Dr. Choudry and Dr. Durant discuss pathogenic germline variants in GU cancers

In this interview, Mouneeb Choudry, MD, and Adri Durant, MD, describe the background and notable findings from the Journal of Urology study “Germline Pathogenic Variants Identified in Patients With Genitourinary Malignancies Undergoing Universal Testing: A Multisite Single-Institution Prospective Study.” Choudry and Durant are urology residents at Mayo Clinic in Phoenix, Arizona.

Please describe the background for this study.

Mouneeb Choudry, MD

Choudry: We wanted to look at the importance of genetic testing in patients with GU cancer and the impact that it has on their treatment decision-making, and the pathways that we put them on. The identification of germline testing, it's affected patients, and it really has important implications in that treatment decisions and their risk of producing future interventions, and cancer screening in general and also the relevance it has in terms of their relatives and the impact it has on their family members. And in recent years, there's been more of a emphasis or concern that's been placed on finding more targeted therapies for individuals with advanced cancers, particularly if you look at patients with prostate cancer, and you look at patients who have metastatic prostate cancer and the use of the PARP inhibitors. And with the FDA recently approving that, there was more of a concern and more of a need, we felt, to better identify the use of universal genetic testing in the GU cancer population. The only other study that really looked at this before was PROCLAIM trial. That was one of the first times where we really looked at comparing universal genetic testing vs just following the guideline-based genetic testing for patients. With all that, and the recent need for a better understanding of the usefulness of genetic testing, that's the reason why we wanted to dive deep into this idea and get some better answers.

What were some of the notable findings? Were any of them surprising to you and your coauthors?

Adri Durant, MD

Durant: This was a multi-site study involving Mayo Clinic institutions across the country, and over 600 patients with GU cancers were enrolled. This included patients with prostate, kidney and bladder cancer. Universal genetic testing was offered to them regardless of guideline recommendations. And when we looked at the pathogenic variants identified, we found that overall, nearly 15% of patients had pathogenic variants that were represented on the genetic testing, which was pretty notable. And then when we looked at these pathogenic variants, actually, two thirds of those patients went on to have clinically impactful changes, whether that's increased screening or surveillance. And then when we looked at cascade testing, or whether their families went on to have changes in their care based on that, nearly a third of those patients went on to have family tested based on these results. And then another, I think, really probably the most notable finding of this was the incremental findings of the test. And that means that patients who were identified to have pathogenic variants who would not have been identified based on current guidelines. We identified a very high percentage within this population. And so of patients with bladder cancer, 100% of the pathogenic variants would have been missed based on current guidelines. In kidney cancer, 80% of patients almost would have been missed based on current guidelines, and over 50% of the patients with prostate cancer with pathogenic variants would have been missed based on current guidelines. And so I think that was really the shocking thing that we found and the really clinically impactful thing that came out of this study

What questions arise from this research?

Choudry: I think 1 of the biggest questions that comes from this is that we are identifying these PGVs in the prostate, bladder, and renal cancer populations. But having a better understanding of which PGVs are really putting patients at an increased risk vs others, I think would definitely be something that needs more investigation. And then I think more work needs to be put into, how do we broaden the guidelines? A lot of times, I think what we struggle with in the medical field is, we have a lot of different tools and resources that we can use to help patients in terms of their overall care and guiding their treatment. But much of that comes back to, do insurances cover that, or do patients have the ability to afford that? Many times, these insurance companies will reference guidelines. I think more work needs to be put into better guideline statements on who needs this sort of genetic testing. That's not to say that we need to make it broad right away and say, everyone who has any concern for prostate, renal, or bladder cancer should have that. But I think there needs to be a little more work and investigation there to pinpoint who needs this and who doesn't. And then I think the other part of this, which we kind of touched on a little bit, and I think more questions need to go into is, like Dr. Durant talked about with the cascade testing, and family members uptaking this once they learn that the family member has these concerning PGVs, how to get more of these family members information they need to want to go and pursue genetic testing. And then once they have that information, what do they really do? We know that it's important, but I think some more work needs to be done to better have an understanding of who really needs it, and what do we do about it?

Durant: I agree. This is, I think, an impressive study from the amount of patients we were able to enroll from the Mayo Clinic sites, but still larger population studies are needed to validate these findings as far as what is the pathogenic variant rate within universal populations, and universal screening. And then as Dr. Choudry talked about, what is the infrastructure we need to help guide patients with these pathogenic variant results? What does that mean to them? And this, I'm sure, will continue to evolve as precision medicine continues to evolve in GU cancers as well.

What is the take-home message for the practicing urologist?

Durant: I think the biggest take-home message is just the importance of genetic testing. I think we were really shocked by the incremental findings or the findings that would have been missed by guidelines and the number of changes that would have happened and impacting patients based on surveillance and cancer screenings and the amount of family members that got tested based on these. And so I think that it's important to remember the guidelines and important to consider genetic testing and just important to consider how germline genetic testing will continue to evolve in its role in GU cancers, as it's important and its implications for treatment decisions, surveillance and impactful for patient family members.

Choudry: I do want to give a special thanks to the Invitae company; they helped us with this trial. And then a special thanks to our mentors, Dr. Tyson, Dr. Samadder, and Dr. Andrews, who really helped us out with this.