Genetic, Genomic Testing in Newly Diagnosed, High-Grade, High-Risk Prostate Cancer

Raoul S. Concepcion, MD, FACS:Good evening, everybody. This is Raul Concepcion in Nashville, Tennessee. Sorry about the delay. I'm having a little technical difficulty and was unable to join via computer, but I'm able to call in. So this may be a little bit convoluted and disjointed, but we'll, we'll make it through. So welcome to our June edition of Urology Times Around The Practice, partnered with LUGPA.

Again, I'm Raul Concepcion. I am your moderator for this evening. And, uh, Jason, if you go to the next slide. Uh, joining me tonight will be our distinguished faculty. So I've got Ms. Rachel Manookian, who is a certified genetic counselor at City of Hope in, uh, Southern California. Dr. Jason Hafron, who is assistant professor of urology at, uh, William Beaumont School of Medicine, and is also the director of clinical research at the Michigan Institute of Urology. And I've got my neighbor, Dr. Kerry Schaffer, who is assistant professor of medicine in the Division of Hematology and Oncology at Vanderbilt University Medical Center here in Nashville. So I wanna thank the three of them for taking the time to join us tonight.

For those of you that have been involved, or have hopefully a- attended these, uh, basically, we wanted to design this as a true, uh, virtual tumor board where we're discussing cases, uh, difficult case management. We're gonna kinda switch up a little bit as we want to keep this, uh, engaged and up to date. So tonight what we're going to do, Jason, if you can go to the next slide. Tonight what we're going to do is really talk about two, uh, prostate cancer cases, and have a, a very robust discussion on the role of, uh, genetic and genomic testing.

So, um, just some, some housekeeping notes. If you have a question, there should be on your screen a Q and A box, uh, for you, you to type in questions so that the panelists can read them and hopefully, we can address. And we're also going to have during the course, a couple of, uh, audience participation, uh, Q and A, uh, some pop-up poll questions, uh, just so that we can get a better feel for your practice and how you're currently thinking about the current role of, of genetic and genomic testing.

So, Jason, if you can go to the next slide. Our first case, um, is going to be a newly-diagnosed, high-grade, high-risk prostate cancer patient. So next slide. So this is an actual case. This is a 62-year-old white male, who presents to his urologist with a rising PSA. His baseline is at 1.3 nanograms per deciliter. And now over the course of a year-and-a-half, has progressed to 3.25. And also presents with acute urina- urinary retention.

Um, his past medical history is really, you know, sort of unremarkable. He's got some osteoarthritis, squamous cell carcinomas, some BPH. He takes some non-steroidal anti-inflammatory agents as needed. Um, has some significant surgical history. Uh, mostly orthopedic. Does have a family history, uh, that at least we know of, that was obtained at the time. Uh, the, uh, prostate cancer diagnosed at age 79 in his father, and as well as the mother with skin cancer. And there is, his social history is fairly active still. He's a retired engineer.

Next slide please. So the urologist basically, because of the urinary retention, uh, the patient underwent cystoscopy. Showed a very friable bladder neck area, and basically had a channeling TUR. And final pathology showed a Gleason group five, uh, with Gleason grade four plus five prostate adenocarcinoma. He had a, on CT scan and staging, he had a markedly enlarged prostate, infiltrating into the left seminal vesicle. And bladder with some left hydronephrosis. And his bone scan on staging showed increased uptake in the sacrum, and basically was read out, was ruled out a, uh, acute fracture versus a metastatic foci.

Uh, next slide, please, Jason. Here is a representation of the scan. And as you can see, he's got a markedly enlarged prostate, um, with a little bit of, of left hydro. But as you can see, it really is indenting into the base of the, indenting into the base of the bladder, as well as, uh, into the seminal vesicle.

So, uh, next slide, please, Jason. On our first polling question. So, uh, again, we want the audience to s-, kinda get a feel here. Does this patient meet NCCN criteria for germline testing? Uh, A, yes. B, no. C, unsure. And again, I think for, um, for the urologists in the audience, and obviously, as well as the medical oncologists, obviously this is a big challenge to how to incorporate germline testing in the standard of care for patients with advanced prostate cancer, as well as newly diagnosed. And, um, so in this particular patient, does, does he meet the criteria?

