Chapters Transcript Video The Role of Genetics in Prostate Cancer Detection and Treatment Neil E. Fleshner, MD, MPH, FRCSC Good morning. How are you? Good morning. How are you? Good. Do you need me to share my screen? Um, yes, you will share your screen so that we can like see your slides. OK, so the entire screen. Share, just let me know you can see it, yeah? Yep. OK, let's see if this works. Nothing like uh sending you the thing at the last second there yesterday, huh? Oh, it's OK. You you're used to it though. Yes, I'm very used to it. Oh yeah. All right, how does that look? Yeah, yeah, good, that should work. Perfect. OK, great. Zoom user. I'm not sure who that is. OK. Uh, there you go. You could see me now too. All right. How's how's Miami this morning? Um, hot and humid. Of course. Yeah, I have a uh a home in Kibuiscayne actually. OK. So I know, know that whole area pretty well. Oh, actually, it's only 77 degrees. Oh my god, no rain yet? Uh, not yet, but sometime around 5 o'clock. I don't want to uh Jinx, but it seems to be so far a good storm season, yeah. Uh, it, I mean, yeah, no hurricanes, but just thunderstorm every day. Good stuff. And you can hear me OK? Yes. Wonderful. I just is Neil. Oh, there you are. Hey Neil, how are you? And I think I saw him on. Yeah. No How's that? Can you hear me now? Yeah. Wonderful. Good morning. 2 or 3 minutes for people to come in and then we'll get started. Super. How are things over in Toronto? Uh, not bad, it's full on fall, which is depressing. Yeah, starting to get cold. It's starting to get cold. The days are getting shorter. It's kind of that's when it's time for me to go to Miami, frankly. Yes, O'Neill has a place in Key Biscayne. I see him here more than there. Uh. But you guys, see, I mean, I guess this this depression for me is actually optimism for you guys. It's getting into the nice season, right? Yeah, yeah. Starts to cool down a little bit in October. Yeah, OK, why don't we get started then? Um, so it's a pleasure for me to have Neil on, uh, for those of you, you know, I trained in Toronto, and Neil is a huge figure in Canadian neurology. He was chief of the UHN when I was training there. That's not Canada's top hospital and, uh, the chair of the University of Toronto, but he's also been, like I said, a huge figure in the Neurology Association in clinical trials, and I'll just give you a quick story. When I was um an intern and I was on urology and I think the first time I ever got called in for a difficult catheter and uh I couldn't find a cystoscope. I mean you may not remember this, but on the cystotra anywhere. And so I called my chief resident and I'm like, I, I can't find a cystosysto this guy and he's like in retention. They're giving him morphine and the residents yelling, I can't help you find a systo. You gotta find this. Cystoscope. That's your job. So I'm looking around. I go to the hospitals. I think I got a laryngoscope at some point that I was gonna try and put in this guy's penis. And finally I, I call it was Kurt Eag. I call him back and I'm like, Kurt, I, I don't know what I'm gonna do. He's like, You gotta call the chief. This is a system issue. So I'm like, call Fleischer. And this calling Fleshner at like 3 in the morning would be like calling Perec, you know, to tell a guy you got urinary retention, but I called him. And I remember hearing stories that Neil never sleeps, and it was like probably 3:30 in the morning when I called you and you're like, So what's going on? How are you? And I'm like, Good, were you in the nephrectomy? I was like, yeah, it was, it was good. I'm like, yeah, yeah, it was, it was good. It was good. I'm like, What's up? Uh and I, I basically said this guy was in retention, couldn't find a systo and um, and you're like, you need to put a soy pubic tube. And I was like, I've never done one. I was like, you want me to come in? And you flew in in like half an hour, put it in, and then we're out the door. It's like 4 o'clock in the. That was like, that was like 20 years ago. But anyway, it's a pleasure to have you here, Neil, and uh the floor is yours. Super. Thank you, Sooj, and uh really uh a pleasure and an honor to, to speak with you guys. I know you have a very, uh, very prolific division, and, uh, it's great to be here. And I just wanted also just a little shout out to Jess Coburn who helped me, uh, prepare some of the slides, and this is a lot of work we're doing together. And we really got interested, and I got interested in genetics and prostate cancer, really out of, oh, how do I advance my slide? Oh, there we go. There are my disclosures. So, I, I'm gonna first share with you three cases, and these 3 cases really um have shaped me in a Big way that got me thinking about prostate cancer a lot and these are three cases that uh over the years has really got me interested in this whole space, and that is, uh, cases that make you scratch your head over the years and you wonder why. So here was Mr. FP 58 year old male, came to see me some years ago, PSA 2.3, very strong family history, as you can see. I order an MRI. It's got an 8 millimeter pi's 3 lesion. Again, I normally wouldn't order an MRI, but because of the family history and the borderline PSA I did it. Biopsy both target systematic negative. Amazing. So I said, you know what, I over was over um conservative here. Six months later, he presents in my clinic, he with pain, not feeling well, he was in urinary retention. And I put my finger inside and oh my God, there was like a bomb went off in his prostate, PSA 860 diffused metastatic disease. And, and at the time, I ordered a color genomics test for germline, uh, anomalies with his strong family history, and sure enough, uh, BRCA2 positive. And, and, and again, this is not supposed to happen in prostate cancer, right? PSAs aren't supposed to go from 20 to 800 in 6 months, and there's this bone scan. A second general, Mr. AF 62 years old, PSA 11, T1C Glen, Gleason 34, this is, uh, you know, again seven years ago