 Welcome to this KCast program titled “Genetic Testing in Prostate Cancer.” I’m Dr Angelo Baccala from the Lehigh Valley Health Network in Allentown, Pennsylvania. Our discussion today is going to focus on current standards of care and future opportunities to help men with prostate cancer. Joining me in this discussion is my colleague Dr Jason Hafron, from the Michigan Institute of Urology. Welcome, Jason. Let’s begin.

 Likewise. Obviously, the genetic world of prostate cancer is rapidly evolving, and a lot of things are happening with the fundamentals of genetics. We’re learning a lot about that as we go along. It’s kind of a new field for a lot of urologists. It would be good, just by introduction, to talk a little about germline mutations vs somatic mutations. Jason, what are your thoughts on that? Do you want to explain a little to those listening and reading what germline mutations are?

 I agree, Angelo. Genetics is becoming a more and more important part of management of prostate cancer. It’s important for urologists to understand basic genetics because it can have a significant impact on prostate cancer progression and disease management, from diagnosis to late-stage disease. We are finally entering this very exciting era of personalized medicine, where identification of a mutation may impact local treatment, the decision whether to do active surveillance or active therapy, and in the late stages of disease, the choice of systemic therapy.

As we realize the importance of genetics and germline mutations, we need to understand it. It goes back to high school biology, but most of us have forgotten more than we know today, so we’ve got to revisit this and understand it. A germline mutation is a mutation that’s basically acquired from your mother and your father. They’re inherited pathogenic variants, and they’re present in all cells of the body. That’s key: that they’re in all cells of the body and really present at birth. To get a result for a germline mutation, you can get it from saliva or blood. However, somatic mutations are a little different. These mutations are acquired; you’re not born with these. To get the results of a somatic mutation, you have to get the sample from either the primary tumor or, preferably, the metastatic tumor site, and that will give us the somatic mutation.

 That’s a great way of explaining it. It does get confusing for those of us who learned about it a long time ago and forgot. But as you mentioned, the germline mutation is really noncancerous cells, and somatic mutations are really tumor-acquired mutations—so these mutations happen in the tumor itself after they have cancer. Certainly, they’re used for different things. But the idea that it has to come from both parents is also important when we talk about the 2-hit hypothesis of both alleles being disturbed or being mutated in order to pass on these hereditary conditions. That’s where family and personal history play a big role. Family history of cancer makes you more susceptible because those alleles are going to be passed on. If you have mutations in both sides, you can more likely get it. So that really explains that a lot. That was great.

 The 2-hit hypothesis is important. We all remember it from biology and premedicine. But either it’s a germline mutation that you’re born with and you may acquire a second hit, or you may be born with a susceptible gene and require a second hit either through environmental or some selective pressure. But the 2-hit hypothesis is definitely something to be aware of. It can explain all cancer because, essentially, cancer is a mutation that occurs. The 2-hit hypothesis is very important.

Germline Mutations & the 2-Hit Theory in Prostate Cancer

 Getting family history is really important, and doing genetic and hereditary cancer testing is predicated upon who is a good candidate. What do you guys do at Michigan Institute of Urology to assess if a patient is a candidate for that?

 Genetic testing starts with a family history. We’ve overlooked this in the past, but we really need to take an accurate family history, for any history of prostate cancer. Within the family, any history of ovarian cancer, colon cancer, ovarian cancer, or pancreatic cancer when you deal with the HBOCs [hereditary breast and ovarian cancers] is also very important. But what’s interesting—and I’m curious, Angelo, you run a large health group and have a big leadership position within your organization—is that we’re seeing with recent approvals that you potentially, similar to what they do in breast cancer, can screen the patients regardless of family history, regardless of Gleason grade, regardless of stage of disease, with 

 testing—that’s something we started in our practice just recently. This is evolving, and we’re getting the wheels in motion. We have agreed in principle—we’re getting it set up so anyone diagnosed with cancer, regardless of family history, is going to be screened for 

 cancer. I’m just curious where you guys are at Lehigh with this.