Uh, the next polling question. Next slide, please, Jason. Is, I would order A, germline testing. B, somatic testing. C, I would do both. Or D, uh, unsure. So again, what we're trying to do is, uh, determine, you know, get an understanding and hopefully, everybody, uh, is learning and trying to get up to date from an educational standpoint on the, on the differences between somatic testing and germline testing. Uh, so Jason, before we, before we move on here, uh, kind of at MIU, uh, give us where you stand with your protocols relative to genomic testing in, in somebody like this patient.

Jason M. Hafron, MD: Thanks, Raul. Yeah. This is an interesting case. Um, at MIU, we've taken a very, I would say aggressive or in-depth approach to genomic and somatic testing. If you look at the, uh, uh, NCCN guidelines, he meets, this patient meets guideline criteria for, for germline testing. He's high-risk, and, uh, NCCN re- recommends germline testing in the high-risk, very-high-risk regional or metastatic prostate cancer. So, which is interesting because this is essentially, independent of his family history. Even though this patient has a family history, they are, uh, you know, he meets guidelines for germline testing.

To get back to your first question, um, we at MIU, which is a little bit different than maybe an academic center like Dr. Schaffer's or, or, or Rachelle's, is, we, uh, start the testing ourselves as the urologist. Um, we've kind of adopted this hybrid model, where the urologist will do the pretest testing and do the pretest visit. And that's where we've, you know, done a lot of work. And in servicing my partners and colleagues about, you know, questions regarding cancer inheritance, um, we talk with the patient about the genes to be tested, the limitations of the test, and the potential results.

So as urologists, we've kind of adopted or mo-, or evolved to this space. And we also talk about GINA, which is the law that pro- pro-, uh, protects, uh, patients aga-, uh, uh, em- employers, protects the patients from their employers using genetic information against them.

So we do all the testing. I think the, the, the key though, is that, once we do the testing, obviously we get the results. And it's very important, um, what you do with the results once you get them. In our practice, you know, if they are negative, we, you know, obviously we'll tell them that. If they're high-risk negative, if they have an extensive family history but they're negative, uh, germline testing, we still refer them to the genetic counselors because there are some risks that we don't know about in further testing. But I think the key here is obviously, if they're positive, they have to go immediately to the genetic counselors.

And then there's a, uh, uh, uh, an, a result that is important, is a VUS, a variable of unknown significance, a variant of unknown significance. I think it's very important that urologists realize that these patients also, even though they're technically negative, but they have a variant an, a, of uncertain significance, which happens quite often, about 30% of the time. These patients also need to be sent to the genetic counselors. Because, even though it's, it's, you know, I'll refer to Rachelle, but even though it's negative at this time, we all know that this can evolve over time. And I, I, you know, I don't think the urologists have the skillset to, to follow these a- and, and do additional testing when, when there's a VUS.

Raoul S. Concepcion, MD, FACS: Okay. So Rachelle, before I hit up on you, so Kerry, thanks for joining us, contrast that to, so obviously, you're in medical oncology at Vanderbilt. I know you guys run a multidisciplinary clinic. Um, for somebody like this, so say, you know, one of the urologists, Sam, Dave, uh, Dan, or somebody, does this patient, how does that work if you've got the newly-diagnosed, high-risk, high-grade patient? Are they being sent to you to determine testing? Is, is the, is the department of urology doing it? Or are they being sent to your, uh, to your genetic counselors?

Kerry Schaffer, MD: So historically, we had everybody going to the genetic counseling team. Um, but because of, um, uh, a long wait time, sometimes for patients, or a low number of genetic counselors, which is a problem nationally, um, we started a model here that's a point-of-care testing model, similar to Dr. Hafron. So we started in medical oncology, and we actually have expanded it into the urology space as well.

Um, uh, as Dr. Hafron said, really key, um, is having the partnership with hereditary cancer clinic. Um, we do offer every patient that gets testing done, uh, access to a genetic counselor. Most patients that are negative, either have a very brief visit or no visit with them. Patients with VUSs we do refer, and then definitely patients with positive test results.

