Case 1: Role of Genetic Testing in Nonmetastatic CRPC


Ganesh V Raj, MD, PhD, and Mary-Ellen Taplin, MD, review the role of next-generation sequencing in nonmetastatic castration-resistant prostate cancer, and who qualifies based on NCCN guidelines.

Jorge A. Garcia, MD, FACP: In October 2019, the patient has met the definition for castration-resistant disease with a suppressed testosterone and has a rising PSA [prostate-specific antigen]. He undergoes restaging scans, traditional scans: a technetium-99 bone scan, a CT scan of the chest, abdomen, and pelvic region. All of these read negative for metastatic disease. His functional capacity remains pretty intact.

Let’s review this case again. He’s someone with high-risk disease from the get-go, undergoes local definitive therapy with surgery, and elects against salvage radiation therapy. His PSA rises. His local team makes the decision to initiate ADT [androgen deprivation therapy], and throughout the process, despite the initial serologic response, the patient becomes M0 CRPC [nonmetastatic castration-resistant prostate cancer].

We talked a little bit about imaging, but if we put imaging aside for now, another red flag that we have seen in this patient is his family history of breast cancer in his mom and sister, [and pancreatic cancer in his brother]. From the urology perspective, Ganesh, there has been a significant concern throughout the country from large urology practices as to how we are going to incorporate genetic testing in our patients with prostate cancer. What do you think is the role for NGS [next-generation sequencing] testing for this particular patient in your practice?

Ganesh V Raj, MD, PhD: I was fortunate to be part of the consensus group, the working group in Philadelphia. We met, and we published in the Journal of Clinical Oncology, Clinical Cancer Informatics the overall plan on when you do germline testing in patients with prostate cancer, when you do it early, when you do it after progression, and when you do it in metastatic disease.

One of the key things is that this fellow came in, an African American gentleman with 3 members in his family—first-degree relatives: his mother, the sister, and the brother—all having either pancreatic, breast, prostate, or ovarian cancer.

Even if they didn’t die from it, if you have more than 3 first-degree relatives who had any one of those cancers, especially on the diagnosis that this patient had of prostate cancer, that itself would trigger, prior to even him going for radical prostatectomy, a referral to our genetic counselor for him and his family to understand if there is a genetic predisposition for them…. Basically, we are looking for any of the DNA damage repair defects, or anything else that would predispose them to getting any of these cancers.

More and more in my practice, this is a red flag item. We look for family history. Even when a patient comes in with an elevated PSA, the moment he is diagnosed with prostate cancer, there’s a consult that he immediately populates for family genetic counseling.

The NGS testing would have started back then, but that’s more germline. The bigger question is: when do you do somatic testing? Do you do somatic testing of the prostate lesion or the metastatic lesion? That is something that is much more controversial. After this patient had biochemical recurrence, one of the easiest things to do before you do another biopsy, especially if he has no evidence of metastatic disease, would be to get the prostate and send that off for somatic testing.

I’m sure each one of us uses a different platform. We are platform agnostic; I use a number of different platforms. That helps us identify if there is a genetic basis for what they’re doing. And it’s not necessarily to manage where they are now, but to get more information so should they have metastatic disease, you at least have a sense of something in your back pocket that you could potentially treat these patients with.

Jorge A. Garcia, MD, FACP: Absolutely. I would argue that most patients with advanced disease coming into an oncology group will probably have some degree of a genomic platform in their tumor, whether it’s liquid or tissue based.

Mary-Ellen, the NCCN [National Comprehensive Cancer Network] guidelines have taken a very strict approach to genetic testing for patients with prostate cancer. Perhaps you could remind our audience as to who are the patients who need to undergo genetic testing based upon NCCN guidelines?

Mary-Ellen Taplin, MD: It’s almost any patient with prostate cancer at this point. I’ve evolved in my thinking. Several years ago, my criteria was a patient with potentially lethal prostate cancer, even if that was localized. But now I feel like I need to know their germline status, even if they have low-risk prostate cancer and they’re going to consider active surveillance. Because we know the patients for instance with BRCA2 mutations tend to have more aggressive cancers. And while they might look low risk initially, they’re really not appropriate patients for active surveillance.

In my practice, regardless of family history, if you have prostate cancer, I send my patients for germline testing, and I think that’s really important. I can tell you an anecdote where I sent a patient for germline testing, and when he came back to see me 2 months later, his daughter was accompanying him, and they had both tested positive for BRCA and she had already had prophylactic mastectomies. The impact that you can have in a prostate cancer clinic goes way beyond the patient sitting in front of you. I would like to underline the importance of this type of testing.

Jorge A. Garcia, MD, FACP: Great point, Mary-Ellen. It is also fair to say that when you look at existing data looking for DNA repair deficiencies in men with prostate cancer, such as the Seattle data, it’s probably less than 10% for germline mutations, but there are some somatic DNA repair deficiencies that may become important for therapeutic perspective down the road.

I often think the biggest challenge knowing someone has DNA repair deficiency is the timing to intervention. Clearly we know they have more aggressive disease that we may not see sitting on an active surveillance-type of approach. But we also don’t know the true therapeutic implication of early interventions now that we have PARP inhibitors. Those patients could go on and proceed down the road. That’s very important.

Transcript edited for clarity.

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