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Neal Shore: Hi everybody. Neal Shore, Medical Director of Carolina Urologic Research Center. I'm a uro-oncologist and I'm really pleased today to be joined by two co-authors and co-investigators. Sarah Nielsen, she's a certified genetic counselor. And Dr. David Wise, who's the Director of GU oncology, a medical oncologist at NYU Langone. I think the three of us have been really steadfastly working on a topic that is very near and dear to our hearts, but also intellectually, and that is the importance of broadening, democratizing, or creating universal accessibility to germline testing for prostate cancer patients. By way of a little background, we wrote an editorial in the JCO back in September 2022, Sarah and myself, and multiple solid tumor experts in breast colorectal, ovarian cancers. And that was published on September 15, 2022, and was entitled Universal Genetic Germline Testing for Hereditary Cancer Syndromes in Patients with Solid Tumor Cancer.

We're very proud of that, and as it got published there, and that was really on the heels of a large thousand patient prospective study that Dr. Wise and Sarah Nielsen and I and multiple co-authors did. I think we're going to talk more about that, called the PROCLAIM Trial, and that's about to be published now in European Urology Oncology. And we previously presented the results of that trial in oral presentations at oral podium presentations at ASCO and also AUA. But most recently we were really fortunate to be asked by ASCO to publish in ASCO Daily News, which came out July 12th, 2023, an article we published called Understanding the Underutilization of Germline Genetic Testing in Prostate Cancer.

So a lot to unpack, but really the common theme is how do we further democratize, allow for universal applicability accessibility for all of our colleagues, healthcare providers who are taking care of patients with prostate cancer, and what are the implications for greater accessibility for germline genetic testing, so specifically for prostate cancer. So with that, let me stop and hand it over to you, David. Tell me about some of the thoughts on this topic and where we've been working, maybe you want to just first touch on this article that we published in ASCO Daily News and at some point let's talk about the PROCLAIM trial too.

David Wise: Absolutely. So that's a great introduction, Neal, and it's so great to work with you and Sarah on this really important topic for our patients. As you mentioned, we're trying to democratize and I think that it's where we need to operate on two levels here to really make this happen. The PROCLAIM study was really operating on the level of the science, right? Really looking in more depth at the types of clinical characteristics that might predict which patients should get germline testing. And what we found is that there are no good clinical characteristics that clearly should restrict some patients from not getting tested. And so this really suggests to us that we should probably be thinking about discussing with those who are developing guidelines to think about broader guidelines about testing more patients.

And then, of course, there's the other level, which is the logistical level, which is even if we should be testing all of our patients. Well, clearly, not all patients are getting appropriately tested even when we know that they should be. And that's a national problem. And that was really the focus of the article, which was this underutilization. So I think that on that level, there's a lot to discuss, but certainly some take home points that were really emphasizing the article, which is we really need to focus on getting better data on how to better expand the patients that really should be getting tested.

Neal Shore: Yeah, I mean, great points. I mean, what we know is certainly the explosion in NGS as it's often been called Next Generation Sequencing. I think that's a little bit too vague. I think what we've discovered is not even everyone understands the difference between germline hereditary versus somatic or acquired genetic testing. The NCCN, and they do a great job, they review all the different levels of evidence. And if you go to the NCCN, you'll see this long list of indications for doing germline testing. What's really provocative to me is that essentially germline testing, and for prostate cancer patients is recommended right now for almost everybody except for grade group one and two localized disease, and particularly those patients who don't have significant family histories of cancer.

So all metastatic sensitive patients, all metastatic resistant and high risk localized grade group three, four, and five regardless of their family history. So Sarah, maybe you want to comment on why we think that it should be broadened to include the grade group one and twos, and particularly the ones who may say they think their family history is unremarkable or maybe they don't really accurately know their family history for cancer.

Sarah Nielsen Young: Yeah, Neal, that's what I was going to comment on is a lot of patients are unaware of their family history or they just don't have large enough families for it to be informative. And aside from the genetic testing being relevant for current treatment, and maybe that may or may not be the case for these lower grade diseases, you could argue it certainly can factor into active surveillance discussions. It's important to remember the information's relevant for their at-risk family members. And if those patients with lower grade disease progress, then the information can be relevant for future treatments too. So I think based on the PROCLAIM study, the more we restrict testing, the more we're inadvertently missing people who don't have a family history or where the guidelines weren't really designed to, they weren't studied based on underrepresented populations.