Um, so we've adopted that model here. For patients who are unsure about testing, or, um, wanna learn more about, you know, possible discrimination, or life insurance issues like that, we ab-, have them see hereditary counseling clinic first. Um, but majority of patients like to do it same day in our clinic. Um, and so, that's a nice feature that we've adopted that, um, I think patients and oncologists both in urology and medical oncology like a lot.

Raoul S. Concepcion, MD, FACS: So both of you, you would, uh, for, so for this particular patient, just for edification for the, for the viewing audience, uh, you know, what I'm, what I'm hearing is that you're definitely ordering germline, but, uh, w- would you both also order somatic?

Kerry Schaffer, MD: So, I think this, the, the time of somatic testing varies a lot at this point. A lot of people nationally are waiting for castration resistance, um, to start the testing process. I personally, um, at the time of metastatic disease, start somatic testing. A lot of the PARP inhibitor trials show that the primary disease or early disease has any [inaudible 00:11:47] mutations of interest. And so, um, we are fortunate at Vanderbilt that we have a fairly cost-friendly version of somatic testing for patients. And so, while it's not completely free, um, the cost of testing is less part of the discussion. And so, I think, um, I'm unique that we tend to do that testing up front, but I know nationally, it's very reasonable to wait for castration resistance, um, to initiate that process.

Raoul S. Concepcion, MD, FACS: Jason, what about you, in a newly-diagnosed, high-grade, high-risk?

Jason M. Hafron, MD: I like to get to somatic testing upfront. You know, I like to know everything right away. You know, I know that it may not trai-, change my treatment options or my treatment plan in the beginning. But I think it's very helpful, because it kinda gives you an idea of what w-, how well or how poorly a guy's gonna do.

So I wanna have that information upfront because I can kinda tailor my discussions, um, and, you know, plant those seeds. Even though we have a mutation or, uh, uh, uh, a defect, even though I'm not gonna do anything differently, I'm already discussing it. We're talking about it. And then I can kind of understand where he's gonna go in, in his, in his pathogenesis.

So I like to have it right up front. And I like to basically get somatic testing on anyone with potentially lethal prostate cancer. I think that, you know, this is an evolving space. And I think when you look at all the new clinical trials coming out, um, it's really important to have this information right up front. It, it, it, it's really helpful.

Raoul S. Concepcion, MD, FACS: Okay. So Rachelle, you're not off the hook. I promise, I will get to you. So, D-, uh, Dr. Hafron mentioned sort of the reporting. And can you help the audience sort of, when, when a mutation comes back, when a mutation is identified, you know, you know, a couple of questions, obviously. Number one, uh, what type of reporting generally comes back, especially since he alluded to this, this concept of VUS, variant of unknown significance? And then number two, how often is, you know, because again, you're a genetic counselor at City of Hope, very robust, strong genomic program. Uh, give us a little i- insight of what you're seeing over the past couple of years, uh, in your world relative to prostate cancer patients coming in to visit with you.

Rachelle Manookian, MS, CGC: Um, I really appreciate, um, Dr. Schaffer and Dr. Hafron having this, um, kind of joint work with the genetics team there. Because prostate, um, tends to be the, the group that is the hardest for us to get all the referrals, um, because there's just a lot of them.

And so, you know, we don't wanna be in genetics the gatekeepers for these patients to undergo genetic testing that could ultimately, impact their care and their family members. Right? So it's important that they get tested, um, especially if the urologists, the medical oncologists, are aware that, you know, they're gonna refer to us after the fact for someone who either has a positive or a VUS. Um, like Dr. Schaffer said, that someone who isn't sure about genetic testing so they don't wanna proceed right then and there. So they come and see us, and we do all the counseling. So I, I think having that, um, network is really helpful for the patient in the long run.

Raoul S. Concepcion, MD, FACS: ... um, so relative to, if a patient like this, are, are, are you seeing sort of this kind of the c-, this cascade effect, obviously with testing, but are more and more families in your experience as pro-, as the prostate literature, uh, evolves, are you seeing more and more patients in your clinic who, because of the awareness of mutations now associated with hereditary prostate, are you beginning to see more patients inquiring directly about their risk assessment for prostate because of family members maybe with breast, ovarian, you know, those types of things?

