Read the Full Video Transcript

Zach Klaassen: Hi, my name is Dr. Zach Klaassen. I'm a Urologic Oncologist at the Georgia Cancer Center in Augusta, Georgia. I'm delighted to be joined today by Dr. Abhi Srivastava, who is a Urologic Oncologist at the Atlantic Urology Clinics in Myrtle Beach, South Carolina. Welcome.

Abhishek Srivastava: Thank you, Zach.

Zach Klaassen: It's great to have you. We are going to talk today about your recent publication with your colleagues in Urologic Practice looking at, basically, germline and genomic testing and how we can improve these aspects in urology.

Abhishek Srivastava: Thank you. Yeah, it's a pleasure to highlight our work with you and UroToday. Happy to be here.

Zach Klaassen: Awesome. From a high-level view outside of the paper, just take our listeners through the importance of genomic and germline testing in advanced prostate cancer and who we should be testing. There's certainly literature out there that we're undertesting a lot of men, so just maybe highlight the importance and those who we should be really focusing on.

Abhishek Srivastava: Yeah. Just to give some background on this paper, also. We are a large private practice group and we are unique in the sense that we do a lot of clinical trials, so we are exposed to a lot of clinical trials that have been published and required germline or genomic or somatic testing initially. Dr. Shore, who heads our research center, was collecting this data because he was involved with these trials. When I came here, we tried to look at the database we had or the data we had collected, and there was a lot of interesting data in a lot of patients that we had in our database. So we wanted to put out our experience, especially towards community practices and try to improve penetration of germline and somatic testing, which to be honest, even though I came from an academic practice, we were not exposed that much. It was great to work through this paper and work with Foundation Medicine who helped us get some data and analysis through.

To start with, the importance of germline testing, right off the bat, the first thing is cascade testing, which, even in my short 4 years out of fellowship, I have kind of influenced a couple of patients just by listening to them, talking about their family history. I have identified a patient with a BRCA mutation who came to see me for just interstitial cystitis, ended up getting bilateral mastectomy as prophylaxis. I have influenced a couple of patients who had not seen a physician before and found Lynch syndrome in one patient, and she has been the biggest advocate for herself now and her family, trying to get them through screening and all that. That's very rewarding. So, definitely, that is number one. And then I would say identifying actionable mutations in patients with advanced prostate cancer and identifying some of these novel treatments, especially the PARP inhibitors and immunotherapy treatments for some patients who have MSI and TMB status high, could influence the care for the prostate cancer patients that you provide. Those are two good things for prostate cancer patients.

Zach Klaassen: The NCCN guidelines do a great job of really highlighting who we should be testing. And it always strikes me in a urology clinic, high-risk patients that are localized should still be getting tested. I think it's getting better. It's not where it needs to be, but that's something that I always try to teach my residents as well as even those patients with Gleason 9 disease that you're thinking about doing treatment on as a urologist, those are patients that we need to be testing too.

Abhishek Srivastava: Absolutely. I kind of follow the NCCN guidelines too, and I printed it out and I put it on either where I do my notes and things like that. So it does help me and it does a great job of identifying patients. I know there have been a couple of papers recently talking about universal germline testing and we won't go there, but there are certain data to suggest universal germline testing can identify more than 50% of the patients that are missed by NCCN current guidelines. So, always look out for that also.

Zach Klaassen: Great point. Going back to the study for today's discussion, tell us about the objective and some of the study design for your guys' paper.

Abhishek Srivastava: Yeah. The objective of the study was of course to kind of highlight our experience, and we noticed that even talking to other urologists and community urologists, there was low rates of germline and genomic testing in even metastatic patients, and even after approval of some of the actionable drugs, there was not improved testing. It was biased towards high-risk patients or metastatic patients, but still, the penetrance was low. So in our single-center analysis, we kind of examined the role of integrating this comprehensive genomic profiling, whether it's germline, somatic, or liquid-based tissue testing in routine management of advanced prostate cancer patients. Again, we wanted to highlight our center's experience being a community center. We are not exposed, we don't have genetic counselors, we don't have a genetic department, so a lot of counseling kind of falls on us, a lot of ordering of tests falls on us. So it's, again, a good experience and a rewarding thing to do for our patients.

Regarding the study design, we looked at the patients who had these tests from 2016 to 2021. Approximately 400 patients were in our database and the data was collected prospectively, but it is, of course, a retrospective study. We looked at the tissue testing or germline testing in our cohort, and then we took a deeper dive into patients who had Foundation Medicine testing because we were working in collaboration with them and the data regarding the types of mutation or rearrangements were available from the testing through Foundation Medicine. So it's basically just putting out our analysis for these patients and how we influenced either putting them on treatment, whether it's olaparib or rucaparib or immunotherapy, and then talking about some of the germline testing, which was consistent with published literature.