So you're missing these patients who just don't have the opportunity for that personalized therapy because they don't meet certain criteria, because maybe the criteria wasn't designed around them in the first place. So I think it just goes back to the democratizing testing, the broader the inclusion criteria. Frankly, the less cumbersome it is for clinicians to have to look through and say, "What very specific family history does this patient meet or not meet?" They may not have time in their consult to be doing that. It's easier to just say, "Everyone qualifies for testing," have an informed discussion, let the patient decide if it's something they want to do at that time or not, but really give it as an option to everyone who could benefit.

Neal Shore: You bring up some really great points. Number one, look, pathology is an art form and there's interpretive difference. So what someone may call a grade group two could actually be a grade group three by another pathologist's standard. So there is interpretability issues there or there's uncertainty. And additionally, a lot of patients and their family members, they just don't know their family histories. And I think that's what we've seen universally across all different cancer types. And then, a third point you brought up, which I thought was great, is so much of our genetic analyses are based on white European population. So patients of color are largely underrepresented. And where our knowledge is really somewhat limited in terms of appreciating both germline and somatic testing, I think we'll talk a little bit more about that with our results from PROCLAIM. And then the fourth thing is germline testing has really, just the economics of it has become much more reasonable over the years.

So I think to your point, if we just said anybody diagnosed with prostate cancer because it is so much more affordable now, let's get the test. And granted it's not going to have a hundred percent clinical utility, but certainly there's going to be values for patients who might have an alteration for approved therapies today throughout the prostate cancer continuum, PARP inhibitors, that tumor agnostic indication for pembrolizumab with MSI high or TMB high clinical trials. And then very importantly, the family members who are at risk who would then potentially be able to get some improved surveillance and screening for other cancers besides prostate cancer. So David, maybe you want to comment a little bit about what we learned in the PROCLAIM trial. You were a key author on that and it was great having NYU involved in that trial. Maybe give our audience some top line interpretations about what we found and what was the basis of that trial.

David Wise: Absolutely. So this was a multi-site trial actually involving a consortium of both community urology practices and academic oncology practices, where we were really looking at asking the basic very simple question which is, how many germline variants are we missing by only testing patients who are currently in concordance with the NCCN guidelines? And so we looked at about a thousand patients, half of whom were in the guideline recommendations and the other half who were not. And we found a strikingly similar prevalence of pathogenic variants in both populations, number one. Number two, like you mentioned in minority populations, we did find higher rates of variants of undetermined significance, which really goes towards the point that you mentioned before, which is that with fewer patients in our databases who are minorities, we have less and less clinical validation of the characteristics of those variants.

We don't know if they're pathogenic or not, they're still considered variants of undetermined significance. This just goes to the point that we need to democratize testing. And then finally, in the data that we presented most recently at the American College of Medical Genetics meeting, what we found was that the vast majority of these variants, both in patients who are tested by guidelines and both were tested out of NCCN network guidelines on the clinical trial, we found a very high rate of actionability. And the actionability was really a broad characteristic, actionable from the standpoint of changes in therapy, but also actionable from the standpoint of cascade testing, and that was really the key.

And so I would say that this study really hammered home a lot of the same points that you made and also really from some of the other data really just goes to the need to make the guidelines simpler, number one, and the need to help inform and educate community practitioners on what these variants mean and how to follow them up. And I think we can talk a little bit later with Sarah on different approaches that we can incorporate to make testing more doable and feasible in the community practice setting.

Neal Shore: That was a great overview, David. Thanks so much. Sarah, it's been a pleasure working with you on this project for the last few years. It's great having uro oncology, medical oncology and expertise of genetic experts such as yourself and genetic counselors. We keep expanding this notion of the multidisciplinary team, but I think it's really important that just genetic education, which if you have a counselor, fabulous, but if you don't have a counselor, you can still do this testing. And I think the burden on us all as healthcare providers, whether it's MDs or advanced practice providers, nurse practitioners, physician assistants, we want to get these reports so that patients can be further informed, and for their families for cascade testing as David says, clinical trials and the clear FDA approved actionability of therapeutics. But Sarah, some of your thoughts on the PROCLAIM study.

Sarah Nielsen Young: So I think the PROCLAIM study was very informative in terms of what David alluded to is that we didn't look just at the rate of PGV findings, we extended it. We looked at what our clinicians are actually doing with these findings. Are they acting on them? Are they acting appropriately on them? And then actually in subsequent publication, we'll look at how patients understood their results and acted on their results. So I think it was this three-pronged approach where we're beyond now in genetics looking at the yield of testing. We know that germline testing is necessary. We know the yield is high enough to do it, but what we're more concerned about is what actually happens once the testing's done and how does that information get delivered to patients, how are providers understanding it. So I think that's also what makes the PROCLAIM study really novel is it's a meaty study where there's a lot to report on.

