Heritable Prostate Cancer: Germline vs Somatic Mutations

Transcript:Raoul S. Concepcion, MD, FACS: Hello, and thank you for joining us today for this OncLive® Peer Exchange® panel discussion on personalizing therapy for advanced prostate cancer. Treatment of castration-resistant prostate cancer (CRPC) has become increasingly complex, not only because of the number of novel therapies available with distinct mechanisms of action, but because of the lack of comparative data or validated predictive markers to help guide choice of therapy. However, there is light at the end of the tunnel. As new platforms for molecular testing continue to emerge, we are entering an era of more personalized therapy. Moreover, the paradigm is changing from one of therapeutic sequencing to one of therapeutic layering.

In this OncLive® Peer Exchange® series, I’m joined by a distinguished multidisciplinary panel of experts. Together we will help you to navigate the most recent information regarding diagnosis and management of metastatic prostate cancer.

I’m Dr. Raoul Concepcion, and I’m the director of the Comprehensive Prostate Center in Nashville, Tennessee. Joining me in this distinguished panel to share their perspectives are: Dr. Michael Carducci, professor of oncology and urology, an AEGON professor in prostate cancer research, and associate director for clinical research at the Sidney Kimmel Comprehensive Cancer Center of Johns Hopkins Hospital in Baltimore, Maryland; Dr. Glen Gejerman, co-director of Urologic Oncology, and medical director of Tomotherapy at the John Theurer Cancer Center in Hackensack, New Jersey; Dr. Neal Shore, medical director at the Carolina Urologic Research Center in Myrtle Beach, South Carolina; and Dr. Evan Yu, professor of the Department of Medicine, Division of Oncology, at the University of Washington School of Medicine, and clinical trials director of Genitourinary Oncology at the Fred Hutchinson Cancer Research Center in Seattle, Washington. Thank you for joining us. Let’s begin.

In this first segment, we’re going to discuss new data relating to hereditary prostate cancer. Evan, historically—especially as urologists—we really only concentrated on family histories of prostate cancer, recognizing that these patients are at an increased risk as well as patients who are African American. What data have come out over the past year to change the thinking that our audience needs to focus in on?

Evan Y. Yu, MD: There have been a lot of data that have recently come out to point towards the fact that there’s a lot more germline alterations in patients with prostate cancer. Namely, the studies have been focusing on patients with metastatic prostate cancer, but they found that a lot of patients, up to close to 12% of patients with metastatic prostate cancer, will have germline alterations. That means they inherited it and it’s in every single cell in their body. Up to 12% will have them and homologous recombination deficiency genes. There’s a lot of different genes on that panel, but these, basically, are genes that are involved in DNA repair.

When you get damage to your cells, to the DNA, these are involved in DNA repair. There are some classic genes that I think most of us are familiar with. Most commonly, we think about BRCA2 and BRCA1, but there’s a whole list of other genes that are important—ATM, CHEK2, etc. They are not all created equal, and we don’t really understand just how important each one is into the development and progression of prostate cancer, but these are genes that clearly can be inherited and can predispose to the risk of prostate cancer—and it can be up to 12%, at least in the metastatic disease patients, that we’re seeing alterations.

Michael A. Carducci, MD, FACP: I think it has been a real change because people ask, “How did I get this?”, “Is it in my family?”, and “What do I tell my children?” I think these data help, but the information is still not telling us why the patient got prostate cancer. These are pretty common mutations in cancer and, from that perspective, it’s still a very small percentage of patients who have a hereditary alteration they passed off.

Raoul S. Concepcion, MD, FACS: Mike, I think people hear these terms and everybody is focusing on their genetic predisposition. So, can you differentiate what a somatic mutation is versus a germline mutation?

