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Genetic Testing and Prostate Cancer

Insights From: E. David Crawford, MD, University of Colorado in Denver; Matthew T. Rosenberg, MD, Allegiance Health Systems; Daniel Petrylak, MD, Yale School of Medicine
Published Online: Wednesday, Jan 04, 2017



Transcript:

E. David Crawford, MD:
So, Dan, we’ve got these drugs. They’re exciting. I think, as you said, the challenge is, how do we sequence them? But, as you and I well know, every cancer that we cure, it’s not sequencing A, B, C, and D. It’s putting 3 or 4 drugs together. That’s lymphomas, leukemias, and testes cancer. Platinum, by itself, doesn’t do it. That’s obviously where I think we need to go in prostate cancer, but it’s a slow ride.

Daniel P. Petrylak, MD: Right. I think we’ve lagged behind some of the other tumors. Of course, the other thing, too, is introducing personalized medicine into all of this. We’re now seeing that there are certain mutations with BRCA or DNA repair that help us to determine whether drugs are appropriate in a given situation. The AR-V7 mutation with the androgen receptor (AR) marks for resistance to abiraterone or enzalutamide. This may help us tell whether somebody should go on chemotherapy rather than going on those drugs. So, not only do we put these drugs in sequence and combine them, but we have to look at markers in this situation, as well.

E. David Crawford, MD: That is a very good point. I think that should be our wrap-up with that because I think there are some real messages that go to the gatekeepers with these patients, at least up to this point, urologists. Let’s talk about germline mutations, just for a second. Urologists might see a guy who has 4 brothers, a father, and an uncle who have prostate cancer. Then 2 years later, his sister is diagnosed with triple-negative breast cancer and dies in a year. That could have been prevented had the urologist actually germline tested that person for a BRCA2 and BRCA1 mutation, which are actually more common in men than in women.

Daniel P. Petrylak, MD: Absolutely.

E. David Crawford, MD: But, we don’t do that.

Daniel P. Petrylak, MD: And, the disease is more aggressive. If you identify somebody, right off the bat, who’s BRCA positive, this is somebody who has a tendency to relapse very, very quickly. Also, they’re sensitive to these drugs such as olaparib, the PARP inhibitors. So, I think that we have things that we can offer these patients. The question is, can we treat these patients with these drugs without the androgen-deprivation therapy? I think that’s going to be a very important question for the future.

E. David Crawford, MD: That’s the personalized medicine. Also, when you find out that they are carrying that gene, you go back and that’s where the genetic counselors go in. You go back and have the sister tested, and see if she has it. And, with her breast cancer, who knows, and it’s also associated with pancreatic, and Lynch syndrome, and various other things like that.

Matthew Rosenberg, MD: You just, again, taught me a fantastic thing here. And, what’s interesting is, as a primary doctor, I’m frequently taking care of the whole family. In the small communities across the country, I have large families, I have multigenerational families, so I’ll know the parents, I’ll know the grandparents, I’ll know the kids. So, Matt, you’re taking care of this guy, this is his lineage here, make sure the sister is getting taken care of, I’ve got that covered. Again, it’s a team effort.

E. David Crawford, MD: We had opportunity possibly to save that sister’s life.

Matthew Rosenberg, MD: We did.

E. David Crawford, MD: We don’t realize that, when we do these germline mutations. And, now, there are companies that have a whole series of mutations they look at which are out there. Let’s finish up with AR-V7. Everybody has been talking about that for a long time, and now I think it will be commercially available. How does that fit into your thought process about taking care of these patients when they respond to abiraterone, when you use chemotherapy, when you stop, when you switch?

Daniel P. Petrylak, MD: So, I think, one of the key issues with these patients, if they’ve been on abiraterone for a long period of time and then they progress, do you switch to another anti-androgen such as enzalutamide or do you go onto chemotherapy or to isotopes? I think that decision will be made easier by having the AR-V7 test present because then if they’re AR-V7 positive, you’re not going to treat them with the second hormonic. You go on to chemotherapy or another treatment. I think, also, again, for primary decisions as far as chemotherapy versus hormones, that will be useful, as well.

