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Zach Klaassen: Hi, my name is Zach Klaassen. I'm a urologic oncologist at the Georgia Cancer Center in Augusta, Georgia. I'm delighted to be joined on UroToday by Neal Shore and Sarah Young, who are going to be discussing their new paper that was recently published in JCO Oncology Practice, "Implementation of Universal Germline Genetic Testing Into Standard of Care for Patients With Prostate Cancer: The Time Is Now." Both of you, thank you so much for joining us on UroToday.

Neal Shore: Thank you.

Sarah Young: Thank you.

Neal Shore: I'm so happy to be on this program today with you and Sarah. Sarah and I have been working with the importance of lifting knowledge on education for germline genetic testing. So we’re really proud of the paper, really proud of the authorship on the paper as well.

Zach Klaassen: I think it's a beautifully written piece. And I know you guys are going to share some slides and get into it. But I will say, when you think about genetics—I'm not a geneticist, I'm a surgeon—I was able to read it. It’s very clearly outlined. It’s an easy read. It’s a very important read, as we'll get into some of the details that you guys highlight. So I just want to throw that out there for the listener: you don't need a PhD in genetics to get through this paper. So I'd love for Sarah to pull up the slides and go through some of the highlights.

Sarah Young: And yeah, as Neal said, we have been working together for a long time now. I have been working in genetics of prostate cancer for over 10 years. And this paper is a nice kind of reflection on where we've been, where we're going, and how much more traction we're getting now. I don't think we've caught up yet with the breast-ovarian cancer world, but I think we're getting there. And I think this paper is proof, like you said, just by virtue of the author list, that we're changing hearts and minds in terms of the importance of genetic testing.

All right, so, yeah, I will go into some background on some topics that were covered in this paper. And this is just a snippet of, again, that very impressive author list.

Neal Shore: I think what's great about that author list, Sarah, is it's medical oncologists—academic, largely—uro oncologists, academic and in the community, and genetic experts with PhDs. And I think that's really one of the proudest things for me about the co-author list.

Sarah Young: Indeed. So just some key takeaways here. We try to illustrate that there is utility across the disease spectrum in prostate cancer in detecting these pathogenic germline variants. So it’s not just the metastatic castration-resistant disease; we are finding unexpected findings and utility across all stages, which we'll talk about.

And importantly, an appreciable number of prostate cancer patients with these germline variants would be missed by current testing criteria. And that's particularly true in some of the underrepresented populations, like the Black population. And we have some data to show that as well.

So really, in a nutshell, our recommendation is that in order to fully realize the benefits of precision oncology, precision medicine, we should be offering comprehensive germline genetic testing to all prostate cancer patients. We realize there's more work to be done to implement that recommendation, for providers to uptake that, for insurance to recognize that, but we believe it at least should be a choice and something that clinicians can discuss with their patients and together decide if it's something that they're interested in.

So in terms of the benefits of germline genetic testing in prostate cancer, these are familiar benefits that people know about, but just to reiterate: for patients, we know that genetic testing can help guide medical management. And this is true now more than ever, again, in this age of precision oncology. Germline genetic testing used to be thought about just for the benefit of family members or for risk of second cancers, and those applications are certainly true and important, but now we know that germline variants can qualify patients for targeted therapies.

So, particularly in prostate cancer for PARP inhibitors—and that is not just BRCA1 and 2; actually, it's a long tail of homologous recombination repair genes, which we're still learning the utility of in genes outside of BRCA2 and ATM in prostate cancer. But that's where clinical trials come in, which we'll talk about too. And those clinical trials often required germline or somatic eligibility.

And for family members, the importance of testing can't be understated. Particularly with prostate cancer patients, testing their relatives to understand both the risk of prostate cancer but also cancers like breast, ovarian, or pancreatic cancer—cancers that often present at later stages like ovarian and pancreatic cancer—whereas if we knew sooner via cascade testing, we may be able to detect early or even prevent these cancers.

This can also inform risk for future generations as well, and make it clear who in the family is at risk and who is not, so that individuals who are not at risk don't have to undergo any of these additional screenings or preventative measures.

We've learned a lot over the years, as I was alluding to in the beginning, about prostate cancer and the genetic risk associated with it. And we know that prostate cancer—it’s more than just a disease of aging that will happen if you are old enough. There are risk factors, and we know that as many as 1 in 5, or 20%, of patients may have a hereditary risk for prostate cancer.

A lot of studies have been done in different settings or categories of risk. So on the far left here, you have the studies looking at advanced or metastatic disease. This would be, for instance, the Pritchard et al. paper—I believe that was in 2016—that got this whole field started. And that, along with studies from Memorial Sloan Kettering, showed the risks between 12% and 20% for metastatic disease for carrying one of these germline variants. And it's that important percentage that led to the recommendation to test everyone with metastatic or advanced disease.