Rachelle Manookian, MS, CGC: Yeah. And I, I would love to hear Dr. Schaffer and Dr. Hafron's experience on this too, because ye-, my short answer is yes. And that's truly just because it's not just about prostate gene mutations, but just the knowledge about genetics. Um, I don't think five years ago I would have ever used the term CRISPR in an, a conversation with someone not in the genetic space, but now more and more people are bringing things like that up. There are documentaries, what have you. And so, absolutely, patients are more aware of these things and are requesting referrals.

So I'm curious, you know, Dr. Schaffer, Dr. Hafron, from your experiences, is that something you are seeing, or is that something patients might prompt? And I'm so sorry, Dr. Concepcion, I took away your (laughs) role and asked the question, but I'm just wondering, you know, do you see that, like patients are bringing that up to you as, you know, "Hey, should I have genetic testing? I have sons," or, you know, brothers, so on?

Jason M. Hafron, MD: Yeah. No, uh, Rachelle, that's a great point because we see that a lot. You know, and we're always asked about that, you know, "When should I get my son tested? Is my son at risk?" And I think what's, you know, I've been doing this a couple of years now with, with germline testing, and now somatic, is that, patients are very open and receptive to it. They understand the, the concept.

And I think it's kind of what Raul you're alluding to. Is that, it's in the lay press so much that when you bring up germline testing or somatic testing, it's very rare that a patient will be resistant to it. You know, y- you know, so they're very open to it and they appreciate the comprehensiveness of your approach to looking at everything. So I, I think it, it, it hasn't been a lot of resistance from the patients. They're very open to it.

Kerry Schaffer, MD: I would agree too. And I think for family members, I am starting to see, and, uh, we are trying to get them hooked in with urology, more patients without a known cancer but a BRCA mutation, and trying to figure out what the right screening methods are, how frequently to get PSAs, what age to even start getting those PSAs. And there are some studies starting to show results about guiding that practice. So I, I think the more patients with a BRCA mutation and no known prostate cancer can get plugged into those clinical trials. Um, that will really help enrich the field with more, um, concrete data.

Raoul S. Concepcion, MD, FACS: Yeah. I me-, I mean, I think, and, and we, you know, you know, we're gonna move on here. I think, I think, you know the point really is, is that we, up until recently have, you know, I think we're starting to become aware of the importance of BRCA2, uh, uh, BRCA2 mutations, especially, uh, in the prostate cancer patients.

And I'm hoping that in the, in the patients who are being seen and are testing positive for BRCA1, BRCA2, maybe ATM, um, with, with other types of cancers, you know, primarily, obviously, breast is the biggest one that we think about, but possibly ovarian. Hopefully, the flip so that they, that they need to be aware for their family members, uh, that, "Hey, you better be thinking about prostate as well." You know, obviously, we think about it. If you have prostate, BRCA2, yeah, "Hey counsel your family members for breast, ovarian, and other tumor types. And I'm hoping the, the corollary is also true."

So let's, let's go to the next slide here. So, um, so this patient actually had a fairly large, uh, hereditary germ panel run of 85 genes, uh, which came back negative. And I think that's sort of, uh, basically what, what Rachelle and, and Jason said. Is that, you know, a lot of the times, the majority of the time it's greater than 80%, it's gonna come back as negative. But then let's go to the next slide.

Um, so in, uh, but this patient also underwent, uh, somatic testing. And basically, show that, had, um, that the biomarker findings was, micro-satellite status was stable. Uh, and the, and, uh, encloses the TMB and from the geno- ... So that's from the sort of biomarker findings. And again, Kerry, I may have you explain to the audience, you know, what the differences here are between, uh, biomarker findings and the genomic findings. Which obviously, shows a, they sh-, they're showing this as a CDK12 loss at exons 10 through 14.

And obviously, therapies associated with that clinical benefit. And we're also seeing an amplification, which was equivocal in MYC, as well as CCND2. So Kerry, explain to the audience a little bit. So when they talk about biomarker findings, looking at micro-satellite stability and TMB, what are they, what's the process that they're actually doing there?