I do a radical prostatectomy. Badish cancer PT3BR0 comes back for his post-op PSA and the PSA is 31.6, and I said, you know what, this doesn't make any sense. And I, in retrospect, had seen a case like this years about a decade earlier. I actually reassured this gentleman that uh something's wrong. The lab screwed up, it's the wrong patient's blood. Let's repeat it and come back in two weeks. And sure enough, his PSA is 103. Um, and he's also BRCA, uh, uh, positive. He is subsequently, of course, died. His daughter actually ended up getting prophylactic mastectomies and, uh, oophrectomy, but I, but it really, again, something you don't see that often. And this one also really clouded me. A gentleman I'd been following for years, and Mr. JB was 68 years old, had a massive prostate. You know, in the 10 sort of 20 to 180 g range, always had elevated PSAs in the 15 to 20 range. Multiple negative biopsies, multiple negative MRIs, did have a strong family history, uh, but not that strong. He had a sister with breast cancer, a bit of, uh, uh, melanoma in the family. He himself had no natural children, and I, I wanted to get a germ line on him, offered it to him, but he, uh, he basically didn't want it. So it's interesting that in, in 2016 now, his PSA had risen to 24. Normally in the 20 range, I said, you know what, let's. Get another MRI 168 g prostate, no suspicious lesions, and I recommended a trust biopsy anyways. Uh, remember this is in the era where we didn't rely, we didn't not biopsy MR negative patients necessarily. So we, he had a 14 core biopsy, one of 14 course Gleason 6 prostate cancer in the left apex. Very small volume, but what was an interesting call is they noted intraductal disease on his biopsy in Gleason 6, which is extremely rare, presented tumor board, Theo van der Cross, world-class urologists. Um, reviewed the reviewed the, um, histology. We all agreed we would treat him, but again, what are we gonna do for him? And so we ended up doing focal therapy, so we I ablated his left apex. Remember, there's no MR visible lesion, so almost just did a, if you will, a segmentectomy, um, and that worked out fairly well, good sexual and urinary function, PSA dropped a little bit. Now we do a follow up lesion in in January. It's now January 2018. He's got no lesions, got volume loss associated with his, his vocal therapy in the left apex and then. His PSA starts going up again and again, we always see a lot of fluctuation, particularly in men with large prostates. I repeated MRI when his PSA went up to 24, and now he has a new lesion in the right base. Remember that the left apex was where he had his, uh, initial lesion and um he has a new 1 centimeter lesion again this there was a normal MRI only 18 months earlier. Biopsy for 3 intraductal staging negative. Well, take him to surgery and he ends up having it's horrible, but PT3B disease, a a positive node, a detectable postop PSMA uh PSA and now has mets on a PSMA PET scan all within about a uh a 1.5 year window. BRCA2 positive as well. So these cases, in my view, really um show you that in, in, in if you've ever encountered these runaway cases where you really feel you're horrible for the patients and really dumb as a clinician, these are some of these cases where it's almost behaving like lung cancer. And really, what's behind this all are some of these strange genetic um phenomena. So just for the, the students in the group, remember, there's two types of genetic mutations you can have germline mutations, those are those here on the left, which are uh donated by your mother and father at conception. Uh, oops, they're present in every cell in the body, uh passed on to your offspring, and you can um measure this for a simple blood test or a cheek swab. And a good example that is what I was explaining the BRCA mutations and then there's somatic mutations which are those that occur within the tumor tissue itself. They're variable, they change over time, they respond to Darwinian pressure. They are not passed on to offspring and these have to be obtained either a biopsy of tumor tissue and more recently, uh, perhaps in a CTDNA but but but basically a signal, uh, that reflects what's happening in the cellular tissue itself as opposed to the entire body genome, if you will. So you know, we've become passionate about this and and doing a lot of work in this space, um, and I think what I've come to recognize is that genomics has opened up our eyes about, uh, understanding the biology of prostate cancer. Testing has become extremely inexpensive. The government of of Ontario here in in in this province. Um, used to spend $8000 to test two genes about 10 years ago. You can now get a high throughput genetic screening of about 75 genes for about $150. Um, and at least in Canada, and I'll talk about this in a bit, testing has no jeopardy. You can't be, um, biased from getting goods or services based on, uh, your genetics, including, for example, insurance. And there's a lot of therapeutic and prognostic implications to this as well, and I'll, I'll briefly touch on that. So we all know the risk factors for prostate cancer, aging, diet lifestyle, um, but family history has always uh been a big player. Uh, we recognize, um, that if you have first degree relatives, you have an increased risk, particularly those who get it at a younger age. This is very common in hereditary cancers writ large. Um, and it's quite interesting. When I was a baby urologist, it was the modeling suggested that only about 5% of prostate cancer was genetic, and now it's now estimated that almost 60% of it is genetic with like 40% being lifestyle. So that to me is, is quite interesting because as the science changes, so does our knowledge and our understanding of of of these risk factors. There are many cancer predisposition genes being found all the time, um, and, and what's quite interesting is as this improves and our understanding improves, then obviously it opens up testing and as I alluded to cheaper