repair mutations have been identified in the germline, most commonly BRCA2, and this has led to recommendations for all patients with advanced or aggressive prostate cancer to receive germline testing. This is important so that patients can know whether they're eligible for PARP inhibitors, but also to trigger cascade genetic testing. So, what were you specifically looking at in this study?

Hiba Khan: In this study, we wanted to take advantage of a large database that was available to us through Invitae, which is one of the largest companies that does germline genetic testing commercially. They had great linkage with a medical records database that allowed us to access coding records along with genetic testing results, and there was a linkage between them. The idea for the study was to see if we could identify some gene-specific associations, including things like population trends, demographic trends, and perhaps geographic distributions that could give us some idea of populations that were perhaps being left behind in testing or to get a broader equity, diversity lens to see where we can make the most impact for the most populations.

Andrea Miyahira: Okay, thank you. Can you describe the patient cohort, including the racial and ethnic demographics, how patients were selected, and how germline testing was done?

Hiba Khan: Yes. This was commercial testing, so they had results for most of the genetic testing that they had done. Any patient that had a prostate cancer code and had undergone genetic testing was included in the cohort. The cohort was predominantly an older population. The median age was 64. The patients were primarily of white background; 66% were white. We had 11% Black or African American ancestry, and about 4% were Hispanic or identified as Latino.

Andrea Miyahira: What were your major findings on pathogenic germline alterations? Was there anything that surprised you?

Hiba Khan: Yes, the major finding was, I would say, not a surprising one, which, as you stated earlier, BRCA2 is known to be a very common heritable mutation that can serve as a driver for prostate cancer. And so that was the most common mutation we found across all racial ethnic groups and geographic distributions. We also found that BRCA2 was associated with more advanced and metastatic disease, also not a surprising finding.

There were a couple of findings that were interesting to me. One of those was that patients with BRCA1 and MMR mutations actually tended to have less aggressive disease. In addition, those patients with BRCA1 and MMR gene mutations, many of them were screened before their prostate cancer diagnosis. So they were found to have had these mutations and then later subsequently developed prostate cancer. So those two things in combination make me think: were those patients perhaps getting screened for prostate cancer more than the average population? Those were a couple of surprising findings. The other major finding was that only a quarter, or 25%, of our patients in the cohort had a code for family history of prostate cancer, which drove the genetic testing. The rest of the patients were screened based on only personal history of prostate cancer.

Andrea Miyahira: Okay, thank you. We've seen in studies from Asia that driver alterations can be significantly different than studies performed in predominantly European ancestry populations. So what was the frequency of Asian and other underrepresented populations in this study?

Hiba Khan: We did not actually have a very large Asian cohort. Only about 2% of our patients in the cohort were Asian. So it was very difficult to sort of make gene-specific associations and find those trends in the Asian population. What is interesting, though, is that about 10% of the cohort had an unclear race. They were either unknown or it was left completely blank. So I wonder if some of those patients were perhaps other minorities that we weren't capturing. It could include Asian populations, it could have been Native American populations or patients of mixed race ancestry and background that we're not capturing.

So, again, it drives home the importance of conducting these kinds of large population-based studies and including race, ethnic background, and similar information so that we can see what the trends are and be able to intervene appropriately if we see that a population's needs aren't being met, to just ensure equitable, both genetic testing, and as you, again, said earlier, just precision-based treatment with PARP inhibitors and immunotherapy.

Andrea Miyahira: Can you contrast germline testing with other methods such as polygenic risk score for identifying patients at risk?

Hiba Khan: Yes. I think polygenic risk scores are very interesting, and I think we're learning a lot about how we can use them, again, on a very large population-based level. There's some great work being done currently at Fred Hutch Cancer Center to look at how we can use polygenic risk scores in a large population-based manner. I think we're still learning about them, and I think germline genetic testing can be in concert with polygenic risk scores, and we can use them simultaneously.

Andrea Miyahira: And what are you and your team doing next in this study?

Hiba Khan: I think it'll be really important, actually, to use that really great data to look at treatments and actually outcomes. That's kind of an interest of mine, is to see if we can identify disparities, can we drive a little bit further and see if there are disparities in treatments or disparities in just large populations like we have to see where if it impacts treatment and outcomes in the future. So I think that's one next step of this study. And then in the future, I think we can use all this information we're gathering to hopefully drive some interventions forward to make cancer care and prostate cancer care in general more equitable.

Andrea Miyahira: Thanks. What would be your key take-home messages for patients and providers?

Hiba Khan: One thing that was really interesting that we found in this study was only a quarter of patients actually had a family history that was coded for. So again, as the guidelines suggest, it just drives home the importance of doing genetic testing, germline genetic testing based on personal prostate cancer history and risk. My ultimate hope is that the more patients we can get tested and screened, not only will they be eligible, potentially, for precision therapies, but we can also screen their family members and loved ones through cascade testing to hopefully find more people who have these germline genetic mutations to impact screening and ultimately the development of prostate cancer and help make a dent in prostate cancer outcomes.

Andrea Miyahira: Okay. Well, thank you so much, Dr. Khan, for joining me. It was really a pleasure.

Hiba Khan: Thank you very much.