 That’s a great point. We are right in line with that. We have already started that process. For anyone who has prostate cancer, it’s part of our follow-up. If they’re diagnosed, when they get that discussion of being told that they are, and because it’s now FDA approved to have 

 testing, we automatically do it for every patient. What’s interesting is we know that for patients with prostate cancer in general, 17% of the metastatic and high-risk and very high-risk patients are going to have germline mutations, but 37% of them are going to meet criteria. When we do germline testing, it’s important to get that history because almost 40% are going to meet criteria for testing, and knowing that information is going to be important. But to your point, we can even jump that and say, “You have prostate cancer. We’re going to go ahead and test you for at least these 2 genes that we know are extremely important.” There’s a lot of downstream effect—which we’ll talk about later—things that are coming out with 

 for our prostate cancer patients that we can use. Knowing that information is huge. So that’s extremely important, for sure.

 Angelo, we’re similar. I’m part of a large LUGPA [Large Urology Group Practice Association] group, with 55 urologists, and we’ve implemented that plan. But I don’t know if you’ve had this experience where you get pushback from genetic counselors that the urologists shouldn’t be doing this, and I think part of that as we’ve evolved is pregenetic counseling. How do you respond to those criticisms or challenges? Because we’re doing it, how do you do it with that pregenetic counseling when you’re ordering these tests? What do you tell your patients when you’re ordering the germline testing?

 We partnered with our genetic counselors because, to your point, I think that’s an important aspect. We’re not there to cut them out. We’re there to include this and make this a better experience for our patients. That’s the part that’s oftentimes misunderstood by genetic counselors. Genetic counselors in most facilities are overwhelmed. There’s a lot going on, a lot going on with our cancer institute, so there’s a lot for them to deal with. For us, as these patients come through the door, the FDA approval part of this has been huge because we’ve been able to stand behind that and say, “This is something we should be doing for our patients,” and they understand that. We do have some counseling with the patient. We discuss the importance—like we’re doing right now—of hereditary testing and why it’s important for them in the future. But if they do get a positive result, we work with our genetic counselors to talk about that result with them. Certainly, they’re trained to do that type of thing. As urologists, we’re not. But getting to those patients, we have better access to them at that point because we’ve been able to diagnose them. We’re following these folks, vs getting them to a genetic counselor where, even if you make the referral, just because of timing and their availability, we may lose a percentage of the patients, and that would really be a shame.

 I feel the same way. The patients are in our office. It’s usually a simple blood test, and as urologists, we’re very familiar with consenting patients. We can tell them the risks, the benefits, and why we do that. But your point about if it is a positive test, if it is a VUS [variants of uncertain significance] or a high-risk negative, that’s an automatic referral to the genetic counselor. It’s similar to when you’re screening someone for kidney cancer or whatever, and you order a chest x-ray and the guy has a lung mass. It’s not like we’re experts in lung masses. We’re going to refer that patient out, but we’ll still screen that patient for a lung mass, and I’m totally comfortable with it. To your point, we don’t have genetic counselors—I’m in a different environment from you on staff—but we work with them. We told them what we’re doing—we’re going to be screening patients—and at first they were a little hesitant, but at the end of the day, they don’t have the bandwidth to do all this screening. The key is that these patients are appropriately screened, offered germline testing, and then the positives, the questions, the high-risk negatives, and the VUSs all should be referred to genetic counselors. I’m not trained and you’re not trained, but the genetic counselors can help with that. That’s true cancer care. It’s comprehensive cancer care to offer those services to our patients.

Gene Testing Criteria in Prostate Cancer

We’ve taken the conversation to the more localized patient with prostate cancer, really looking at the benefits for these patients. It’s huge, and we understand that, but it’s hard for the patients to understand it at that time. They think, “I have localized cancer, and I know what those options are,” and you may have discussed it with them. But explaining that to the patients is important. What do you tell the patients in terms of the benefits of genetic testing at initial diagnosis if they have localized prostate cancer?

 It actually is an easy conversation because most patients are receptive to genetic testing. They’ve heard about genetic testing, it resonates well, and they’re always concerned about their family members and if they could carry this on to their sons or even daughters with 

 testing. Patients are very open to it. But it’s similar to a standard consent—state why we’re doing it, what the risks are, what the benefits are—and you clearly have to say that this could affect your offspring because the results of this testing may affect them and may affect your risk for other diseases. Generally, it’s a quick discussion, and I don’t get a lot of pushback. Another key that you have to discuss is there’s a lot of legal protection with the genetic results. Insurances and payers can’t hold that against you, and sometimes people will question that. Thankfully, the breast cancer surgeons have cleared a path for us where there are good protections, where this genetic information can’t be held against you.

