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Alicia Morgans: Hi, I'm thrilled to have here with me today Dr. Jacob Berchuck, who is a Medical Oncology fellow at Dana-Farber; as well as Dr. Mary Allen Taplin, who's a Professor of Medicine and a Medical Oncologist at Dana-Farber. Thank you guys for being here with me today.

Jacob Berchuck: Thanks for having us.

Alicia Morgans: I wanted to talk with you about some of the more controversial areas in prostate cancer around genetic risk, and controversial only in that it's hard to identify these patients because we don't necessarily have the means to screen everyone or I guess the operating procedures to work that into our clinical workflow. Then, we don't always know what to do with the information when we have that information. What are your thoughts and what are you doing to change all of these issues in the field?

Jacob Berchuck: Sure. We've known for quite some time now, a number of years, that these germline mutations in DNA damage repair genes are associated with more aggressive forms of prostate cancer, more advanced disease, so higher rates of Gleason 8 or higher disease, higher rates of being diagnosed with T3 or higher disease, and for men who are diagnosed with localized disease and then are treated with definitive local therapy, higher rates of recurrence after definitive therapy and higher rates of death from prostate cancer. These gene alterations that we're finding are really associated with worse outcomes. For a while now, the field's been interested in understanding which of these germline DNA alterations are the ones that actually are associated with the worst outcomes, and then what we do with these mutations when we find them.

An area that we're interested in studying is the high-risk localized population. The reason being is that this is a group that has localized disease, so potentially curative with definitive local therapy, but we know that approximately 50% of them are going to recur after radical prostatectomy or radiation with hormone therapy, and many of those will go on to die of prostate cancer. That's the population that we're really focusing on trying to understand the impact of these germline DNA repair mutations.

In collaboration with Mark Pomerantz here at Dana-Farber and Phil Kantoff at Memorial Sloan Kettering, we have a Prostate Cancer Foundation Challenge Award funded project where we have isolated germline DNA from 3000 men with high-risk localized prostate cancer and are performing germline sequencing to identify the full spectrum of DNA repair mutations in that cohort. Historically, we've mostly seen BRCA2 mutations but a number of other DNA repair genes like CHEK2, ATM, BRCA1 and other rare variants as well that have been identified in GWAS studies that other previous studies maybe haven't been powered to detect. That's the first aim.

Then, the second aim and really the important part of the study for patient care is what do we do with those? Which mutations are the ones that are high risk? All of these samples have really detailed clinical annotation, so we can ask the questions of which of these mutations are associated with a higher risk of recurrence. I think that's the really important question because when we find these mutations, knowing who's really at high risk and who isn't is important. Unfortunately, the prostate cancer field is years behind where breast and ovarian cancer are, where they've really done a great job of categorizing which of these mutations portend a worse outcome, and that's where we're trying to get in prostate cancer.

Alicia Morgans: Wonderful. What are your thoughts in terms of whether we can use that information at this point yet or are we still at the point where we still need to screen and understand who the patients are in our clinical practices?

Jacob Berchuck: That's a great question, and that's the million dollar question. Right now, I'd say we can definitively say that some of these BRCA2 mutations are the really high-risk ones that portend a worse outcome. As I mentioned, we're trying to really sort of discover which of the other mutations are associated with worse outcome, but what to do with those, we don't really quite know yet. That's another aim of this study. While this would be, I think, the hypothesis-generating and we need to show this in a prospective, randomized, large clinical trial. One thing that we're going to be able to do is look at men with pathogenic germline variants that we find, compare outcomes for patients who got surgery versus radiation therapy with hormone therapy, and potentially look to see whether recurrence rates differ depending on which local therapy patients receive.

We know that a lot of these men with a germline mutation, specifically BRCA2 will go on to develop metastatic disease, and so that inherently says that a lot of these men have the microscopic systemic disease at diagnosis. Again, this is speculative, but might it be that getting radiation and hormone therapy where you're giving some systemic therapy with initial local therapy, might that be a better approach for these patients? Just want to be clear, this is speculative-

Alicia Morgans: Of course.

Jacob Berchuck: ... but it's something that we're interested in looking at in this study and may be able to provide a rationale for further clinical trials.

Alicia Morgans: Well, and you need that sort of hypothesis-generating retrospective data before you can start in a prospective manner. The other interesting thing about these DNA repair defects is that some people hypothesize that radiation may be more effective or maybe very effective in those patients. Is that a better approach? As you said, we don't know, but you're able to look at that and at least give us some information as a field. How big is this study?

Jacob Berchuck: This is 3000 men. It's a collaborative effort between the Dana-Farber Cancer Institute Gelb Center, which is a bio-banking effort here at Dana-Farber as well as the Harvard School of Public Health.

Alicia Morgans: That in itself being such a large population-based study, that's huge, I think, in terms of providing that preliminary data for us to design further trials. Although we can't necessarily, it sounds like, use that information for treatment changes for those patients right now, for the patients, we see in the clinic right now; we certainly can use that information potentially to guide them in cascade testing for their families. That's something I think that's really important in your practice and I know in Mary Ellen's practice. How are you at the Dana-Farber implementing these practices and trying to help families of patients you're identifying in these kinds of trials else?