But as we move along the spectrum, we see that the risk is also prominent in other categories of prostate cancer or other studies that have been done. So there have been retrospective studies, often these lab-based cohorts or biobank-based cohorts of, quote unquote, "unselected" patients. But any patient who's been tested at a genetic testing lab, obviously, has some other risk factors or reasons to be tested. Those studies have shown between 10% and 17% risk of finding one of these germline variants.

The most informative studies, which are sometimes the hardest to do, are these prospective studies. And we will talk about one in particular that we led, called the PROCLAIM trial. This is where we're testing unselected patients across all stages of disease, regardless of family history, regardless of any other personal history characteristics.

This gives us a true idea of the true incidence of identifying one of these variants. And those studies have shown between 8% and 14% of patients carry these variants, so certainly a lot more prevalent than we might have thought when we were only looking at advanced or metastatic disease.

Certainly, on the lower end of the spectrum—but still clinically relevant—is the localized or low-risk disease, where the risk could still reach around above 10% for carrying these variants. And as we'll talk about, knowing the risk there can be important for management of localized disease, as it relates to active surveillance conversations or having a lower threshold for intervening with surgery.

So we know that the yield of germline testing is very significant, is important. I don't think the argument anymore is whether we should do testing; is the yield high enough? It is. But we need to be able to show the clinical utility. And I think in prostate cancer we have shown that across, again, this spectrum of disease.

So to the left here we have those at risk for prostate cancer, where there's a variety of studies—one led by the NCI—where they are considering germline risk in terms of how to screen for prostate cancer. And then across the spectrum, you can see the clinical trials in blue. To the very far right, you see those approved targeted therapies, growing by the day, that include both germline and somatic eligibility—starting with olaparib and progressing now to these combination therapies and, of course, pembrolizumab, the tumor-agnostic approval for mismatch repair deficiency.

Neal Shore: Even since this slide, we also now see for patients who are HER2-positive, there's a tumor-agnostic indication now for T-DXd. And so it's incredible, to your point on here—all those HRR mutation PARP inhibitors, the tumor-agnostic indication for pembrolizumab, for T-DXd—but also now the combinations, Sarah, to your point, really spanning easily the resistant disease population. And there are so many studies that are ongoing now in the sensitive disease population. So there's clinical utility, as you say, and then there's this enormous opportunity to benefit family members who are at risk, too.

Sarah Young: Certainly, yeah. So I think the argument there is that the earlier your germline status, the more you can plan for the next step if the disease were to progress, or, again, be part of these clinical trials where we're giving these targeted therapies, like you said, in the hormone-sensitive stage as neoadjuvant treatment. So I don't think it's something that needs to be reserved only once you reach castration-resistant status. Clearly, there's utility before that.

So, despite all of that utility that we've just talked about, we know that genetic testing and germline testing is vastly underutilized in prostate cancer. And you can see that even in—this is a study Neal did, actually. Even in metastatic castration-resistant disease, where we should be testing everyone, rates of documented testing were only 13%. And this is documented testing. So certainly there are papers out there that will tell you, "I recommend testing 60% of the time," or "I do testing 60% of the time," but we have few studies that actually show that testing is getting done. So that's a pretty starkly low rate.

There is also a study, this 1%, where we looked at the SEER databases from California and Georgia—and we will be expanding nationwide with that study—but prostate cancer across all stages: only 1% of patients had documented testing. So that's just a pretty shocking number. And that percentage was actually even lower in Black/African American patients, which is discouraging, as we know these patients often have more aggressive disease.

So, clearly, there are barriers to testing. Some we have explored and we know about; others we might still be scratching our heads about. But we try to discuss some of those barriers and some solutions in this paper as well.

Neal Shore: I just think this is such a wild slide. To me, it's not if you're going to do germline genetic testing (and then, clearly, additionally, somatic testing in metastatic patients)—it's not if you're going to do it, it's "Why aren't you doing it now, and when are you going to start doing it?" Because it's a standard of care. And this data is going to be reviewed at the AUA in 2025. I'm proud we're going to have a plenary session on this. I'm proud of the paper that we've written; we've actually brought this—and many other authors have, too. It's really a wild slide. We're really underutilizing an opportunity to enhance clinical care, both for our patients and their families. But we have other examples of this, too, in advanced prostate cancer. We're still seeing patients who present with either de novo or recurrent metastatic hormone-sensitive prostate cancer; 40% in the US are still getting monotherapy ADT. So this is not unprecedented, we just have to do better.

Zach Klaassen: Yeah.

