Zachary Klaassen: Hi. My name is Zach Klaassen, urologic oncologist at the Georgia Cancer Center. And I'm delighted to be joined on UroToday by Dr. Tom Jayram, who is a urologist and director of advanced therapeutics at Urology Associates in Nashville, Tennessee. Today, we're going to be discussing somatic and germline testing in prostate cancer.

This is based off of a presentation that Tom gave at the 2025 interdisciplinary GU cancer forum. Tom, thanks so much for joining us on UroToday.

Gautam Jayram: Thanks for having me, Zach. Pleasure to be here.

Zachary Klaassen: So let's just kick it off at a very high level, in terms of the difference between somatic and germline testing, just for our listeners to set the stage for our discussion.

Gautam Jayram: Yeah. It's something that we, as urologists, we just don't do this very often. We're not really introduced to it, especially in training. We learn a lot about cancer and treatment, but this is of one layer before that. But, basically, somatic and germline are two kinds of routes towards carrying a mutation that can drive behavior of a tumor.

Germline is basically present in every cell in your body. It's passed on through generations. It is a heritable scenario where a mutation can be passed on to offspring. And so that carries importance because, not only may the mutation-- can the mutation be a driver in terms of how the cancer behaves, but the mutation can be found in other members of your family.

So there are some real familial implications to that.

And somatic is a tissue or a tumor specific phenomenon where you may not have acquired, or inherited a mutation, but the tumor has acquired the mutation over time and can behave differently because of having the mutation. So there are really two ways of having it. And so you can-- to simplify, somatic is tumor specific, germline is patient specific.

And the two can be related. If someone has a germline mutation, they should have the corresponding somatic mutation. But if someone has a somatic mutation that doesn't necessarily mean that it was derived from the germline.

Zachary Klaassen: That's perfect. When we look at the last decade or so, since some really seminal papers in 2016, 2017, we've really seen the importance of testing in prostate cancer. Maybe just break that down for our listeners, why is it so important to test these mutations in prostate cancer?

Gautam Jayram: Yeah. It's a great question. And there's still actually some debate on really the relevance. But big picture is we know now there was really important data that came out in about 2014, 2015, that patients who harbored germline pathogenic mutations, specifically in HRR genes, are more likely to have advanced prostate cancer, or more likely to be associated with having castration resistant prostate cancer.

So the incidence in that group, of the patients who had CRPC, the incidence of having one of these mutations was about 12% to 13%. And when you compare that to, say, the wild type, or the group that doesn't have that, it's about 3% or 4%. So you're significantly more likely, if you have one of these mutations, to potentially have it be a driver mutation in advanced prostate cancer.

And now that set the stage for a lot of studies, but the one that most people are familiar with is a study called PROfound, where patients who had mutations, either somatic or germline mutations, in their prostate cancer, or driving their prostate cancer to be CRPC, benefited from PARP inhibitors as opposed to being treated with next best standard of care, which may have been an additional androgen receptor agent.

So now, not only is it more likely to be present in advanced prostate cancer, but we have a therapeutic that can be targeted that can target the alteration as well.

Zachary Klaassen: That's great. I think when we take specifically germline testing, the NCCN does a great job, ASCO does as well, so highlighting who we should be testing, maybe just lay that out for our listeners. Who should we be really thinking about germline testing?

Gautam Jayram: Yeah. There are a couple of consensus type of papers and meetings that have been out there. But, basically, anybody who has regional disease or worse. So if they're node positive, metastatic, hormone sensitive, hormone resistant, they should have testing because they are more likely to harbor a mutation.

We talked about that range can be anywhere from 6% to 13%, 14% in the germline setting.

So really that's the biggest thing is patients who have nodal disease or worse. And then you start talking about localized disease, patients who have what we would consider very high risk disease, Gleason 9 or above. And then patients who have high risk disease as well, Gleason 8 or above. Those patients should be offered testing as they do have a higher risk.

And then the last way to think about it is the familial component. So people who have a really strong family history. And there are some specifics about first degree, second degree. I would simplify it to say that if someone has multiple first degree relatives, a father and a brother, multiple brothers, that patient should be tested regardless of their prostate cancer status.