testing, uh, for us to offer patients with important consequences. So first I'm gonna talk about snips and and a snip is is basically I describe it to a patient as a typographical error in their genomes, so little single base pair differences in the population. And um and and and these uh can be located in genes either in exons or introns or around genes or or even unrelated. Sometimes there's a lot of junk DNA that still has no known function in our genomes and but these are basically markers, and, and you'll hear this term GWAS or genetic wide association studies of people have done a lot of work trying to um You know, associate these snips and every so often there's a new locus discovered, um, and, and what's quite interesting now is we're finally at the point, I think, where you can model these snips and, and have a sense of prostate cancer risk, uh, and this is, um, for example, a recent Nature Genetics, uh, paper, uh, but really this article I think was quite um. Illuminating, and we actually contributed quite a bit of DNA to this study, but basically this is a polygenic risk score, so it's taking all of the snips and aggregating them, and each individual 1 may increase your risk for cancer, it's say 0.5% or 1%, but because you have so many of them, you can aggregate this into a model. And in this particular study just published within the last year from Rossiel's group. In London, uh, you can see that that this polygenic risk score was, uh, utilized to identify significant disease. And I think one of the limitations of, of snips in in the past was that it was mostly associated with cancer, yes, no, as opposed to say high grade or significant prostate cancer. Uh, but in this particular case, this polygenic risk score, uh, had actually better uh predictability, if you will, of identifying a cancer in a patient. Than either MRI or PSA, so I think this is a, a, uh, peek into the future. These algorithms are now becoming available for those who are doing uh this type of research and we're doing a little bit of work here with polygenic risk scores, particularly in the black community here in Toronto, uh, but nonetheless, I think this is something that you're going to see in the next 5 years that patients won't only get PSAs, but they'll probably get a PRS and, and that information will be utilized clinically. There are limitations of SNPs. Um, because their functions are unknown, you may have spurious associations, right? Particularly in a disease like prostate cancer, where diagnosis is so, um, dependent on how hard you look. So health seeking behavior, snip, if you will, may be associated with having prostate cancer, even though biologically it doesn't. Uh, PSA expression, you know, there are snips associated with higher versus lower PSA expression. You could imagine that makes you more likely to be diagnosed with prostate cancer. Large volume BPH would be another because of, again, uh, any excuse to examine a prostate increases your risk. And as I alluded to, it seems like snips for aggressive disease are finally starting to become validated. They weren't, but I think we're getting close, as evidenced in that particular, uh, paper that was published this year. Let me move away from steps because those are the minor genes. I think the major cancer susceptibility genes are increasingly important. I'm sure many of you are familiar. I think this paper that was published now, I guess it's 8 years ago, 9 years ago, I think it's been a classic and it and it's not often you can get a paper published in the New England Journal of Medicine just publishing, um, basically a demographic study, but this is what they did. And what they did is they took men with metastatic prostate cancer and basically ran um a DNA um germline test and found that patients with DNA repair uh were at significantly higher risk of metastatic disease. And in particular if you look here and the the bigger biggest players of course are BRCA2, which con con uh conformed a 18.6 or depending on which control you use up to 26 fold increased risk of metastatic disease, uh, BRCA1 is there about 40% risk. Oh, but in particularly this BRCA2 is something quite impressive as is CE2. And why this is important is actually if you look in localized disease, the, the, the prevalence of these anomalies is, is, is kind of fairly small, obviously depending on the population you choose to have a look at maybe 1 to 2%. So it seems that having these anomalies doesn't is not so much associated with getting prostate cancer, but it's progressing right through to the metastatic pathway very quickly and very aggressive subtypes. And I think this is, this was very interesting because of of that particular uh observation and probably explained some of these crazy cases that I that I started with where you can have fairly rapid progression for seeming from seemingly uh tumor just um or or origin if you will, to metastatic disease. And again, if you're looking at these genes, um, and their makeup, it turns out it's about 12% have germline anomalies and about 12% have somatic anomalies. Here's but it's about 12% or 1 in 8 patients with metastatic disease, if you will, were born with one of these genetic anomalies, the most common being BRCA2, as I mentioned, ATM check 2, BRCA1, and then there's a smattering of others, and I think these are important, um. Genes to understand it and I also think it's extremely important to take family histories on your patients around some of these key decisions, whether it's surveillance, whether it's diagnosing prostate cancer, um, and certainly around therapeutic, um um implications as well. So, so these are important genes to understand and it's important to understand their prevalence. Now, a lot of this work has been done. In those sort of the white, if you will, European type populations. Obviously, we're still learning more about this, particularly in other populations. And this is just a recent paper from our group where we actually um collaborated with a group in uh in India, in the Delhi area. In northern India and sure enough, it's amazing. 