Sarah Young: So I think in prostate cancer, one of the barriers has been the complexity of the criteria. We've finally gotten to the point where it's pretty straightforward that you can test patients with high-risk, advanced metastatic disease. But when it comes to the lower grade groups, the criteria for testing is very cumbersome and not something that a busy urologist is going to have time to collect—this level of family history in clinic. Not to mention, family histories are often very uninformative, and I don't think it's what we should be using as the end-all, be-all for testing. A lot of our studies show that.

So this is just the most recent NCCN criteria condensed. I think the other step back we took is that they took all of the germline testing criteria for prostate cancer out of the prostate guidelines in NCCN and put them only in the hereditary breast, ovarian, prostate, pancreatic guidelines, which most urologists are not familiar with. You have to toggle through a 100-page document to find where those guidelines are.

So I think that we're really trying to break down the barriers here, and one of them, we believe, is the testing criteria, which is a downstream effect, again, into insurance and coverage. In pretty much every other common hereditary cancer, the guidelines have broadened to where you could at least consider universal testing of cancers like breast, certainly ovarian and pancreatic, now colon, now endometrial. Really, prostate cancer is the only one where there's not a single society—NCCN is not allowing consideration. So we really feel it should not be an exception at this point.

So to prove that point, there have been studies done using the NCCN criteria to show what is the yield of finding variants in patients who meet criteria versus those who do not. And it's pretty similar, as you can see here in the studies that have been done.

So in our PROCLAIM study, and in a couple others, almost 50% of patients with these germline variants will be missed with the current criteria. So I think that just speaks to these criteria not being as sensitive as we might think they are, particularly in certain populations—again, in the Black/African American population, we actually saw a higher percentage of pathogenic variants in patients who didn't meet criteria compared to those who did. And that's just because these criteria were designed based on studies that primarily tested white, European individuals.

We haven't done as much testing in Black/African American patients, so we get data back that is not as easy to interpret in these patients. But it's a chicken-and-egg thing—the more testing you do, certainly, yes, the more uncertain results you get, but the more data you get to feed back into these algorithms and normalize genetic variation over time. So, certainly, the more testing we can do, the barriers we can try to bring down to make testing more accessible to certain populations, it's only going to benefit everyone in the end.

And just really briefly on the PROCLAIM trial and just some of the main findings here—Neal, I don't know if you want to speak a little bit about the PROCLAIM trial.

Neal Shore: Yeah, so what we were able to show in basically about 1,000 patients, prospectively, with academic and community-based practices is that we had an equal number of patients who had PGVs who met NCCN criteria versus those who didn't—those out of criteria. And so if we'd only followed the NCCN criteria and left out patients with Grade Group 1, Grade Group 2, or didn't have a family history, we would have missed a lot of patients. And you can see the breakdown of the different genetic mutations.

We actually found it was disproportionately high among nonwhite populations, and even a much higher variant of uncertain significance, which we don't know—there's no clinical utility for that yet—but being in the Black population, over time, that could ultimately lead to more PGVs, more access and education in those communities. So this is really a very compelling bar graph of what met criteria: the in versus the out.

And I think another thing that's important to recognize is in the current NCCN, they say, well, if you're Grade Group 1 or 2 and you don't have a family history, the challenge that I've had from a practical standpoint is so many of my patients—they just don't know what their family history is. Maybe they're just not knowledgeable, maybe they were adopted, maybe they're dislocated from their family.

And then the other concern is the Grade Group 1 or 2 histopathology—we know there's interobserver variability in community and some tertiary academic pathologists. So somebody's calling something a Grade Group 2, some other pathologist could call it a 3 or even, arguably, in a small percentage, a 4. Likewise, a Grade Group 1 could be a Grade Group 3.

So I think our plea is just universalize it, democratize it, make it standard—like it is, as you already said, in pancreas, ovarian, breast, endometrial, colorectal—so we're at an equal playing field. And once our colleagues—it's demanded upon them that they have to get germline testing, it opens up a whole other important area of education regarding somatic testing, whether you do tissue-based somatic testing, or blood-based, or what we call the liquid biopsy. At the end of the day, it's all about optimizing therapeutic selection and patient care.

Zach Klaassen: Thank you both for just an absolutely beautiful presentation and a great summary of your paper. As you said, Neal, almost make it default to do it. I mean, we get confused by the NCCN criteria. If it's part of the workup—they get diagnosed, they get their testing, we talk about treatment—it becomes part of the dogma. What are some of the educational resources—I know you guys mentioned a few in the paper—that will help with this new onslaught of testing among providers?

Neal Shore: Well, one of the things—the knocks or the naysayers regarding democratizing germline testing—is, "Well, the urologists, they just don't know what to do with the information."

Zach Klaassen: Yeah.