And I think that prostate cancer is a good example of where we can be using these novel genetic service delivery models. Because we don't have as much history of germline testing in prostate cancer as we do in breast and ovarian, where there is this precedent where you had to meet with a genetic counselor, spend an hour going through your genetics education, your family history, then meet with a counselor again to receive results. I think since testing's newer in the prostate space, there's more flexibility and we know that men learn differently and may need a different amount of education than breast or ovarian cancer patients. So a lot of the literature actually in these novel service delivery models are in prostate cancer. So we outline those in our ASCO Daily News article about how they've been shown to be successful that using these more abbreviated pretest education videos or using telehealth.
I think in prostate cancer, and what we learned from the PROCLAIM study is been a successful model is what we call a hybrid model where the urologist or oncologist will order the genetic testing upfront, and then for any positive results or complex or uncertain results, we'll refer downstream to a genetic counselor if it's available. But we do highlight in the article, one of the take home points is it's a collaboration between providers, patients, geneticists, genetic testing laboratories to provide these post-test services to help not just the patients, but the clinicians understand what are the next steps when I get a result. What's the best way to deliver this information in a way that patients and clinicians can understand and actually act on? Because it doesn't mean anything if we're testing people and then not doing anything fruitful with the results.

And the last point I'll make there is that there's so much emphasis on positive results and what the impact that has on the patient and the family. But I don't think we should discount that it is valuable information to get a negative result that that can, actually, in some cases, deescalate treatment or at least provide reassurance to the patient and their family members. So although you look at the statistics, you say, "Yeah. It's a relatively small chance to get a positive result," there's also value in negative results as well.

Neal Shore: Yeah, that was great. You're absolutely right. I mean, the health economic outcome reporting of a negative result, the implications to the healthcare system financially could be remarkably positive. And even a positive result where you can detect a cancer in a family member early or change your therapy, which is really what we saw in PROCLAIM. But interestingly, not all of the recommendations by our physicians were necessarily sensible, to be perfectly blunt. And that's where we need more education, understanding what does a VUS really mean. But at least getting patients into the system so that VUSs in the future that may be reported later on as PGVs, especially in underrepresented populations becomes very provocative and important. So those are just tremendous comments from both of you. Let me just wrap up by saying David and Sarah, any final thoughts. David?

David Wise: Yeah, I think my final thought is these PGVs are relatively uncommon, but when we find them, they can have a massive impact on people. And I'm sure, Neal, you have patients like I do with Lynch syndrome or MSI high, and you see some of the durable responses they can have to immunotherapy. People that otherwise would've gone on down the chemotherapy and more and more AR targeted therapies and not be cured. And then you see them have multi-year complete responses, and yes, that's only anywhere between 2% and 5% of cancer. But when you find it and you make that dramatic impact, that it's certainly worthwhile when we're talking about doing a test in order to find that patient. So I think that there is an infrastructural demand here to make this happen. I think simplifying the guidelines is definitely one important way that we can do that, but it really is something that deserves a lot of effort to be able to identify these changes for our patients and potentially their family members.

Neal Shore: I couldn't agree more. When you find a positive PGV, it's oftentimes one of these eureka moments, as for the clinician. And of course all the PARP inhibitors that are now getting approved, whether it's monotherapy or in combinations and could potentially move up into the sensitive population that clearly now have a role in resistant populations. But thanks, David. That was great and it's been such a great pleasure to work with you and to you said earlier, having our tertiary academic centers working with community and PROCLAIM, which was 15 different trial sites, a thousand patients in the U.S. prospectively captured. Sarah, final thoughts?

Sarah Nielsen Young: Yeah, really echo and agree with everything everyone said. I think the next steps here, we want to hear from people. We want to know who's doing this already, how are you implementing this? I think we can all learn from each other. There's not one way to do things, but I think the next step is implementation studies and seeing how this is actually working or not working, and how we can problem solve together.

Neal Shore: I think that's a great point. I mean, you alluded to it. And over the course of the last few years we keep evolving how we make this demystify the implementation and enhance the learning so that everybody benefits, particularly with germline testing for the patient, their family members, clinicians, patients, what are the responses and even the health economic implications, of course. With that, Sarah and David, it's been really a pleasure. I know we have a few more publications we're going to be getting out into the literature, so thanks very much for all your efforts.

Sarah Nielsen Young: Thank you. My pleasure.

David Wise: Thank you, Neal. Yup, agreed.