11% of patients with metastatic disease in our in our particular study had one of these variants very similar to what was found in the Pritchard paper and interestingly though, the, the most were BRCA2, but then we had uh more RAD 51 and less if you will, check 2. And uh and less BRCA1 than some of the other studies. So as these studies start to internationalize, I think we'll find some of these distributions change a little bit and this was just, uh, again this is 276 patients that we reported on. We're doing similar work now in Africa, Malaysia, and, uh, we're trying to get a study started in the uh indigenous uh population in Australia. So these uh got us thinking about how do we model what the risk of, of metastasis and death is in patients um with prostate cancer, and this is a study that we did, um, and. Will soon be published, but basically what it's doing is we've taken the data from the Pritchard, uh, paper and tried to model epidemiologically what the lifetime risk of metastatic diseases, and I, I think those who don't really think about this really understand that when we ask patients what what they believe, if you will, their risk of metastatic disease. And if I told you what I'm curious what you would guess for BRCA2, but I'm sure you wouldn't say this. We think that the the lifetime probability of metastatic prostate cancer is probably depending on your estimates about the uh the lifetime probability of metastatic disease as well as comorbidities and risk of dying once you have metastasis, but we think your risk of metastatic disease probably approaches about 25 to 30% and certainly in a recent um. Um, panel I was are with, with Pritchard, and he, he tended to agree, and I don't think people realize their who if they they're BRCA2 carriers and men that really the risk is that high. And really one of, one of the biggest shames is, you know, over the last 20 years, maybe up until the last 5, everybody's been so focused on women when when a woman comes in with breast cancer and has BRCA2 or BRCA1, and there's been very little attention paid to the male, um, 1st and 2nd degree relatives. Um, moving on from that, I wanna talk a little bit about prognosis. So, so if you have some of these genetic anomalies, I think we're starting to learn that, um, your, um, and this could be whether it's germline or somatic, then you're starting to be able to prognosticate how patients are gonna do even if they have metastatic disease. So as I just mentioned the DNA repair type of anomaly genotypes do badly, but I think we're also learning there are hyper ADT sensitive profiles so. Uh, uh, genes like FOXA1, SPOP, uh, CDH1, and, and it's, these are, are anomalies that probably confer hyper ADT sensitivity and probably explains, you know, this odd man with metastatic disease who you'll see surviving 1015 or 20 years. So it goes both in both directions. In general though, if you have DNA repair anomalies, your outcomes are worse. This is the Castro paper looking at uh groups of of men who either got uh surgery or radiation with BRCA mutations and, and, and you can see that these patients tend to do worse, uh by the orange curve versus the black curve which are are non um BRC anomalies. And again, there's a massive difference between BRCA1 and BRCA2. The BRCA2s would do even worse in this particular uh subset. And even an active surveillance, this was a small paper that came out of the Hopkins Group looking at ATM BRCA 1 and 2 on grade reclassification, you could see the risk for upgrading is significantly higher. And again, in the BRCA2s in particular. Um, it would be higher certainly currently in, in our clinic if you want to go on surveillance and have an, uh, uh, any of these HRR defects, we are advising to get radical treatment so we would not offer surveillance to patients with BRCA1 2, ATM check-2, any of those particular anomalies in their in their germ lines. So what are the therapeutic implications of some of these genetic subtypes? Well, obviously PARP inhibitors have entered the foray. These are the four major ones in the market. And of course, we all, I think, hopefully all understand this concept of synthetic lethality, where, where you have to have, um, if you will, it's almost like a um A chair with, uh, with, you know, like a stool with three legs, but basically, if you have a a normal cell and you're a non-BRCA mutation carrier and you're exposed to this drug, you will, and you are subject to the DNA damage uh stress, you still have sufficient, um. Um, if you will, um, uh, function for repair and survival on the basis of your BRCA is fine. If you have a normal cell with a BRCA mutation and expose it, um, to a PARP inhibitor, but you only have one allele, which would be the uh situation of a carrier. Then again, you have a sufficient function to continue normal repair and survival with the DNA damage stress. But if you have bieic loss, because you're probably born with one and acquire one, if you will, then you, you're exposed to PARP inhibitor and you can uh kill the cell. So, so again, there's lots of data and really not the point of this talk, but just basically saying we do now have therapeutic options in general, as I tell patients, particularly with advanced disease with this problem, we don't want you to have it, but if you do have it, at least we have something. This is the original um profound trial the basis on which Elaparib was um approved. These were patients who had failed uh ARPI drugs and basically uh randomized to either a laparib or physician's choice typically was an ARPI switch, and you can see here patients had a, uh, basically improved both RPFS and OS even with crossover adjustment. And this led to the um uh approval. This is the cohort a group of that which were the BRCA 12 ATM group. There was a second cohort B, which was a smattering and aggregate of all the other anomalies also showing