Charles Ryan: Hello everybody, welcome. Today, I'm sitting down with Veda Giri, who's an Associate Professor at Thomas Jefferson University in the Department of Medical Oncology, where she also has a joint appointment in the Department of Urology and Cancer Genetics. And she hosted a very important conference last year, and it's resulted in a paper just published in the JCO, which looks at consensus building and consensus guidelines essentially, for germline genetic testing in prostate cancer. Very important area because of the recent approval of two PARP inhibitors, but also our standard of care understanding of where we are with this disease. So welcome Dr. Giri, a pleasure to have you on and talk about your paper. So walk us through the process of how you did the consensus conference and what's the result?

Veda Giri: Sure. Thank you so much for having me, I'm thrilled to be here. This has been a very exciting time, as you know, in terms of the expansion of indications for genetic testing and germline testing in particular, as we're talking about here, particularly regarding the implications for precision medicine. And so I think this paper is really coming out on the heels of some very important FDA approvals for PARP inhibitors, for the treatment of metastatic disease. The reason that we really held this consensus conference in October of 2019, was because of us and others in the field, we were really noticing that there were some challenges that were arising while there was this expansion and testing going on. So for example, there was a lot more data coming out about potential genes that are found, genetic mutations in men with metastatic disease, also potentially genetic mutations that are being found in men with earlier stage disease, and the role in active surveillance potentially. And then the long-standing question about the role of genetic testing in prostate cancer screening and early detection and so from a risk standpoint.

So that was one area in terms of thinking of how do we weigh in with expert consensus to synthesize all of that evidence and literature that was coming forth into a framework that can help providers think about incorporating genetics into their processes, and management, and care. That was one major area that we noticed needed consensus.

The second area was, the fact that NCCN guidelines have incorporated genetic testing for prostate cancer in multiple places. And so the hereditary breast and ovarian cancer guideline now, including pancreas guideline, hasn't had prostate cancer included for genetic testing, so has the prostate cancer guideline. And then the early detection guideline references genetic testing as well for prostate cancer. So the challenge has been that there was variability noted across those guidelines. And so providers were coming up with confusion in how to implement the guidelines in their practices, knowing that those are now standard of care when it makes it into the NCCN, but looking at the variability was making that challenging for them. So we wanted to try to streamline the guidelines as much as we could or inform streamlining.

And then the third big area that we wanted to address was this growing population of men that need genetic testing for prostate cancer and recognizing that the demand for genetic counseling was rising. And that model of referring all men to genetic counseling was just not sustainable and to rapidly gain access to genetic information in practice for the treatment of metastatic disease, or surgical decision making, or just various different aspects of care, we were noticing that oncologists and urologists have been more and more ordering their own genetic testing. So we wanted to provide a framework of how to do that responsibly and collaborate with genetic counseling. So those were the three key aspects that we wanted to address in this conference.

Charles Ryan: And what do you think moving forward are the most significant barriers that clinicians face in practice in terms of genetic testing? Is it the availability of counselors or is it the knowing which patient to test and who not to, or what's the key challenge faced now?

Veda Giri: Yeah, I think that it's probably both of those, access to genetic counseling and also identifying the patients for testing and thinking of what to order when it comes to testing. From the aspect of identifying patients for genetic counseling, one of the main indications that we came away with, which is also of course in alignment with NCCN guidelines is to test all men with metastatic prostate cancer. And this has been well known and endorsed by the NCCN as well, which includes men with castration-resistant disease, as well as castration sensitive disease.

One of the things that we added from our consensus conference about this is that the ability of panel testing has also rapidly expanded, so genetic testing can include just a very small set of genes, four, or five, six genes, or 80 genes, 80 plus genes. And so how does a provider know or think about what to order in that setting? So our consensus panel weighed in and thought, it might be better to think about a broader cancer panel in the metastatic setting because it could open eligibility for clinical trials and so on and so forth.