Michael A. Carducci, MD, FACP: I think Evan started to define it very well with germline—it means that you’re born with it, that it’s in every cell, and it’s going to be with you from the beginning to the end. Whereas, somatic are things that happen over time, particularly in tumor cells. As they mutate, they can mutate again, and there’s an ongoing process that, whether our therapies affect that or just the environment, multiple hits occur over time.

Raoul S. Concepcion, MD, FACS: Neal, you’ve been involved in this, specifically over the past couple of years. This information is beginning to proliferate and, we see, obviously, a lot more advertisements about companies offering genetic testing. What has been your experience as the patients come in, now, and talk to you about this?

Neal D. Shore, MD, FACS: Frankly, very few patients are asking, once they’re diagnosed, about their hereditary risk of prostate cancer for their offspring—their first degree, second degree relatives. What I’ve started doing now on my own, because of my interest in this, is getting a much better and more detailed history that I never historically did. I never learned to do this in medical school or residency. And this is incredibly important because these DNA repair mechanism defects, when found, oftentimes herald a more aggressive disease—a disease that’s more likely to convert from androgen-sensitive to castration-resistant. And really, it predicts a worsening risk for mortality.

The flip side to this is, when you have somebody who particularly has a germline mutation, there’s a worry that this can be affecting their members of their family. And there’s other syndromes where there is a risk: there’s documentation of ovarian cancer, male breast cancer, as well as female breast cancer, and pancreatic cancer. In that first degree, and even to some second degree, offspring are at higher risk for getting these malignancies. So, what’s troubling to me is that I’ve done a really poor job, historically, about getting that in-depth family history. I haven’t done a good job of counseling my patients who would have this risk.

Additionally, as we get to more treatment of CRPC, in patients who might have somatic defects as opposed to the germline, there’s also some potential for better counseling that we could be doing. During the conference that you alluded to, which I think was incredibly important, there were a lot of great messages, and we can talk more about some of these unmet needs. But one of the biggest things, to me, was the nascency of where we are, especially in urology. We’re just at the beginning of the beginning. We have to do a much better job. There’s a lot of challenges to it, and we can talk about it.

I’d love to hear Mike and Evan’s thoughts about genetic counseling and the accessibility to that. Who should be tested, and what do you do with that information? But, quite frankly, it all starts with getting a better family history and, then, referring patients who should be tested, and getting the counseling.

Michael A. Carducci, MD, FACP: I think both Neal and Evan have said 2 important points: 1 is regarding better family histories and knowing who to test. As a medical oncologist, I see folks later in the course of their disease. I want to know, for reasons about therapy options, that I may have better options if I know that they’ve got these germline or somatic mutations. And yet, if I really am looking and I find a germline mutation that has implications for the family, how far do I go? Does the patient want to know? Does he want to know for his family? This has all been worked out in breast cancer. What Neal brings up is we’re not trained to provide that information, and it’s easy if you test and they’re negative. “Oh, there’s no risk for that kind of thing.” But if they’re positive, it really has meaning for their family.

Evan Y. Yu, MD: Yes, and I’ll just echo the whole family history issue. I think, traditionally, in the field of urologic oncology, if we do a family history, we might ask, “Do you have a family history of any genitourinary malignancies, prostate cancer, or bladder cancer?” Breast cancer—I bet most people don’t ask about it. Ovarian cancer, gastrointestinal malignancies, a lot of these can travel in some of these families that have germline alterations, and so, it’s really, really important for us to all work better to improve family history. That’s something that we can work on and do right now.

I think the second component there is a greater challenge that I think we all realize—there is a shortage of trained genetic counselors in this country. To adequately counsel a patient before you do germline testing requires that you talk about all the implications—the ethical implications, potential financial insurance implications, and implications for all the family members. It’s not just implications for therapy, which we oftentimes think about as medical oncologists because there are potential implications for therapies. We can talk more about that later, but the whole familial thing is something that we, as a field, have to get together and work better to figure out just how we’re going to get this done. We don’t have all the answers yet.

Transcript Edited for Clarity