benefits. Interestingly, the ATM, uh, sub cohorts do not respond. So I think there's good evidence now that ATM does not respond to these drugs, um, and again this is just showing, uh, the data from another, um, if you will, this is the, um. Uh, RPFS data as well. Um, and of course, these drugs are now also worked their way into earlier disease. So this would be the classic older, if you will, CRPC definition, so patients who are failing LHRH alone. Uh, we don't see many of these because so many patients get the ARPIs up front, but nonetheless, I'm sure you're familiar with Propel where patients are treated with a lab and Abe versus a placebo and Abbi, and you can see here overall there's an RPFS, uh, difference, but it's particularly the bottom panel, which are those who have DNA repair defects that's driving the vast majority of those data, um, and I think, uh, certainly now. Uh, there tends to be utilization of these drugs in that population. Again, however, uh, finding these patients is getting harder and harder just because patients are typically getting the abbey, if you will, or the abbey-like drugs up front. How do we measure for these anomalies? A germline test is easy. You can take saliva or blood, of course, that's gonna be limited because you'll miss half of the anomalies. Remember, half are germline, half are somatic. So you need, uh, either some tumor tissue, a biopsy, and more and more CTDNA testing is getting, um, uh, obviously more and more sensitive. This is junk DNA in your plasma emanating from the, the cancer cells themselves that can be interrogated, uh, uh, for a lot of these anomalies. Who should we test for germline anomalies? Uh, it's quite interesting. Uh, certainly, it's now recommended by NCCN that basically any, um, high risk or very high risk patients should be tested. So any sort of Gleason 8, PSA over 20, uh, metastatic patients should be tested, uh, for a germline, um, mutation. Uh, and then if you even if you have very low or lower risk disease if you have a family history or intraductal histology, it is recommended that you do get tested, um, with a germloid test and we, we do this mostly because we have interest and with our collaborators here in the genetics, uh, space we do lots of this stuff. Little word about genetic nondiscrimination. I think this is an extremely important point, uh, and particularly I'd love to hear maybe in discussion the landscape in Florida or in the US, but, um, I hate our last government, but the one good thing they did was pass the Genetic Nondiscrimination Act, which again suggests that a patient cannot be biased from goods or services based on the results of a genetic test. So, um, for example, if you wanna insure your life, if you want to insure your, uh, family, if you want to adopt a child, uh, in fact, I recently, I was trying to up my insurance and, um, in one of those sort of insurance rate or phone calls, at least 3 times the person on the phone call said, if you've had a genetic test, we don't want to know the result. Um, so they'll actually go out of your way here to ask you not to reveal it. Um, and I think it's important, and I understand, I think, I think, I don't know if it's a state by state or or a US federal issue, but may perhaps it'd be interesting to hear about that. So what are we doing here at at at Princess Margaret? I've set up something we call the genetic risk assessment program or the GRASP clinic, um, where we um basically uh have a embedded within our clinic. We have uh the genetics team, um, and, uh, we have a dedicated, um, within our clinic we follow genetic carriers. Uh, we now have gotten very spoiled because provincial criteria, uh, for genetic testing has got very, uh, sort of relaxed, uh, so we get, um, any high risk biopsy, for example, is, is somatically profiled and, and getting, uh, germline testing is quite easy. If some patients don't fulfill it, uh, criteria but we're interested, we'll just send them off and get a, an invite or color test, but more recently, frankly. Uh, we could pretty much get any, any, um, blood tests through. We just order it and it just seems to happen by magic. Uh, we're looking again, um, not only in, in patients with high grade disease, surveillance patients as you heard about in the locally advanced and metastatic, and again we're also looking at patients with intraductal and ductal prostate cancer. So even ductal prostate cancer, which is a rare subtype of prostate cancer, was a recent. A paper about 5 years ago showing that about about 20% of those also harbor these um. Um, germline anomalies and, and, and the point about this clinic is not only to bring in the patients but also their family members. We get them tested we typically do, uh, annual MRs for the BRCA2s and every second year MRs for all of the others because of the perceived, uh, risk. Um, I think, uh, perhaps controversially, we have started also here, I believe it's the first, uh, program of prophylactic radical prostatectomy. So I do offer BRCA to patients prophylactic radical prostatectomy. I, it may seem, um, extreme to some of you, and I'll try and, uh, tell you the rationale about it. But having said all that, we've, we've, I've done about 6 that we're trying to wait for 10 to write up our first paper. Uh, but nonetheless, we do offer this for patients. Um, obviously, a prophylactic radical prostatectomy is a massive long conversation we have with patients. Um, but even, even some doctors in this particular hospital, I've operated on, um, with this sort of goal. So why do I think high risk carriers should uh should be considering a prophylactic prostatectomy? First of all, I don't think aggressive screening is gonna work. First of all, screening is not that good. If you look at high grade disease, which is that those type of cancers that particularly the BRCA 2 patients get, and you look at screening studies and you look at surgical trials at the most, you're gonna reduce mortality by 25-30%, but it's not. 80 or 90% like it is with