Kerry Schaffer, MD: So, um, the tumor mutational burden and micro-satellite statu- status, um, often parallel each other but do not necessarily. So some patients will have high MSI, um, meaning that they have, um, changes in their micro-satellite regions. Um, and that often reflects the presence of a mismatch repair gene mutation. Um, tumor mutational burden is simply the, um, degree of tumor mutation that's present. So often when someone has a mismatch repair defect, they will have both MSI high status and TMB. Um, but they are not, uh, necessarily always present together.

But if someone has MSI high or a high TMB, that might cue you to look at those genomic findings and look for a mismatch repair gene alteration. Um, the CDK12 feature is something that in prostate cancer, there's some data showing that they might have like a more aggressive clinical subtype, sometimes higher Gleason, more metastatic disease, earlier castration resistance. And so, um, there, there is approval for PARP inhibitors with the CDK12. Um, there is some suggestion that perhaps this class of prostate cancer might be more susceptible to immunotherapy. Um, uh, the PARP inhibitor data has been a little underwhelming with the CDK12, but it is approved. Um, and then I think the, the study showing potential for immunotherapy are pretty early, but, um, there is some hope there.

Raoul S. Concepcion, MD, FACS: Right. I m-, I mean, that was ... Jason, wouldn't you agree that, I mean, I mean, I mean, that's kinda what I was, I was, that, that I was surprised when they put that, but, you know, when I saw the [inaudible 00:22:52]. I thought that most of these folks with, uh, biolitic CDK12 loss, uh, were gonna be more appropriate for, for immunotherapy as opposed to [inaudible 00:23:02].

But anyway, let's, let's go to the next slide. So basically, this patient was started on an LHRH antagonist. Transitioned to Eligard. Uh, got radiotherapy to the primary, which again, there's a, there is a whole nother, uh, element of discussion. Um, then get started on an androgen receptor targeting agent, including enzalu- enzalutamide at 160 milligrams daily. Um, and then also got some bone-targeted therapy of denosumab, 60 milligrams, sub two every six months, uh, supplemental vitamin D and calcium.

So Rachelle, um, with this patient, uh, and, and that was, and those genomic findings, um, sort of how do you at this point, if that, if that family, if there was a proband in the family, a, a s-, a son or a daughter, or, um, you know, uh, what, what's kinda the process that you as a genetic counselor walk through relative to, uh, try and to find out more? And I guess what I specifically want you to address for the audience, uh, which I think is critically important, and we don't do a good job, is the importance of an in-depth, detailed family history of [inaudible 00:24:15].

Rachelle Manookian, MS, CGC: Yeah. There's a couple of points there. One, there's always empiric risk, um, to as-, to think about. So genetics is not everything. Um, and so, obviously, I don't have to tell this audience that prostate cancer has a huge familial component. So if this patient has a son, um, brothers, that's important for them to know. And their doctors to know that there's a family history of prostate cancer, even if the genetics is negative.

Because, you know, most often, most times you might hear, you know, and, and I should add, we also said that his father had prostate cancer. Right? So that's two prostate cancers in the family. And sometimes patients will be, um, kind of falsely reassured by a negative genetic test result. And we wanna make sure that we inform them that there's empiric risk for people like brothers and sons that, that need, still need prostate screening, of course.

Um, and then as it relates to the somatic, the comment I just wanted to make, you know, somatic germline, um, you know, for this patient, it's fortunate that they had both. Right? Sometimes patients will only have the somatic testing and, um, we don't do the germline. And there are no, um, BRCA or other mutations in the somatic testing that they would warrant germline.

Um, but I always say, the somatic is not everything. Right? It could have missed mutations. Um, and there could be reversion mutations. Uh, sometimes depending on what somatic lab you're using, they actually filter out possibly germline variants so you could be missing something there. So I think that's the important thing to remember too, is if, if a patient were only to receive somatic, um, still considering germline testing.

Raoul S. Concepcion, MD, FACS: Yeah. I think you just brought up a great point, which is basically this pair testing. And I think unfor-, I, I, I think in the urology world, um, you know, we, we look at pair, they think of pair testing as reflex testing. Where your germline, if your germline is negative, then test somatic.