E. David Crawford, MD: So, AR-V7 is a mutated androgen receptor, and doesn’t have a ligand. It just can work by itself. It doesn’t need testosterone.

Daniel P. Petrylak, MD: Exactly. It’s active, regardless of whether there’s testosterone present or not.

E. David Crawford, MD: That’s a big step forward about what direction to go.

Daniel P. Petrylak, MD: Exactly. There’s a cost issue with this because you’re not giving a drug unnecessarily to a patient. There’s a toxicity issue, as well. So, I think both of those will be very, very important to our management.

E. David Crawford, MD: So, Dan, AR-V7 mutations, you just talked a little bit about those—help guide the future direction. Take it away. Somebody is on Zytiga, or abiraterone, and they’re mutated.

Daniel P. Petrylak, MD: I think there are several ways of looking at how we can potentially integrate other hormone treatments. One, of course, if they are AR-V7 positive, you’re tending not to want to go on a second hormonal agent. However, I think we have to start looking at some of the differential toxicities that are involved with some of these newer anti-androgens. So, the AR-V7 could help us determine whether these patients still are active against these particular drugs. And, we have other newer anti-androgens that are being evaluated in this situation, like ARN-509. This supposedly has less CNS toxicity because it does not cross the blood-brain barrier at the same level that enzalutamide does. This is a problem that we see with our patients. They become depressed, they can become fatigued. They may not even be able to add common figures because there is, of course, an effect of testosterone on the brain. I think that we’re going to be able to refine our androgen-receptor antagonists further in the future. There are randomized trials comparing, for example, abiraterone to abiraterone plus ARN-509, to see if a further blockade of the androgen receptor will give you a better progression-free and overall survival. So, I think that this test will be very helpful in determining what to do next with these patients.

E. David Crawford, MD: I like the whole concept of putting things together. That’s the way forward. Thanks.

Transcript Edited for Clarity
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Transcript:

E. David Crawford, MD:
So, Dan, we’ve got these drugs. They’re exciting. I think, as you said, the challenge is, how do we sequence them? But, as you and I well know, every cancer that we cure, it’s not sequencing A, B, C, and D. It’s putting 3 or 4 drugs together. That’s lymphomas, leukemias, and testes cancer. Platinum, by itself, doesn’t do it. That’s obviously where I think we need to go in prostate cancer, but it’s a slow ride.

Daniel P. Petrylak, MD: Right. I think we’ve lagged behind some of the other tumors. Of course, the other thing, too, is introducing personalized medicine into all of this. We’re now seeing that there are certain mutations with BRCA or DNA repair that help us to determine whether drugs are appropriate in a given situation. The AR-V7 mutation with the androgen receptor (AR) marks for resistance to abiraterone or enzalutamide. This may help us tell whether somebody should go on chemotherapy rather than going on those drugs. So, not only do we put these drugs in sequence and combine them, but we have to look at markers in this situation, as well.

E. David Crawford, MD: That is a very good point. I think that should be our wrap-up with that because I think there are some real messages that go to the gatekeepers with these patients, at least up to this point, urologists. Let’s talk about germline mutations, just for a second. Urologists might see a guy who has 4 brothers, a father, and an uncle who have prostate cancer. Then 2 years later, his sister is diagnosed with triple-negative breast cancer and dies in a year. That could have been prevented had the urologist actually germline tested that person for a BRCA2 and BRCA1 mutation, which are actually more common in men than in women.

Daniel P. Petrylak, MD: Absolutely.

E. David Crawford, MD: But, we don’t do that.

Daniel P. Petrylak, MD: And, the disease is more aggressive. If you identify somebody, right off the bat, who’s BRCA positive, this is somebody who has a tendency to relapse very, very quickly. Also, they’re sensitive to these drugs such as olaparib, the PARP inhibitors. So, I think that we have things that we can offer these patients. The question is, can we treat these patients with these drugs without the androgen-deprivation therapy? I think that’s going to be a very important question for the future.

