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Melanie: Welcome to Better Edge, a Northwestern Medicine podcast for physicians. I'm Melanie Cole. And I invite you to join us as we discuss germline testing for prostate cancer, some challenges and considerations. Joining me in this panel today is Dr. Ashley Ross, he's a professor of urology at Northwestern Medicine and, Dr. Brittany Szymaniak, she's a genetic counselor with expertise in prostate cancer at Northwestern Medicine.

Doctors, thank you so much for joining us today. And Dr. Ross, I'd like to start with you. Tell us a little bit about yourself, how you came to Northwestern Medicine and what you feel is the role of genetic screening prior to diagnosis of prostate cancer.

Dr Ashley Ross: Thank you very much for having me today. I'm a urologist and a surgeon scientist. I had done most of my training back in Baltimore, Maryland at Johns Hopkins, my MD and PhD there, my residency, and then I was on faculty there. I eventually came to lead the Urology Prostate Cancer Program, continued my work in prostate cancer when I then moved to Texas, and finally was recruited up to Northwestern Medicine, starting here over the summer. And I was recruited to Northwestern mainly because of the expertise it had here, the infrastructure and sort of the excitement around Northwestern Medicine as the system continues to grow and evolve.

In regards to genetic testing for prostate cancer before diagnosis, the role is little bit limited and it becomes more important, and we'll talk about this later, after the diagnosis of cancer. But before diagnosis, I think there's the realization that though prostate cancer is a fairly common malignancy, the most common non-skin cancer among American men, that aggressive prostate cancers often seem to have a genetic component to them. And so if a man comes from a family with a known germline mutation in particularly genes involved in maintenance of the DNA, like BRCA1, BRCA2, or some genes that are involved in other DNA maintenance components like those that are involved in Lynch syndrome, the mismatch repair genes, then those men should be screened for prostate cancer at an earlier age, usually starting at age 40.

The same thing is true for men with strong family histories as well. One more thing to add here is there's a lot of work being done to determine whether or not we can get genetics and look at SNIP analysis, which is single-nucleotide polymorphisms or other alterations in someone's baseline germline DNA, so every cell in their body, early in their lives and then determine if they should have more intensive or less intensive screening, even apart from their family history. And these would be looking at polygenetic risk scores. That is evolving. It's almost ready for prime time. There are a couple of testings that are near to the market, but not yet heavily utilized.

Melanie: Well, then Dr. Ross, as genetic testing is now recommended for patients with prostate cancer some of the time and there's been expanded guidelines and options for targeted treatments, speak a little bit more about the benefits of this testing and how Northwestern is using this approach, the germline genetic testing, to deliver precision oncology to patients with prostate cancer.

Dr Ashley Ross: So we've seen the approval of medications that are targeted to specific mutations for prostate cancer over the last year or so. One of the large ones has been the approval of PARP inhibitors, both olaparib and then the accelerated approval for rucaparib. PARP inhibitors are small molecules that affect a salvage DNA repair pathway. And for cancers that have mutations in their homologous recombination machinery, PARP inhibitors can then act on those cancer cells and selectively make it so that they can't manage their genetic stress and the cancer cells will preferentially die.

PARP inhibitors have been approved in breast and ovarian cancer, for example. And now we see that extension into prostate cancer. And this is one of the reasons it's important to check the genetics of men with metastatic prostate cancer, because the approvals for those PARP inhibitors has been in the castrate-resistant prostate cancer stage, so men with more advanced disease.

Similarly, there's been a blanket approval now a couple of years back for immunotherapies pembrolizumab in all people with cancers that have mutations in their mismatch repair machinery. These are like the MSH-2, MSH-6, the Lynch syndrome genes.

And so at Northwestern, we talk about genetic testing for all men with advanced prostate cancer, meaning metastatic disease. We suggest it for all men. We like to check their germline in those men and also somatic genetics. I will say that there's a recognition that in high-risk prostate cancer that's localized and maybe some of the even intermediate risk prostate cancers, while for those men, we would not use things like these PARP inhibitors outside of clinical trials, there is again the recognition that about 5% of these men might have germline genetic variance in genes that affect not just prostate cancer, but other cancers. And these are the people that I will also recommend germline testing for, and we'll try to link them with a genetic counselor, both to set them up early for future targeted therapeutics, but also to allow for cascade testing, which is what we were talking about a little bit earlier, where if that man has been found to have a mutation, let's say in BRCA2, they can work with the genetic counselor to get screening programs in place for their sons for prostate cancer, for their daughters and breast cancer and more.