patients uh in other types of cancers. And then I say to myself, well, who am I typically operating on? You know, I'll see a 62 year old's got a bit of uh GG2 disease or 3-4 disease, maybe a bit 15% pattern 4. and I, I, I look at that gentleman and I, and we're all eager to have him sign an OR, uh, consent to do a radical prostatectomy. But the fact of the matter is that 62 year old with a little bit of GG2 disease. Uh, frankly, has a much lower risk of dying of prostate cancer than the 62 year old carrier with BRCA2, who has no prostate cancer at all. So if we're gonna offer that man surgery, why wouldn't we offer surgery to the man without, uh, cancer? Um, and also, of course, you can do aggressive nerve sparing, um, and not wait for high high grade disease to to appear. And I think one of the cases I showed you where a patient actually had an MRI within 18 months was basically incurable. Leads me to feel that even aggressive screening with with MR as opposed to just PSA probably is not gonna be good enough in many of these cases just because they start off bad and they metastasize fairly quickly. There was, uh, this is not, uh, certainly the only place in the world in the sense there there was a case, the first, I think, uh, prophylactic case was described in 2013, done in Europe. Um, and there was a case, uh, an op ed, uh, published, uh, in, um, in 2013, of course, Angelina Jolie, the woman who started this off, and that's how we sort of often describe it for, for patients. It's an Angelina Jolie type of, um, idea. So we're, we're doing some research we're, we're looking at satisfaction in these patients, of course, we've actually found cancer in some of them as you'd expect. Uh, but we're just waiting for a few more cases to come through and try and get a manuscript out and describe that. Um, I'm gonna just shift now and tell you what we're doing more on the somatic side. I think quite interestingly, for many years, we've been interested in neoadjuvant treatment for high risk disease and we've done some, I think some of the pivotal studies looking at abiratero and abiratero and chemotherapy, the, the, um, Uh, the data that we've published over the years and, and more recently, Martin Gleeve and I have, uh, sort of joined forces, um, and, and have started to learn about some of the molecular landscape of high risk disease and, and incorporated this into our guns protocol and I'll try and explain it, uh, with you. So these are the sites, uh, of this particular trial. Uh, Marty uh is the genetics sort of hub. Our site is the, um, we're the guts, so we're actually running the trial out of the CRO we have a little CRO here in my back office, and you can see the particular sites, um, all high-quality individuals, um, um, and, um. And of course, like typical US um uh red tape, I think we BC and Toronto had about 130 patients in before the first US site even got approval, uh, because of all the red tape with getting these types of trials approved, INDs, etc. Um, so, so the idea here is what we're doing is doing a genomic biomarker driven neoadjuvant study. So what we're doing is trying to identify certain genetic profiles. In the cancer cells themselves, and then um try to use uh best available knowledge to perturb those particular drivers of of of oncogenesis, and then we take out the prostate and we try and use that as a model to learn about uh treatment sensitivity and treatment resistance. Uh, we know historically. Uh, ARPI, uh, the, the, the, uh, complete response rates are quite low, but if you look at the concept of MRD or minimal residual disease, you can get up to about 30%. Um, so, so, you know, this has been an effort to try and understand the biology and then ultimately perhaps use this for better treatments for patients with virus disease, but frankly, also for, for metastatic disease. So this is our study right now. I'll try and explain it, and we're in the process of opening two additional sub-protocols. So basically, we have this master protocol, patients with essentially super high risk disease. We get them enrolled, we get the um the tissue from the biopsy and it's sent to tempest. Uh, genomics and a, uh, a genomic profile is, is basically, um, determined. And from there we have a weekly tumor board, and this is one of the, I think one of the greatest tumor boards I've ever been associated with because it's essentially a molecular tumor board, and we have, um, you know, representation from some of the smartest people I think in North America. And what we do is we basically subcategorize patients into one of 4 profiles. Uh, and the, and while this is all happening, patients get LHRH andapalutamide. The subp protocol one is this group and I that I alluded to which has this high AR axis, so we think extremely hormone sensitive subgroup of patients with frankly no targetable alterations, they would get randomized to LHRH plus APA versus a triplet. So they get ABA plus ABBY. Now many of you may know there was a randomized trial of ESA plus ABI in metastatic disease a few years ago that showed up an improvement in RPFS but not an OS. And I'll come back to that in a moment. Sub-protocol 2 are patients who have bad um um sort of genetic uh profiles in the sense that they either have significant um mutations in some of those cancer associated um genes or loss of tumor suppression. So these are the sort of the P10, RB, P53 MCC type patients. And those patients get um LHRH and AY or LHRH IB and docetaxel so we've added the chemo thinking even though we showed in our prior study that adding chemo to ABBY didn't improve we're thinking well maybe in this subgroup of patients because of this particular profiling that adding Docetaxol will help. We have a sub, uh, protocol 3 which is basically the DNA damage type group which get not randomized, they all get a PARP inhibitor along with LHRH and ABBY and then there's the 4th, which is the rarest is the immunogenic if you will. This is almost like a Lynch syndrome type of sub