Whereas what you just mentioned, which I think was, uh, is, is very critical is that I think in the, in the, in the true, trying to figure out what the molecular driver is, that if, that you really, you should, you should do, y- you know, if you can, if you can get both somatic and germline, what, what Jason, uh, tends to do. And if you, if you have mutations at, in both, is to be able to subtract out the germline and, you know, hopefully, you will be able to maybe determine what is the true driver, uh, you know, of the, of the progressive disease.

Um, Jason, what are your thoughts? You know, a little bit of, a little bit of a change here, but, um, you know, with this gentleman's family, with, with this ... He doesn't have a ton of cardiovascular risk. Comment just briefly, and then we'll move to the next case. Comment briefly on two things. Number one, uh, advantages, agonist versus antagonist. Number two, uh, which again, Rachelle woul-, uh, w-, uh, kinda cued you up is somatic testing role of liquid versus metastatic biopsies.

Jason M. Hafron, MD: Yeah. So, you know, I always start with an antagonist, but I think it, it's immediate direct castration. Now, it avoids the surge and it avoids subsequent micro-surges. So I try to give a couple of months of, uh, antagonist. And then we c-, for convenience switch to the agonist. So, uh, the cardiovascular toxicity, uh, we know based on some of the Albertsen data from European Urology is that there's a potentially 50 per-, retrospective, not prospective, 50% reduction in, in, CV risk based on Dr. Albertsen study from European Urology. As far as the, you know, the somatic testing, you know, um ... Uh, I'm sorry, Raul (laughs). I forgot. What were you, you were asking?

Raoul S. Concepcion, MD, FACS: It was liquid, it was liquid, liquid versus metastatic biopsy.

Jason M. Hafron, MD: Well, you know, if you look at, I think the best information, there's two ... I think that, you know, based on the, uh, PROfound study, is that, um, we know that metastatic biopsies are the best. Especially the fr-, the fr-, the fresh stuff. Um, archival prostate biopsies are the worst. Whole mount prostates are, you know, the second worst. So it's always better to get metastatic lesions when you have it. In this case, it was fresh. It was right from the beginning.

We had, uh, ample tissue from, from the TUR specimen. So we, we, we got it right away. So I don't think a, a liquid was, is needed at this point, but in progression and in, in, further, uh, pathogenesis, I like a liquid biopsy a lot. I think, you know, there was just a big study, um, of over 3,000 liquid biopsies. And there was good con- continence, uh, of the liquids with the tissue.

Um, I think, and there was, uh, CT, uh, circulating tumor DNA in over 94% of the patients. And then liquid, you know, and based on that study, over 3,000 patients, um, actually picked up some, some additional mutations that weren't picked up in the tissue. So liquid is new. It's evolving, but I think it's very appealing. Especially, you know, my, you know, method, or I try to keep everything as simple as possible, somatic-germline upfront. But then any progression, you know, any failure or, or lines of therapy failure, um, if I can't get a metastatic biopsy, I, I will just send liquid to see if there's any change.

Raoul S. Concepcion, MD, FACS: Kerry, I'm gonna let you have the last word on this case. What are, what are your thoughts of liquid versus metastatic, uh, metastatic biopsies?

Kerry Schaffer, MD: Um, I, I tend to like metastatic biopsy if it's, um, available. The one I struggle with is sometimes the bone. If it's bone-only metastatic versus a liquid, um, I, you know, I might do a liquid in that circumstance. Um, if there is low disease burden, that is somewhere where I really try to push for a biopsy, um, rather than a liquid sample. Because I have some patients with low disease burden that just did not have an impressive, uh, genetic f-, outcome. And then we did a sample of their biopsy and it was, um, revealing. And so, uh, the disease burden is also something I take into consideration.

Raoul S. Concepcion, MD, FACS: Yeah. I think your point is well-taken though. Uh, you know, as, as we all know, the, the difficulty, especially, uh, to, to do really good bone biopsies and get, and get good tissue is very difficult due to the, just the processing, the decalcification, and those types of things. So, anyway, great discussion.