Melanie: Okay. So that was a perfect segue. Dr. Szymaniak, based on the parameters that Dr. Ross pointed out, what is the role of other family members being evaluated and to understand their risk and by identifying at-risk family members before the onset of symptoms, how does that all tie together with what we're talking today? And what is the outreach? What are you guys doing in that regard?

Dr Brittany Szymaniak: So when there's an identified mutation in the family, just like Dr. Ross was mentioning, this can be a really powerful information for the family because now, even if we have somebody who was identified that has a current cancer diagnosis or they currently have prostate cancer, we can then start testing unaffected family members. So especially their kids or their siblings who don't have any cancer history. So we can start implementing that screening sooner to hopefully prevent a cancer from happening or be able to detect one earlier so that we can actually more effectively treat it.

So genetics is certainly family and has wide-reaching implications for the family. So genetic testing information isn't going to just help for that patient in understanding their risk and potential implications for treatment, but could have implications for the whole family. And so when we have patients that come in that do end up having a positive test result or have one of these gene mutations, then we can think about this cascade testing that Dr. Ross mentioned, and actually encourage these patients to share this information with family members so that they themselves can also get tested so that they can better understand their risk.

Melanie: That's a great point. And Dr. Ross, discuss the role of genetics and genomics as we're discussing this today in your treatment decisions for localized prostate cancer, as well as treatment decisions after radical prostatectomy or how genetics can guide this treatment of metastatic prostate cancer. How are you taking this research to the patient? And how is it changing the landscape of what you're doing?

Dr Ashley Ross: I think that there's a lot of considerations and it's broad, so I'll try to keep it brief. The major thing is there are recognized genetic mutations that push aggressive prostate cancer. Again, perhaps at the forefront of these is mutations in BRCA2. If we see a man with localized prostate cancer and a BRCA2 mutation, even if they have low risk disease that's clinically localized, I will usually discourage surveillance of that disease and push them towards definitive treatment.

If that same man has escaped sort of diagnosis when they were localized and we're diagnosing them for the first time in the metastatic setting, then particularly as they progressed after first line of therapy, we'll be thinking about utilization of targeted inhibitors, like PARP inhibitors. Right now, PARP inhibitors are approved in castrate-resistant metastatic prostate cancer, but there's a host of clinical trials moving them into earlier space and we're investigating them at this earlier space in the context of clinical trials.

For genomics, which I think is a broad and separate subject of the gene expression of the cancers, we are routinely using genomics, which is now looking at the expression of genes, not necessarily the germline DNA, but what's going on at the RNA level, for treatment decisions about therapeutic intensification, both in primary treatment, meaning for the first line of treatment, and after initial localized treatment when deciding on adding on salvage radiation or not adding antigen deprivation to the salvage therapy.

Now in the guidelines doing genomic testing, these are tests like for example, the decipher genomic classifier. There's good evidence now linked to randomized clinical trials that you can use that in your clinical decision-making to do kind of precise risk-benefit analysis with your patients.

But where the germline genetics and some of the somatic genetics to the DNA level is really helping us is for these targeted therapeutics and for the recognition that people with these low frequency, but very actionable wheels like BRCA2, need more aggressive treatment.

I'll say one more thing here and maybe we can have Dr. Szymaniak expand on it is that we are again looking also at these polygenetic risk scores, that's early stages, but the thought there are a lot of considerations there about what does this mean for men that are considering surveillance again. And also, again, in a clinical trial way, what does this mean for men potentially considering focal therapy to treat their cancers.

Dr Brittany Szymaniak: I can certainly expand on that a little bit more too, in that what Dr. Ross was mentioning with these polygenic risk scores is that we see families with these clusters of prostate cancer history, but there's not a single gene that we identify on testing for these patients. So we think that there is some component of familial risks. So multiple genes that are being shared between close relatives that are altogether kind of increasing this risk for cancer. But we really haven't been able to fully characterize this like we have been in previous years, and I think this is really the way that a lot of this testing might be moving into the future, is actually looking at these multiple genes and how they could be contributing to that risk.

Melanie: Well, Dr. Szymaniak, you recently published work in the Journal of Clinical Oncology. Tell us about your role as a genetic counselor with regard to these relatively new recommendations that we're discussing here today and some practical considerations for challenges that you might see with germline testing for genetic counselors.