E. David Crawford, MD: That’s the personalized medicine. Also, when you find out that they are carrying that gene, you go back and that’s where the genetic counselors go in. You go back and have the sister tested, and see if she has it. And, with her breast cancer, who knows, and it’s also associated with pancreatic, and Lynch syndrome, and various other things like that.

Matthew Rosenberg, MD: You just, again, taught me a fantastic thing here. And, what’s interesting is, as a primary doctor, I’m frequently taking care of the whole family. In the small communities across the country, I have large families, I have multigenerational families, so I’ll know the parents, I’ll know the grandparents, I’ll know the kids. So, Matt, you’re taking care of this guy, this is his lineage here, make sure the sister is getting taken care of, I’ve got that covered. Again, it’s a team effort.

E. David Crawford, MD: We had opportunity possibly to save that sister’s life.

Matthew Rosenberg, MD: We did.

E. David Crawford, MD: We don’t realize that, when we do these germline mutations. And, now, there are companies that have a whole series of mutations they look at which are out there. Let’s finish up with AR-V7. Everybody has been talking about that for a long time, and now I think it will be commercially available. How does that fit into your thought process about taking care of these patients when they respond to abiraterone, when you use chemotherapy, when you stop, when you switch?

Daniel P. Petrylak, MD: So, I think, one of the key issues with these patients, if they’ve been on abiraterone for a long period of time and then they progress, do you switch to another anti-androgen such as enzalutamide or do you go onto chemotherapy or to isotopes? I think that decision will be made easier by having the AR-V7 test present because then if they’re AR-V7 positive, you’re not going to treat them with the second hormonic. You go on to chemotherapy or another treatment. I think, also, again, for primary decisions as far as chemotherapy versus hormones, that will be useful, as well.

E. David Crawford, MD: So, AR-V7 is a mutated androgen receptor, and doesn’t have a ligand. It just can work by itself. It doesn’t need testosterone.

Daniel P. Petrylak, MD: Exactly. It’s active, regardless of whether there’s testosterone present or not.

E. David Crawford, MD: That’s a big step forward about what direction to go.

Daniel P. Petrylak, MD: Exactly. There’s a cost issue with this because you’re not giving a drug unnecessarily to a patient. There’s a toxicity issue, as well. So, I think both of those will be very, very important to our management.

E. David Crawford, MD: So, Dan, AR-V7 mutations, you just talked a little bit about those—help guide the future direction. Take it away. Somebody is on Zytiga, or abiraterone, and they’re mutated.

Daniel P. Petrylak, MD: I think there are several ways of looking at how we can potentially integrate other hormone treatments. One, of course, if they are AR-V7 positive, you’re tending not to want to go on a second hormonal agent. However, I think we have to start looking at some of the differential toxicities that are involved with some of these newer anti-androgens. So, the AR-V7 could help us determine whether these patients still are active against these particular drugs. And, we have other newer anti-androgens that are being evaluated in this situation, like ARN-509. This supposedly has less CNS toxicity because it does not cross the blood-brain barrier at the same level that enzalutamide does. This is a problem that we see with our patients. They become depressed, they can become fatigued. They may not even be able to add common figures because there is, of course, an effect of testosterone on the brain. I think that we’re going to be able to refine our androgen-receptor antagonists further in the future. There are randomized trials comparing, for example, abiraterone to abiraterone plus ARN-509, to see if a further blockade of the androgen receptor will give you a better progression-free and overall survival. So, I think that this test will be very helpful in determining what to do next with these patients.

E. David Crawford, MD: I like the whole concept of putting things together. That’s the way forward. Thanks.

Transcript Edited for Clarity
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TitleExpiration DateCME Credits
Clinical Vignette Series: 33rd Annual Chemotherapy Foundation Symposium: Innovative Cancer Therapy for Tomorrow®Feb 19, 20173.0
Community Practice Connections™: New York GU™: 9th Annual Interdisciplinary Prostate Cancer Congress® and Other Genitourinary MalignanciesMay 27, 20171.5
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