And then the other thing that is becoming more important is this understanding of the relationship between breast cancer and ovarian cancer and prostate cancer. So I always ask patients, do any women in your family have a history of breast or ovarian cancer? And, obviously, you'll be surprised at what you find when you ask that question.

So I would say that bad disease and then family history that's concerning, also with a focus on breast and ovarian cancer.

Zachary Klaassen: Yeah. Great point. I know a lot of trainees listening to our conversations. And especially when you're getting that family history, not just focusing on the prostate, but focusing on those other BRCA-related cancers, such as ovarian and breast, like you mentioned. That's perfect. Let's talk a little bit about ctDNA.

I know you mentioned that in your presentation at the meeting. How are you using that? How should we be thinking about using that? I know there's been a lot of work in the bladder cancer arena with ctDNA, but specific to prostate cancer, how are you using that?

Gautam Jayram: Yeah. ctDNA is really exciting. It's the darling of oncology right now in terms of trying to really understand and get a biomarker that is exciting and actionable. In prostate, really, what it comes down to is liquid-- this concept of liquid biopsies. Basically, if you look at the PROfound study, a couple of things stick out.

Number one, tissue really has a higher yield rate than blood. So if you have tissue, and in PROfound we saw what that looked like. But recent tissue, fresh tissue is the best thing possible.

So the common example is someone who had a radical prostatectomy three years ago that develops metastatic disease. That tissue is still very, very relevant, within five or six years.

There's some debate over at what point does it become less actionable. In PROfound, you had seven eight year tissue that gave you some results. And anecdotally, in my practice, I've had 10 year, 11 year tissue that gives you results.

Certainly the older it gets, the less actionable it gets. But if you have tissue, you want to use tissue.

And then germline, we talked about that's an easy blood test. Anybody can get it. But your incidence of finding a mutation to treat is a little bit lower because you're excluding the somatic component of the mutation.

You're just looking at the germline. And that's where liquid may come into play, especially in patients who have a high tumor burden but they don't have recent tissue, or they don't have accessible tissue.

So the classic example is the patient that has CRPC. That's bone only disease. Their PSAs are 20 or 30. It's going up. And it's just-- it's not easy. We all know that getting bone biopsies is not super easy. It's painful. It's difficult. Most IRs don't love it. Patients certainly don't love it. You get non-diagnostic results a lot.

So that's a great case for a liquid biopsy, or ctDNA. The only problem is if your PSA is fairly low, and you don't have a lot of disease, ctDNA is not going to be super effective.

It tends to be very correlative with how much disease you have. So it's tough in those patients who have-- or non-metastatic whose PSA is three or four. That group of patients, when they've been studied, there hasn't been a big hit rate on finding something.

So I think it's really good in that group of patients who have bone-only disease or disease that's difficult to access. But, you know, obviously, they have-- their cancer's getting worse. It's certainly worth a try to send ctDNA in that situation.

Zachary Klaassen: Yeah. Great explanation. I think when we look at the rates of testing, either somatic or germline in the community, also in academic centers, it's not as high as it should be. I mean, we think about, even that Gleason 9 or 10, which is a lot of our patients, we're not necessarily offering testing. It's an impossible question to answer, but I'm going to ask it anyways.

What are your thoughts on why that is low? I mean, maybe it's that hit rate of being only 3% to 5%. What are your thoughts on why it hasn't quite picked up yet?

Gautam Jayram: Yeah. It's a good question. We talk about this quite a bit. I think it's a couple of things. Number one, we're urologists, right? We're not oncologists. And that is a little bit different, because you talk to the oncologist in this space, really, the first thing they do is send this. And part of the reason is a lot of them are looking at clinical trials.

A lot of them are just looking at new options, different ways to think about this. And I think that's something we can borrow from them in that approach, especially our urologic oncology colleagues who see a lot of these patients.

So it's a cultural thing. It's kind of a mind frame thing. You're not necessarily thinking about that right away.

When you have your Gleason 9 patient in front of you, obviously, you're concerned about getting them through the process and they are concerned about that as well. And then I think the other part of it is the logistics.