Dr Brittany Szymaniak: So the purpose of this paper was really to help providers that are in the urology space, in the GU oncology space, to really help them wrap their heads around some of the components with genetic testing for prostate cancer, especially since it is so new. As genetic counselors, our role is to evaluate the family history for patients, perform a risk assessment, help determine if we think that the family history actually looks like it could be due to a hereditary cause and go through the components of testing with a patient.

But importantly, a component of that is whether or not a patient actually qualifies for genetic testing. And that's where these guidelines and recommendations come into play is how can we then apply what the recommendations are to this family and that helps us guide what the utility of the testing might be for these patients. Do we think we're actually going to find something with the testing?

And so with a lot of the prostate cancer genetics being a little bit newer, I would say, than some of the other cancers that we've been testing for, you know, things like breast cancer or ovarian cancer, a lot of information is still kind of pending for a lot of the genes that we're doing testing for.

And Dr. Ross mentioned BRCA genes, BRCA1 and BRCA2. We've been studying those genes for a number of years. 30 plus. So we know a lot about them, but some of these other genes and their implications with prostate cancer, it's still a little bit newer. So I think it can be very difficult for providers sometimes to think about doing this testing because of the implications for the cancer risks, as well as some of the implications for treatment may not be as clear. So a lot of what we were trying to do with this paper is to conceptualize this information for the challenges of the genetics and the interpretation.

Melanie: Well then before, as we wrap up, I'd like to give you each chance for a final thought. So Dr. Szymaniak, tell us about some practical strategies to overcome barriers to genetic testing. What are some of the practical aspects? I mean, it must go together with genetic counseling, which includes evaluation of the patient's emotional status, preferences, family history. There's a lot that goes in to this cascade of genetic counseling. Can you let other physicians know what you would like them to know to ensure that appropriate patients are systematically identified, referred for testing and even family members identified as well?

Dr Brittany Szymaniak: That's certainly a lot to cover in some final thoughts. But one of the things that I would like to emphasize is that these guidelines are certainly constantly evolving. We published that paper not that long ago and the guidelines are already different, so they're going to continue to evolve. So I think it's really important for these providers to be asking about family history, not just for GU-related cancers or prostate cancer, but other cancers that could qualify a patient for genetic counseling or genetic testing.

And I will say that if a patient is curious and they have questions about the family history or they have questions about genetic testing, it's always appropriate to refer them to a genetic counselor because that's our role, is to help walk these patients through that. And just because they're going for genetic counseling doesn't mean that they need to have testing.

So that's part of our role in how we're here to help. And so providers can think about that family history and they can think about what resources for genetic counseling would be available to them, either at their institution or maybe at an independent genetic counseling group.

Melanie: What a fascinating subject we're discussing today, and really it's amazing the progress that you all are making. It's such an exciting time in this field of genetics. Dr. Ross, your final thoughts for other providers on germline genetic testing, what you would like them to know and what you're doing that's exciting at Northwestern Medicine.

Dr Ashley Ross: So I would say first for germline genetic testing and prostate cancer, certainly for anybody that you think has incurable cancer, so metastatic disease, or progressing to metastatic disease, they need germline genetic testing. You'll find about 10 to 15% of those men are going to have a germline mutation.

That germline genetic testing should be done if possible, in partnership with a genetic counselor to handle the downstream implications for those men's families if they have a positivity, and preferentially, I think with slightly expanded panels, if possible. The second thing I would tell you is that it is a new field, just like Dr. Szymaniak was saying. We're partnering to figure out ways to take down barriers and make this easier for the clinicians. Both her and I are in a grant supported by Northwestern, which will hopefully become a national effort to look at the barriers that providers face in germline testing.

We're trying to work with some of our electronic medical record to establish different prompts for physicians, and also make sure that we can streamline things so that we have adequate capacity and people can have the same type of partnerships that I have with her in terms of relying on her as a genetic counselor, to really make sure that if we do find abnormality, everything is triaged correctly and we're doing our service for the patient as part of a team, as opposed to having it all beyond just the immediate treating provider.

Melanie: What great information, doctors. Thank you so much for joining us and sharing your expertise for other providers today. To refer your patient or for more information, please visit our website at nm.org to get connected with one of our providers. That concludes this episode of Better Edge, a Northwestern Medicine podcast for physicians. Please remember to subscribe, rate and review this podcast and all the other Northwestern Medicine podcasts. I'm Melanie Cole.