Zach Klaassen: That's great. Tell us about some of the key results. We're going to go through some of your plots here in a minute, but tell us, from a high-level view, the findings that you guys had.

Abhishek Srivastava: Yeah. Again, out of the 389 patients we published, data on 15% of the patients, or 59 patients, had actionable biomarker, whether it was germline or genomic, which was a significant number considering these patients were metastatic and had failed maybe first or second-line treatment. Germline testing, we were able to identify mutations in approximately 10-11% of the patients, again, consistent with published literature. We were able to initiate PARP inhibitor treatment in approximately 2% of the patients out of the 389, we tested. Most of all, the clinical trial, again, a lot of the clinical trials required being tested. We tested 42 patients, and I think 22% of the patients we were able to enroll in a clinical trial based on their testing. And then we'll go over the plots on which mutations we identified, but that was the high-level view of the data that we had.

Zach Klaassen: Excellent. Perfect segue into the plot. Take us through. The first one is at the tissue-based testing, and then we'll walk through the liquid-based testing as well. Take your time, walk us through the highlights of the tissue-based plot that we have here.

Abhishek Srivastava: These are comutation plots to identify the kinds of genetic alterations we saw in our patients, and these were, again, as I said, based on Foundation Medicine tissue testing, and we were able to identify the TMPRS and ERG rearrangements in most of the patients based on tissue testing, 44% and 32%. We were able to identify PTEN in 27% of the patients, again, TP53 in 23% of the patients. It depended on the kind of mutations that were available. Like for TMPRS or ERG, they were mostly rearrangements. For PTEN, it was deletions, truncations. For TP53 could be point mutations. Similarly, if you go down the list, in SPOP, there were point mutations. These are, again, established well in the literature that these mutations have a role to play in prostate cancer tissue testing.

Zach Klaassen: That's great. Let's move to the liquid-based testing. We see a little bit different plot here.

Abhishek Srivastava: Yeah, and it took me some time to understand after being in practice when to order liquid-based testing, when to order somatic testing. Again, just broadly, if there is no good biopsy or metastatic biopsy site available for tissue testing, then we default to liquid testing. We won't be able to identify a lot of the mutations and depends on the genes that are kind of associated with clonal hematopoiesis, where these genes are amplified more in blood. So we were able to identify TP53, again, point mutations, in liquid testing, but a AR was identified with a greater frequency in liquid-based testing and DNMT3A was also identified in liquid-based testing, which was not identified on tissue-based testing. In those two genes, the AR and DNMT3A, there was significant difference when we compared liquid to tissue testing on those two genes being manifested more in liquid testing because of clonal hematopoiesis.

Zach Klaassen: Other than maybe tissue not being available, as you mentioned, is there other reasons you may favor liquid testing versus tissue testing?

Abhishek Srivastava: Yeah, I think if there's only bony metastatic sites, some of the ways that these genes are isolated and sequenced could be difficult from only bony metastatic sites. Sometimes it could be a difficult location where IR is not able to biopsy or for some reason the tissue is not available if the patient has tissue somewhere else. So then we would default to a liquid biopsy testing.

Zach Klaassen: That's excellent. Two final questions. One is, if there's anything else we haven't hit on, go ahead and highlight it, and then leave our listeners with a couple of maybe actionable things they can take to the clinic tomorrow based on your guys' study.

Abhishek Srivastava: No, I think we covered the paper pretty well and thanks for all the questions. I really appreciate it. But yeah, again, starting off as a young urologic oncologist or a urologist in your practice, I think listening to the patients, focusing on the family history, whether they're oncology patients or general urology, you can kind of extract a good history from the patient. Germline testing, follow NCCN guidelines for now. I don't think we are where we can do universal germline testing, but the PROCLAIM trial, which Dr. Shore was part of, is a good study if somebody wants to review the data and summarize that. And then if your practice is focused on metastatic patients, definitely focusing on genomic testing, especially when something changes, like a new metastatic site is developed or the patient fails a treatment, kind of identifying these resources because you can offer life-changing treatments based on the new data from all these clinical trials we have and can definitely change your practice,

Zach Klaassen: Especially with the approval of the PARPs now. We're seeing this more and more, and it's going to be in the urology clinics more and more. And even as we mentioned off the top, getting those high-risk, even localized, patients tested just for the future and options for these patients is huge.

Abhishek Srivastava: Absolutely, a hundred percent agree with that.

Zach Klaassen: Thank you very much for your time. This was a great discussion. I enjoyed it, our listeners will as well. Thank you very much, Abhi.

Abhishek Srivastava: Thank you, Zach, I really appreciate it.

Zach Klaassen: Awesome. Thank you.

Abhishek Srivastava: Thank you.