subgroup, and these patients get LHRHAPPA and PDL1 just so you understand the reason they don't get AI, uh, APA in this group is there is a DDI. Drug drug interaction between APA and Docetaxel. So patients are actually starting on APA and they get switched over to ABBY. Our goal is to have 23 patients per arm. We, we've, we're starting to close sub protocol one, and we're opening up additional subp protocols. We have an, an easy to. Um, inhibitor, uh, and we have uh another one probably in the luteum space. So, very interesting way of, of, uh, looking at this. So the aims here are to characterize the landscape. No one's actually ever done this of high risk localized disease. It's been done mostly in metastatic disease and it's interesting to compare them. We have a paper coming out on that. We're trying to understand mechanisms and predictives of response and and resistance, and also investigate the role of lineage plasticity. Uh, as well as sort of clonal evolution and Darwinian, if you will, selection. Um, and then we're gonna ultimately get some hints to see how we can, uh, better treat this disease. So this is just some of the first number of patients, these maps just showing some of these anomalies we get. Obviously, this X SPOP, FO. These are the most common, the very highly ADT sensitive type groups, and then you get these chemotypes, uh, the P53, P10 RB and then you get a a smattering of other anomalies. Um, just a little bit about the subprotocol 4, which is this high tumor, uh, um, uh, mutational burden group that are mismatch repair deficient, if you will, lynch-like, and we're treating these with, um, azolizumab on the, on the thought that they're immune hot. Again, we know there's evidence that these drugs don't seem to work writ large in prostate cancer, but who knows, maybe there is a subset. Um, that, that can actually, um, inhibit response, and this is what we're, we're trying to, to learn. Just a little couple of tidbits because the data are just trickling out now, but, um, our, our, our, we're having about a 30% or 9 of 30 in our 1st 30 seem to have at least a CR or minimal residual disease. To me, the most interesting early finding, and this will be published soon, and we have presented this. Is that the MRD rate in the subp protocol one groups, remember that's the group that we think is entirely hormone sensitive, using the triplet versus the doublet, so meaning AI plus APA versus just Abi uh alone, um, uh, sorry, APA alone, we're actually getting a higher statistically uh rate of MRD and it gets me thinking. That maybe if that randomized trial uh was was reproduced but only in the patients with the genetic subtype that maybe the triplet would be better than the doublet so lots to learn here and and this is the type of data that we're kind of excited about getting of course this was generously funded um uh by not only grants but uh with a large grant from uh Jansen Pharmaceuticals. So this is just some acknowledgements um for this. So, um, I'm gonna just wrap up, I have a little bit of time to um to talk, I hope, uh, just first of all, thank you again for, for having me, um. Speak with you. I certainly very well of your department and the great stuff that you guys are doing. I just want to conclude saying these genes that you're born with matter in in context of of prostate cancer, but uh not only uh the germline but somatic uh change also has profound impact on outcome treatment response prognosis. And although uncommon, these 12% of patients uh with germline anomalies have a major impact on risk of prostate cancer death. Um, and I think you know it behooves us as investigators to learn how we can incorporate this information into the clinical landscape, and I think the guns, um, yeah, protocol is one example of that that I think hopefully will not only improve treatment for high risk disease but also for, as I alluded to maybe and positive patients ultimately. And, and again, also taking this information, trying to streamline it into a clinic where patients at risk can be sort of hyper monitored, if you will, and also be a living laboratory, right? For us to learn uh about these genetic anomalies and how they um transform. And I, and I, of course, these patients are also at high risk for other diseases, of course, such as, you know, pancreatic cancer and And skin cancer, and we try our best, best to get the patients sort of screened for those as well as part of this um this um group effort. So that's it. I'm happy to take any questions and, and uh I thank you uh for your time. Neil, great talk. Um, really exciting what you're doing with that guns protocol, the neoadjuvant. I just, um, a quick question before we open up to everyone else. Do you, are you going to probably open up like any or expand any of those subp protocols like and if you do, is it based on like success in MRD or are you looking at like biochemical recurrences like going to expand it out? We, well, first of all, it depends. Our goal is to get um Uh, you probably saw we're trying to get like 25 in each arm. We're probably not going to actually pull it off for the high TMB group because um they're rare, and um we're we're getting worried that maybe our we're gonna lose funding from that subgroup, so we're trying to figure out what we're gonna do with them, but we're opening up new subgroups. As I alluded to, we're gonna have an EH2 inhibitor group. We're also gonna have a P10 MTOR pathway uh with Herbisartab. So we're opening up new ones. Uh, we'll probably get also the new PARP inhibitor in once we close that. So if we can keep the machine rolling, of course, funding, we, we got, I think $8 million from from Jansen, so if we can keep the funding rolling, then we will um Uh, keep it open and keep opening new arms. Uh, but we're close to kind of, you know, we're gonna have to see what happens. Of course, Martin and I are starting to get older. We need young people to get involved in all this too, and, and, and probably take over. But, um, but