Mary Ellen Taplin: Well, Alicia, about two years ago we stopped and said, "We have a new appreciation scientifically that germline mutations are playing a role in prostate cancer," but patients weren't aware of it. To be honest with you, even the treating physicians either weren't that aware or weren't implementing any genetic counseling in their practices. We wrote a trial, we call it ProGen, and working together with a company called Ambry, who provided us approximately 600 genetic testings for the trial. We wrote a trial in which a very loose definition of anyone with potentially lethal prostate cancer, from localized high risk to metastatic castration resistant, would be eligible for the trial.

We are testing a way to do more efficient genetic counseling because the medical community is going to be at a loss. We don't have enough genetic counselors. Some hospitals don't have any genetic counselors, physicians and/or patients don't have access to them. In our study, we're looking at the standard of care genetic counseling where the patient meets with a counselor, through history's taken, advice given over about an hour, to an eight-minute video that we made, which gives all the important information. We're doing that study.

We've enrolled 450 patients in about 18 months, and the germline sequencing has been amazing I what we found. We can't wait to put this paper together. We've found Lynch families and we've had men with BRCA2 mutations whose daughters have been screened and positive who have gotten prophylactic surgeries because of the work that we've done. We feel that we've been literally saving lives of our patients and their family members, and so we're very excited about this work and trying to help the greater community of genitourinary oncology and urology to get the word out to consider this where patients with potentially lethal or serious prostate cancer.

I will just note that many guidelines now for our practicing doctors who follow the guidelines, NCCN, the AUA guidelines all include guidance for the referral of patients for genetic screening and testing and/or I know a lot of urology practices don't refer. You can actually get your patients tested through certain companies. One of them is Color Genomics and they have counselors available to assist the doctors and the patients in interpreting the results. It's evolving, and a lot's going to be happening in the next couple of years in prostate cancer and genetics, but it's exciting.

Alicia Morgans: Absolutely. Currently, at least all patients with metastatic prostate cancer should undergo these tests. We were talking earlier about the fact that the lack of genetic counselors within so many hospital systems, the lack of time can lead to physicians just not testing potentially, but part of this study is thinking about how do we use other methods besides face to face genetic counseling to at least do the pre-counseling before genetic testing. Is that a reasonable and feasible way of rolling this out in a larger manner? Can you tell us a little bit about what does that look like in the trial?

Jacob Berchuck: Yeah, so this is an eight-minute video produced here at Dana-Farber. It's a short segment, actually featuring Dr. Taplin, where she explains why germline testing is important for men with prostate cancer, how it impacts disease, as we discussed earlier in the segment, and how it could potentially impact what therapy they receive down the line. Then, that's followed by a short segment with a genetic counselor, where it's more of a broad over strokes about what germline testing involves, what the actual test is, that blood or saliva is obtained for the testing, and then how the results could both impact them as well as family, so it goes into cascade testing, which is a really critical part of understanding, for men to understand what they're getting involved with and what the potential implications are, not just for them but for their family.

We're licensing this video and the hope is that we could then distribute it to the community. It's a way that we could really scale-up the effort to meet what the guidelines now recommend, which is for all men with high-risk localized prostate cancer on through metastatic castration-resistant prostate cancer to be screened for these germline events that we're finding could impact them, their treatment, and their families.

Alicia Morgans: Absolutely, and a large number of men, so I'm really so excited that the Dana-Farber is really taking this proactive approach to not just create the video to counsel patients, but also to study it, which is one thing I love about the approach, to study whether this is actually going to be feasible, to be interesting to patients, that they can get what they need out of it, so that's really, really useful. As we wrap up, I'd love to hear what is your message to folks who are interested in understanding more about this and certainly your work about genetics in prostate cancer.

Jacob Berchuck: I think the big thing is that to really keep testing in mind when seeing these patients who are at high risks, have high-risk localized disease on through the disease spectrum, and keeping in mind that this is something that's going to impact potentially how the patient does as well as what treatments they receive and treatments that could be life-prolonging. I think keeping it in mind for that population and thinking about how you can implement testing for the patients that you see, be it in your practice referral to a more high-volume center, and keeping an eye out for sort of other opportunities that may be a little bit more innovative, but really thinking about how can I deliver this guideline recommended test to my patients.

Then, something that's a little bit more novel and coming down the line is how are we going to utilize this information to improve care for patients. As we talked about, we're interested in figuring out how we can utilize this to better stratify patients with high-risk localized disease. Something we haven't really touched on, but that's a really active and exciting area of investigation is PARP inhibitors really across the disease spectrum from neoadjuvant to high-risk localized to the more metastatic setting. I think those results are evolving, but it's something that could really change the field for patients with these germline alterations.

Alicia Morgans: I think you're right, and I think that there's a lot more to come. We'll have to continue the conversation with both of you to see how things go. Thank you both so much for taking the time today.

Jacob Berchuck: Thanks for having us.

Mary Ellen Taplin: Pleasure, Alicia.