So when you test, as you know, we're all running around. We're busy. You gotta fill out a form, or your MA's got to fill out a form.

You got to send it in. You got to fill out all these clinical variables on what you're looking, for what you need. The test comes back. Who does it come back to? Does it get into your EMR efficiently? So all of that has to happen.

And then you said it, 3% to 5% hit rate. So the vast majority of patients are not going to have a positive result.

But guess what? There's going to be another 5% to 10% of patients that have a variant of unknown significance. They have something there, but we don't know what to do with it. And so that makes a lot of people nervous.

Well, what do I do with this? How do I screen my patient who has a Lynch syndrome gene, or something that I don't really know what to do with?

So the actionability of it limits us. And then there are, and I've talked to some urologists, they're concerned about liability and what-- if I order this, then now I'm responsible for making all their appointments downstream.

I think a couple of things have happened that have improved that.

Number one, the companies have gotten a little bit better. They've gotten-- they understand this. There's built-in genetic counseling options for a lot of these companies.

Most big health systems, or most cancer centers have access to genetic counselors. We know that genetic counselors are not ubiquitous, but most of them have some of these in place, which helps to take the load off of us.

And then I think, ultimately, there is this notion that you don't have to-- you're not on an island with this stuff. The nature of multidisciplinary tumor boards, and the nature of our practice, everything is becoming so multidisciplinary.

I'll send a message to my oncologist, hey, what do I do with this mutation? Or does this mutation respond to a PARP inhibitor as well as BRCA does?

So I think there's a couple of things that are starting to move forward. But you're right, testing is still a lot lower than it should be in the community and I think that it's really just do it, operationalize it.

It's really-- it's not that much different than sending your genomic classifier for prostate cancer, or sending your IHC tests for prostate or bladder cancer.

All of that stuff is coming, and I think this is pretty similar.

Zachary Klaassen: Yeah. Absolutely. I think you guys have done a great job at your place and you specifically have. Getting this into the workflow, maybe just share for our listeners how that looks in your clinic, whether it's germline or somatic testing.

Gautam Jayram: Yeah. So a lot of practices, like mine, as you know in the community. We have big APCs, big advanced prostate cancer centers. And so we have a nice team that's mid-level, a physician's assistant, a navigator, a nurse navigator, and then we have an oncology RN as well.

And they kind of, at this point, they know what to look for.

So for the patient in our advanced prostate cancer clinic that's coming in, it's a checklist approach where, OK, make sure they're on bone agents. Make sure they're up to date with their GnRH, check labs if necessary, and then have they had any sort of testing.

So it's almost a little bit ingrained into how you see these patients.

And so I would advise that really utilizing some of your staff and your mid-level providers to help you with this. But even if you don't do that, it's really just something that you can-- I mean, my medical assistant knows to pre-populate the chart to almost to remind me to say, OK, well, this is-- we call them ATC advanced therapeutics patients. If this is an ATC patient, she'll just put it there.

And then we use our EMR to search if they've had one before and then we go from there. So we try to do, again, we try to build it in almost to the encounter. It's still not 100% foolproof, but you could also argue, and like we've talked about, you really want to test the people that are most likely to get a benefit. I'm still not a fan of every single patient walking through the door getting a test for some of the reasons we mentioned.

But if you can test the people who are most likely to get a benefit and you get some positive results back, it makes you feel better about ordering more.

Zachary Klaassen: Yeah. Awesome. That's fantastic. Tom, always a high level discussion. Appreciate your time. Any closing remarks, any take home messages for our listeners?

Gautam Jayram: No. I mean, I would just say that it's an important part of cancer medicine now. And really as urologists and urologic oncologists, we really want to embrace the disease. This is part of the disease. And as you know, Zach, it's not just in prostate, we're going to start seeing FGFR in bladder and various things in kidney.

So I think this is a really important thing in our field to get our doctors proficient with this because it's going to start taking off in all of the tumors that we treat. So really trying to understand how it helps and who it helps is going to be important.

Zachary Klaassen: Yeah, absolutely. Well said. I think educating the community, just like we're doing right now, is a huge step. So thank you for your time, as always, on UroToday.

Gautam Jayram: Great. Thanks for having me.