Neal Shore: Well, there's a lot of things that get brought into our field with level 1 evidence, and we have to learn, whether it's surgical technique, or biomarker, a therapeutic, or an imaging modality. And so thank goodness for the AUA, and the SUO, and the EAU, and ASCO, and ESMO, and LUGPA, and specialty networks. There are many organizations—UroToday does an incredible job of saying, look, you've got to up your game.

Zach Klaassen: Yeah.

Neal Shore: And advocacy groups, I think, are really going to continue to insist upon it.

Zach Klaassen: Yeah.

Neal Shore: So, and then the other thing I hear is, "Well, we can't do it because people don't have the ed—" Well, you have to become educated.

Zach Klaassen: Yeah.

Neal Shore: You have to constantly—that’s de facto why you're a physician, a physician-scientist. Number two, I hear, "Well, everyone needs a genetic counselor." Well, the truth of the matter is that would be fantastic; we just don't have the person power so that every patient can see a genetic counselor. If you can, fantastic. But the companies that provide the germline testing have free telemedicine genetic counseling—that's an answer. But, also, it's really incumbent upon physicians—and it could be in the form of advanced practice providers—but we have to basically evolve.

Zach Klaassen: Yeah.

Neal Shore: Then some will say, "Well, there's data that folks are irrationally responding to findings of, say, a variant of uncertain significance, a VUS." And I've seen that data, but my response is we've just got to educate better.

I've seen this where 85% of ovarian cancer patients newly diagnosed present with metastatic disease.

Zach Klaassen: Yeah.

Neal Shore: We all have these patients who have prostate cancer—"Oh, yeah, my brother had prostate cancer, my mother had ovarian cancer, my sister's got breast cancer"—oh, shocking, you've got BRCA2. So if you're not testing and you can't help your own daughter, or your niece, or your sister, or your brother prevent an early prostate cancer, or an early pancreatic cancer, or an ovarian cancer—this is incredible. This is an opportunity not only to impact other folks' lives who may not be in your clinic, but if you think about the health economic implications, these diseases are curative when they're localized, not when they're metastatic.

Zach Klaassen: That's right.

Neal Shore: That's another thing that people will say. So the answer is we have to do better. And a third thing that comes up is, "Oh, it's cost-prohibitive." The cost has come down dramatically for germline testing. It's on the order of a couple hundred dollars.

Now, I realize that could be a lot of money to certain patients in the US; it could be a lot of money outside the US, but that's where we need the payers to come in, the national health care associations, to say, "This makes sense. This has to be democratized." That's really, I think, where Sarah and I have been really pushing this. That's what PROCLAIM taught us. We see disparities among different groups. We need to do better with that. To me, it's such a no-brainer.

But we still have to get out there and get our message across. This paper is one of those things that we hope will move the needle with the guidelines association colleagues.

Zach Klaassen: Wonderful answer. Sarah, any last minute remarks to conclude your study?

Sarah Young: Well, I was just going to tag on to Neal's comment there. I think the cost-effectiveness of germline testing is really hard to argue. It's a one-time test; it has benefits for the patient and for their family members, as opposed to somatic, where you're going to have to repeat the test at multiple times, multiple stages. This can get you to the same eligibility with one test. You don't have to go back to that biopsy that was banked however many years ago, trying to get enough tissue to do somatic testing on. You just take a new blood draw, and you get the information you need much quicker and much more cost-effective.

And I think, just again, to make the analogy to breast cancer, where testing has broadened and people were—or at least the guidelines have somewhat broadened—and people are worried, oh, well, the floodgates are going to open and these patients are going to be rushing my office, getting testing—I mean, it's not the case. In that same study where we showed 1% of prostate cancer patients getting tested, I think it was about a quarter of breast cancer patients getting tested. So even though there are universal testing recommendations—why am I blanking on the name of the society—Breast Cancer Society back in 2019, we really haven't seen testing, for better or worse, skyrocket.

And I think there's so many what we call alternate delivery models available now that are just becoming pretty routine. You watch a video about genetics, even at your home or your doctor's office while you're waiting. You don't have to see a genetic counselor up front. I think men may learn differently than women, and so we don't have to do it the way we always did it with breast-ovarian cancer, where you have to have these hour-long pretest sessions. I think there are a ton of studies out there showing the acceptability, feasibility of other ways to get this information delivered to patients and, to Neal's point, to return the information to patients, whether it's the physician, the advanced practice nurse, the genetic testing lab. There's someone who's going to be able to communicate that to the patient.

Zach Klaassen: Yeah, well said. Thank you both for an excellent discussion. Neal, as you mentioned, the paper is highlighting this, and certainly your time in putting this video together will also continue to get the message out there. Thank you both for joining us on UroToday.

Neal Shore: Thanks, Zach.