But I really think that as urologists, we have to get to the level of how breast cancer is managed. Of women who are diagnosed with breast cancer, the majority are getting 

 testing. It’s well understood throughout the lay press, and they almost expect it. If you look at the incidence of 

 in prostate, that story is not told, but it has a higher incidence. There’s more 

 positivity than there is in breast cancer. It’s almost as if we should change the name from 

. But getting back to your initial question, as urologists, we’re very comfortable consenting patients. We understand the consent process, and it’s similar to how you would consent a patient for a surgical procedure.

 I get a lot of questions from patients: “What are we going to do with this specific test? We’re testing 

, but are there other genes?” Certainly there are. That’s why partnership with a genetic counselor is important. If they’re positive for that, they can run panels for different things. They ask about some other genes, like 

. These are some of the other genetic mutations that we may be looking for, but we’re FDA approved for the 

, and starting with that really helps in our role to get the ball rolling for them. It’s probably the most common for them.

As you said, I explain to them that it is important for them to know for their own knowledge, but this may change their candidacy for something like a clinical trial or a treatment with a PARP inhibitor or something like that in the future; that if this becomes more aggressive and we treat it and then they recur, we’d have those opportunities for them. Having that information in hand is important.

Genetic Testing in Localized Prostate Cancer

 The other important thing is that, for some of our patients who show up metastatic at initial diagnosis, or unfortunately become metastatic while we’re treating them, genetic testing really does help treatment approaches and decides what we’re going to do for them in these patients with advanced prostate cancer. Do you want to talk a little about that, Jason, in terms of what your thoughts are and some trials that maybe have shown some good data?

 Definitely. This is 1 of the most exciting areas of urology right now. The FDA has approved 2 PARP inhibitors for men with metastatic, castration-resistant prostate cancer. When I encounter these patients, I will order somatic and germline testing on all these patients. The reason why it’s so important to do somatic and germline testing is there have been 2 major trials that have read out this past year: the PROfound trial and TRITON2.

PROfound was a positive trial for olaparib. Basically, they compared olaparib in patients who were failing oral oncolytics. For the comparator arm, the patients were flipped to a secondary oral oncolytic, but in the patients who had a homologous recombinant mutation, they were switched over to olaparib. The data are pretty strong that there was a 66% reduction in progression or death. So it’s a very positive trial. Switching patients with homologous recombinant mutations, you can reduce progression and death by 66%. When you look at that trial, you really see the patients with 

 mutations responded very well, and if you pare it down or dig into the trial, you’ll see that those patients pushed or propelled most of the response in the entire cohort.

The other trial was TRITON2. It was a phase 2 trial that looked at rucaparib. Rucaparib is a PARP inhibitor as well. Its end point was objective response rate, and it showed a 44% improvement in objective response rate. The only subtle difference between that trial and the olaparib trial, or PROfound, was that with the rucaparib, patients also had to fail taxane. They had to fail oral, they had to fail taxane, and then they could qualify for the PARP, which is in their label.

Those are 2 major trials that offer a lot of benefit to our patients. In our practice, we have started using PARPs. We’ve been involved in—not these trials, but other trials—looking at PARPs. The safety and tolerability are good, and we can extend life with these patients. It’s very exciting to offer another line of therapy. Again, these patients who qualify for these drugs have to have a homologous recombinant mutation. Olaparib allows about 14, and then rucaparib is 

 That’s an excellent summary of that. Thank you.

Genetic Testing in Metastatic Prostate Cancer

Genetic Testing in Prostate Cancer

Specialists in urology discuss the significance of germline testing in prostate cancer.

Genetic Testing in Prostate Cancer

EP 1: Germline Mutations & the 2-Hit Theory in Prostate Cancer

EP 2: Gene Testing Criteria in Prostate Cancer

EP 3: Genetic Testing in Localized Prostate Cancer

EP 4: Genetic Testing in Metastatic Prostate Cancer