it's been, it's been really interesting to learn about this, um, you know, how these tumors behave biologically. Neil, great talk. fantastic. Really good to see you. Good to see you again. Hey, Neil, let me ask you something because we came out with our men's health checklist last year. We updated, uh, the SMSNA. Um, do you think there's a role for routine screening other than the BRCA and targeted individuals? Is there a routine screening for other, uh, other types of, um, somatic mutations indicated? And, and what age would you, would you generally recommend that? Right, so you, I think you're talking about germline, but, but I think, um, you know, our, our feeling is that, you know, we're still learning, and, and, you know, when you do your men's Health Week, again, I, I think a lot of this tends to be probably, you know, I'd be curious who you're actually testing, and that's why it's so important. We do a lot of work here in the black community, we're finding, it's really interesting, like in theory that the black community is at high risk for prostate cancer. Uh, and death, and, uh, yet a lot of little is known about the genomic landscape of Uh, PSM, uh, which is very, which is highly, uh, we think maybe, uh, a gene that's part of sort of the lynch, uh, pathway that we think is highly prevalent in, in the black community. So, so I think, um, the answer is yes, and I think in 5 years, you'll add a PRS to that because I think the PRS now, of course, to do a PRS you've got to do effectively a whole genome, right? But as the whole genomes get cheap. Um, it's all gonna happen, right? I suspect a whole genome will be $100 in in 34 years, and then you can easily model the PRS. So, I don't think we're there right now, but I think it's really around the corner. Great. Very, very exciting. Thank you. Hey, Doctor Fleischer, how are you? This is Chad Rich, one of the faculty here. Hey, um, I had a question regarding the prophylactic process that can be very intriguing, and I, I think in Italy there was a group many years ago doing a similar, uh, similar protocol, but I haven't seen any. They were doing that. I think they were doing pin pin. That's right, yeah. And I was curious out of this small cohort you had, has anybody happened to have like a biochemical recurrence or not but. Um, but as I mentioned, we, we have found cancers. They, they've been, uh, I think two patients have had Gleason 6s, but, you know, I, I, frankly, if I take out a little Gleason 6. In a, in a bracket 2 carrier, I don't feel that bad. I feel way less bad than nothing. But honestly, you have to have the conviction that you really are helping them overall. You know, it's not easy. It's a high pressure operation. Yeah, yeah, I know. As you can imagine, uh, but, but, but, um, but, you know, unfortunately, like we've had good outcomes so far, you know, on the just on the functional side, but, but there's no doubt, like, I mean, I, I think if you really, you don't wanna obviously. Uh, sort of push a patient into it. It tends to be like a, a year in many visits before you really want to, uh, and document it well before you want to embrace that. Yeah, no, it's, it's fascinating because it certainly you get a handful of patients every year who ask about it and of course, you know, here in the US we're very sort of uh conservative because of medical legal um issues. I'm sure it is there in Canada too, but uh I wonder. But that's the beauty of having a protocol, Chad, right? Like open the protocol and then, and then you're sort of covered, right? Yeah, yeah, definitely. I, I also wonder too if, you know, years down the road if one of these patients have a biochemical recurrence, the reason I ask is because, you know, a lot of our medical oncologists or radiation oncologists wouldn't treat somebody with, you know, let's say their PT 0 and happen to have a rise in PSA. What do you do with that? It is an interesting question in the future. Hopefully we don't see that. Yeah. Look, I think there's good examples of patients getting phrectomies and still getting ovarian cancer, right, because now we know half of ovarian cancers actually originate in the tube, not in the ovary. So if you if you don't take the, if you leave tube behind, there's risk. And they have these weird primary peritoneal tumors that are like ovarian-like, so it happens and it also happens with mastectomy because even with the subcutaneous mastectomy, there are glands left behind. So, so these things can happen. Yeah, definitely. Well, thanks again. Awesome talk. I appreciate it. What about genetic risk? How does, how does genetic testing uh happen in Florida and what's the implications for things like life insurance or medical insurance? I mean, I don't think that we, I mean, right now we, so for example, I don't think we're testing as many people as you guys are testing. We don't test everyone on surveillance. I don't think most of the local eyes get tested. A lot of it happens through our medical oncology, um, and I think they're doing NBA and things like that. And to be honest, I don't, I'm not sure about the landscape in terms of insurance and other things like that. Does anyone else know? Yeah, I, I haven't seen anything in terms of like insurance denials based on that, but they also don't ask like what Neil was saying, they don't ask people, you know, this won't affect your insurance or anything. I've never seen that either, so there's not protection against it, so to speak. So in theory it could happen where they deny you. Yeah, I mean, you know, so, so it'd be interesting. I mean, obviously that's an important uh piece that before you offer a genetic test to a patient, I, you know, I think, um. Um, obviously you should sort that out. You'd hate to be, uh, You'd hate to ruin someone's life in a weird kind of way that way. Yeah. Great talk, Neil. Um, thanks again for, for doing this and, um, talk. OK, thanks, guys. Have a great one. Right. Yeah. Published September 11, 2025 Created by