In the earlier stage setting, identifying those patients probably goes more along with thinking of the features of their prostate cancer, such as do they have intraductal pathology, what is their Gleason score and stage of their disease? And then other factors too, such as of course, family history and ancestry. So we wanted to tie in all of those features to think about, for example, if a man with early-stage disease is thinking of active surveillance, should genetic testing be done in that scenario as well? And there, for the early-stage prostate cancers and also from a screening standpoint, we really thought that perhaps a reflex type testing approach would make sense. So start with the genes, a smaller set of genes that are impacting management, and then expand to further genes based upon family history or other features of that patient and their family history, but hand-in-hand with that is the collaboration with genetic counseling. So as you mentioned, really referral upfront for genetic counseling has just become very, very challenging and the wait times have become longer from that.

And so genetic counselors are also very eager to work with providers to develop a way to see patients after genetic testing is ordered, as long as that testing is conducive to the full evaluation that would be necessary when a counselor sees them. So for example, perhaps the counselor could uncover more family history and if the testing was already done, then insurance may not cover that, and so that's where the reflex model becomes really important. So these are the kinds of things that come up in practice.

Charles Ryan: So predictors of a positive test, let's say in a urology practice would be high Gleason grade, a patient with a significant family history of other members with breast or other endocrine cancers such as breast, or ovarian, or even pancreas cancer, and then intraductal pathology. Am I missing anything? Is that, those are sort of the big three for a urologist to keep in the back of their head as they approach this question? And of course, metastatic diagnosis?

Veda Giri: Exactly. Yeah. So advanced disease, like you mentioned, T3 or higher would be a qualifying intraductal or ductal pathology as you mentioned already, and then Gleason group 4, 8 or higher, so those would be sort of the pathologic features. But in addition, considerations Ashkenazi Jewish ancestry would be of importance to keep in mind. And then as you mentioned, there was a strong endorsement for family history of prostate cancer, particularly young age of onset, like less than age 60, men who died of prostate cancer or who had metastatic disease, as stronger considerations for testing. But as you mentioned, prostate cancer is also a part of other hereditary syndromes like hereditary breast and ovarian cancer, and Lynch syndrome. So that's where, breast cancer family history, ovarian cancer, colorectal cancer, pancreatic cancer, become really important to have an intake of, so that can inform the genes that we want to test.

Charles Ryan:  So a lot of academic institutions are now sort of struggling with developing a comprehensive program around not only testing but obviously the counseling and the therapy. What are you familiar with, either at your center or other centers where people are bringing it all together in terms of a program and what would you expect would be the model for a program to be done at a large academic center?

Veda Giri: So at a large academic center, for the most part, what we have seen is a genetic counseling program that is also available. So I think that puts academic centers in a unique, truly through to their unique advantage because they have that right there in their space. This is the issue in community settings where that might not be readily available. But in our center what we have done is, and what we encourage others to do is, have proactive conversations first of all, between the genetic service, and urologists, and oncologists, about how they want to approach their patients, when do they want to refer to the genetic specialists, and who's going to take a family history, will it be the genetic specialist on the backend or will it be the providers on the front end?

One of the things that we have done is, germline testing really does need to have optimal informed consent for patients about what they're stepping into, in terms of this testing. So, even for men who have advanced or metastatic disease, identifying a BRCA2 mutation would significantly give information about cancer risks for their children, for their siblings, in terms of cascade testing for the relatives and then potentially these other cancers that are linked with BRCA2 such as breast, ovarian, and pancreas. So that informed consent has to be delivered to patients before they make a decision about genetic testing. At our center, we've utilized the video, for providers to be able to use. And have studied this video now, to make sure that men are understanding this information, and just presented these findings at ASCO, and really there's high satisfaction with the use of tools and technology like a video to be able to give that information.

Charles Ryan: Do you track how far the information goes after a patient has a positive test, for example, if you see a gentleman with prostate cancer, he's found to have pathogenic BRCA2 mutation. Do you track whether his siblings all get tested, his children all get tested? Do we know... What I'm getting at, is how much does that penetrate and permeate a family, in a clinical world?

