Integrating Genomics and Genetics into Clinical Care for Prostate Cancer, A Pathologist's Perspective - Colin Pritchard

September 16, 2019

In the era that genomics and genetics are really making an impact to clinical practice and with the recent positive results of the PROfound study, Alicia Morgans and Colin Pritchard have a discussion thinking about this data, how do we implement it, and how do we work with our pathologists to make things happen? Colin highlights this game-changing genomic markers data, particularly for homologous recombination DNA repair, a class of DNA repair pathway in predicting PARP inhibitor responses. Lastly, they discuss the topic of a prostate cancer-specific assay test for mismatch repair. A test historically validated for colon cancer, testing for microsatellite instability, a test to look for defective mismatch repair, and one of the tests that can be used in the United States, if positive will qualify a patient for checkpoint blockade immunotherapy.


Colin C Pritchard, M.D., Ph.D. is the director of the Genetics and Solid Tumors Laboratory at University Washington Medical Center, as well as a University Washington associate professor of Laboratory Medicine.

Alicia Morgans, MD, MPH is an Associate Professor of Medicine in the Division of Hematology/Oncology at the Northwestern University Feinberg School of Medicine in Chicago, Illinois.

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Alicia Morgans: Hi, I'm thrilled to have here with me today Dr. Colin Pritchard, who is an Associate Professor of Laboratory Medicine at the University of Washington, and we're talking at APCCC 2019, where we just heard a lovely talk from you about molecular characterization of our tumors, specifically thinking about genomics and genetics. And I think in this era where we have just heard, at least by press release, that the profound study has been reported positive, still waiting on the details, genomics and genetics are really coming into the limelight in our practice, and I think we need to think about how do we use that information, how do we implement it, how do we work with our pathologists to make things happen? So what are your thoughts on integrating genomics and genetics into clinical care for prostate cancer from the pathologist's perspective?

Colin Pritchard: Thanks, Alicia. It's really an exciting time, particularly with this press release you mentioned, where it looks like maybe some positive data from a large trial with genomic markers, particularly for a class of DNA repair pathway called homologous recombination DNA repair in predicting PARP inhibitor responses. So that's going to be game-changing.

In terms of pathologist's role, so I'm a molecular pathologist. This is what I do for a living. We've had a lot of discussions about how pathologists can get more involved. I think it is important for there to be a partnership between medical oncologists, radiation oncologists, urologists, other cancer providers in the clinical side and pathologists increasingly as these complex genomic biomarkers are now going to become critical for how we treat our patients. So we already have, in the United States, recommendations in the NCCN guidelines for using some of those genomic testing already for advanced prostate cancer, and like you talked about with these large trials, it's only going to increase.

You asked how to work with pathology. So we recognize this as an emerging area for all of us, including in pathology and lab medicine. It is an issue that we're all trying to learn as fast as we can, and so I think we have a lot of education to do. That's why meetings like this are a great opportunity to educate as many people as we can about what's coming. I think this will evolve organically where ... I certainly know as someone at an academic medical center who's training our own residents and fellows, and particularly in molecular genetic pathology, I'm very confident that the next generation of pathologists and laboratorians is going to really be up to this task.

Alicia Morgans: Great. And we need you to be. And I think that as clinicians, we are trying to figure out which of these genes are the most important to focus on in prostate cancer. Your talk today was beautifully simple in that you broke it down into a few genes involved in homologous recombination and then specifically in microsatellite instability and maybe checkpoint sensitivity. Can you talk us through that and help us just to focus on the highlights for genetics and genomics in prostate?

Colin Pritchard: Sure. Well, thanks for your kind words. I was trying to keep it as simple as possible and not too simple, so I'm glad to hear that-

Alicia Morgans: It was perfect.

Colin Pritchard: It's a tough thing because there's so many genes now, and there's what we like to call the long tail. So I like to divvy these up into what I like to call the heavy hitters and the long tail, so you're asking, "What are the heavy hitters?"

Alicia Morgans: Exactly.

Colin Pritchard: So in terms of pathways, there are the two, the homologous recombination DNA repair and mismatch DNA repair. Those are the two heavy hitters in terms of pathways, and then if you look within those pathways for homologous recombination, BRCA1 and BRCA2. That's really the top two. If you want to go a little bit further down, ATM, PALB2, maybe CHEK2, so those would be the genes to remember. But BRCA1 and BRCA2 are really where we know the most and where there's the most evidence that loss of function of those genes within advanced prostate cancers is going to be predictive of ... Well, we already know from a variety of Phase II trials and earlier studies is very likely predictive of PARP inhibitor response and also from smaller studies, predictive of platinum chemotherapy.