Veda Giri: Yeah, that's a great question. And I think it's really understudied in a male population. There's a lot of great work that's going on for females in the setting of breast and ovarian cancer testing. And what we have found is, we've been doing a lot more qualitative interviews with our patients on study to get a sense of, have they been able to discuss the results with their family members? What have been the barriers around some of these things? And it really varies between families. Communication styles really do vary between families. So we have found some of it to come down to stigma related to cancer and genetic mutation status. Thinking that the results only matter for males and not thinking about females, so their discomfort in discussing some of these cancers cross-gender in families. So we're actually trying to get all that information together and then really start to develop patient resources so that they can convey this information to their relatives because it is critical, especially when a mutation is found.

Charles Ryan: Do you have any idea what proportion of prostate cancer patients are undergoing germline testing now? And maybe another way to put it is, do you have any sense as to how many patients for whom it should be recommended are actually getting it done?

Veda Giri: Yeah, I think that would vary widely across centers, across geographic regions. I think that there are many centers that are widely and systematically testing men with metastatic disease, I think that's happening in some of the more high volume academic centers around the country. I think where we're missing is men with early-stage disease, where family history factors in and these other pathologic factors have to be weighed in. And I think that becomes just challenging in a busy practice, to be thinking of these things. So one of the things that we're trying to develop is a web tool or an app for a provider to have to just glean information that is almost more strategic to just pinpoint these questions that could help them make a decision quickly in their practice, about whether to refer a man for genetic counseling or offer him testing in their clinics. Though I think it's going to vary widely based upon the center, and the region, and the patient population.

Charles Ryan: I think we're also in a transition where perhaps, a generation ago or even just a few years ago, clinicians face with these patients almost feared doing some of the testing because of some of the implications that might arise and not sort of knowing, "Oh, if I get a positive test, what do I do with this patient differently? What do I do with his family?" et cetera. Of course, the PARP inhibitors is a great opportunity, but those are really for now, for men with metastatic CRPC. And actually, they're only confined for men with metastatic CRPC who have, for going on label progressed after an AR-targeted therapy and even in chemotherapy with the case of rucaparib. So, the question that also comes up is, finding out that a patient with locally advanced disease has a BRCA2 mutation, how's that going to manage the therapy in the current year, and even in the current coming years, is it or is it not?

Veda Giri: No, I think we're going to see this field really expand in the coming years, but already from the data that has been reported, men with BRCA2 mutations who have early-stage disease may consider in their discussions about whether to go ahead with definitive treatment versus active surveillance, they may consider going towards the side of active treatment, now that's really just more of a doctor-patient discussion, a shared decision at that point. Because there have to be a lot of factors weighed in, in addition to the many factors that are weighed into those discussions such as a patient's longevity and other factors of their prostate cancer. But that was one of the key questions that the consensus conference considered was, what about in the setting of early-stage disease and inactive surveillance? And the experts together really had stronger recommendations to consider BRCA2 in those discussions and lower level for ATM, which has been popping up more and more particularly in metastatic disease, but it just doesn't have that robust of the scientific findings and in association with poor outcomes that BRCA gene has right now.

But no, I think that was the key thing is in the decision making. But a key aspect in early-stage disease to is that these men are expected to be cured from their prostate cancer, who are followed and managed with active surveillance. Therefore, a second cancer that could be linked with BRCA2 is an important aspect to keep in mind for those men. So those men could be at risk for male breast cancer, pancreatic cancer, melanoma, and so these are cancers that need to be addressed and the risk needs to be managed. So we actually do recommend that men have a clinical breast exam who are BRCA2 carriers with their doctor. There's more and more discussion happening about pancreatic screening based on family history and BRCA2 status, we do refer those men to high-risk GI for those discussions, dermatology for full skin exams. And so these men have other cancer risk discussions that need to happen, in addition to thinking about their management of their prostate cancer.

Charles Ryan: Well, it's opened up a very complex set of issues for patients, their caregivers, their families, us clinicians. And I want to congratulate you on the publication and the leadership of this conference, and being involved in the formation of a consensus and appropriate clinical guidelines, and clinical arenas for these patients to pursue. So a pleasure talking to you and I look forward to your further work in this area.

Veda Giri: Thank you so much. Thank you for having me. And I really would like to thank all of our consensus participants, couldn't have done it without the team effort.

Charles Ryan: Very good.

Veda Giri: Thank you very much.