Heavy hitters on the mismatched DNA repair side ... So mismatched DNA repair, loss of function predicts immunotherapy, and so in the United States there's already FDA approval of one drug, pembrolizumab, for any cancer that has evidence of defective mismatch repair. So that's already standard of care in the United States.

The genes that are heavy-hitting in prostate for that, there's four genes that are part of mismatch repair that we think about as most important: MSH2, MSH6, MLH1 and PMS2, but it's really MSH2 that's the key, key gene in prostate cancer, which is interesting because that's not necessarily true for other tumor types with defective mismatch repair. So if we're going to remember one gene for prostate cancer in that pathway, it would be MSH2.

Mismatch repair ... Both of these pathways are ... They can quickly get very complicated in terms of how the testing works, and so again, that's why I'd make a plea for my own colleagues but also for oncologists and other people who are seeing cancer patients. We really need to have that specific diagnostic expertise in order to be able to guide how to navigate all of these different complicated tests. Just even with these two pathways in these two areas in prostate cancer, there's so much complexity already, and it's only increasing.

So my temptation in talking in this interview is I want to talk about, "Oh, we can do this signature analysis and then this protein-based test and this test," and I'm realizing as I'm talking about it that's too complicated. The answer is you need experts to help us navigate through this really, really complex and exciting area of diagnosis.

Alicia Morgans: So the final thing I want to ask about is something that was recommended and I think is important for everyone to understand as they're trying to implement it. So we can test for mismatch repair at many institutions, community practices. There are even institution assays where you can look for this in colon cancer patients for example or whatever histology. But I think the recommendation was to use a prostate cancer-specific assay.

Colin Pritchard: Yeah.

Alicia Morgans: So where does one find one? Are there any examples you could mention without giving a brand recommendation necessarily? But that was something that I learned in that talk and thought, "Well I'm sending it off and I don't know if it's a prostate cancer specific assay."

Colin Pritchard: Yeah, I think the question ... So what you're getting at is for the test for microsatellite instability, which is, that's one of the tests to look for defective mismatch repair, and one of the tests that can be used in the United States if positive will qualify a patient for checkpoint blockade immunotherapy.

Alicia Morgans: Yes.

Colin Pritchard: So that's what we're talking about. So historically those tests were developed for colon cancer, and they were very well validated for colon cancer because that's really the only area where there was clinical utility until relatively recently. So the problem is that when using those colon cancer tests, they don't necessarily always work perfectly for prostate. Sometimes they do, sometimes they don't.

So my recommendation is just to recognize, ask the lab, "Has your test been validated for prostate cancer?". It doesn't mean that the same test can't be used for multiple cancer types. It's not that you have to have a prostate-specific test for microsatellite instability, but you need to have a test that has been validated for that cancer type. You can't just assume because the test has been used for one cancer type that it's going to work very well for another. That was the point I was trying to make.

Alicia Morgans: No, and you made it well. So for people to actually implement that in their institutions, they just need to reach out to their pathologist and say ... which actually as you say that, I know that we have a GU pathologist and I know that he is using something that he has talked to me, I'm sure, about how it's been validated in prostate cancer because it is a different assay in my institution than the one that is used for colon cancer patients.

Alicia Morgans: But the first step would be for people to just reach out to their pathologists and say, "Has this been validated in prostate cancer populations?" and start the conversation and explain the importance, and the team as a group can move forward and try to make sure that that's done if it's not already in place. So that's really practical advice, and I really appreciate you sharing that. Do you have any overall message for clinicians who are trying to implement this in their practices from a pathologist's perspective?

Colin Pritchard: Well, I think what you just said is a good message, to think about this as a team approach, right? So medicine in general with a big M has become so complicated and so sub-specialized that we're not in the era anymore where there can really be a general practitioner who can do everything, and so if we take that down into cancer care, it's also true in cancer care. So we're no longer really in the era, I think, where if you take medical oncology, the medical oncologists can really do all of the things that they used to be able to do. It's just gotten so complicated, and so I think the big message is recognizing that and recognizing that there needs to be a large team, including diagnostic physicians, molecular pathologists on that team if we're really going to be able to implement these biomarkers in the best way possible. We recognize that we need to build that team. There aren't enough molecular pathologists. There aren't enough medical oncologists probably either. 

Alicia Morgans: That's true!

Colin Pritchard: Or there aren't enough of those various groups that have this subspecialty knowledge, so we need to build those teams, but we need to work together of course.

Alicia Morgans: Of course. Well, thank you. That's really such a practical message and a really uplifting message, too, that we can all work together to get to the next stage for these patients with prostate cancer as we move even further into an era of personalization, targeting these targets. So thank you for your time and have a fabulous meeting.

Colin Pritchard: Okay. Thanks, Alicia.