Association of Inherited Mutations in DNA Repair Genes with Localized Prostate Cancer – Kara Maxwell

February 4, 2022

Kara Maxwell and Alicia Morgans discuss DNA repair defect alterations in patients with localized prostate cancer. Dr. Maxwell highlights DNA repair in conjunction with prostate cancer, as well as the Penn Medicine BioBank. The conversation concludes with a discussion on the future of prostate cancer genomics.


Kara N. Maxwell, MD, Ph.D., Assistant Professor of Medicine and Genetics, University of Pennsylvania, Staff Physician, Corporal Michael Crescenz VA Medical Center – Philadelphia

Alicia Morgans, MD, MPH, Genitourinary Medical Oncologist, Medical Director of Survivorship Program at Dana-Farber Cancer Institute, Boston, Massachusetts

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Alicia Morgans: Hi, my name is Alicia Morgans and I'm a GU Medical Oncologist at Dana-Farber Cancer Institute. I'm so excited to have here with me today, Dr. Kara Maxwell, who is a Cancer Geneticist and a Medical Oncologist at the University of Pennsylvania, and also does work at the Penn VA. Thank you so much for being here with me today, Dr. Maxwell.

Kara Maxwell: Thank you so much for having me.

Alicia Morgans: Wonderful. So I wanted to speak with you a little bit today about a European Urology paper that you and your team recently published. It was so interesting in that it really dug into looking at DNA repair defect alterations in patients with localized prostate cancer. Can you tell us a little bit about this?

Kara Maxwell: Yeah, so the impetus for this study really came from this really increased awareness of the role of DNA repair in prostate cancer susceptibility. And also, the really important implications recently with the FDA approval of olaparib in treatment of metastatic patients with DNA repair mutations. And so the question we had was, okay, we have pretty good data at this point in metastatic patients. We all can agree that we should do testing, there is a treatment implication. But what about the localized setting? That is the vast majority of prostate cancer patients that we see.

And as I often say, a lot of my research questions get driven by things that happen in my clinic. And the urologists kept asking me this question. And I said, "Okay, we have to figure it out." So we were able to be fortunate enough to use the Penn Medicine Biobank, which is an awesome resource here at Penn Medicine that collects DNA and clinical information on, really, just sort of all comers that show up in the system, not just at our main academic hub, but at our spoke sites as well. And so we decided to do this study to look at DNA repair mutation rates in all patients who presented with prostate cancer.

Alicia Morgans: So that's so important because, as you said in the localized disease setting, there is some guidance from the NCCN that says that for patients with high-risk disease and very high-risk disease, we really should be thinking about doing this DNA repair defect germline genetic testing in all of these patients. And the data isn't necessarily as strong as we see in the metastatic setting. So tell us a little bit about that and how you and your team really tried to sort that out with your biobank?

Kara Maxwell: Exactly. So we started to look into this after our urologists were asking about this. Realizing that, my gosh, if we really tested every patient with localized prostate cancer, that would just be a burden on the system that would probably be, frankly, unnecessary. So what we decided to do first was just to answer that question. Which was to take all 2,400 patients that we had really deeply phenotyped in the biobank, and really knew their prostate cancer status, and their histories. And so we first looked, and in fact, yes, the burden of genetic testing, even just for high-risk and very high-risk patients, would be pretty high, but at least doable. And so then the question was, okay, is it going to be safe to do genetic testing just in high-risk and very high-risk patients? And to do that, we wanted to understand what the DNA repair mutation spectrum rate was in spectrums across all of these patients.

So we were able to get DNA from almost 1,600 patients. And what's important, I think, hopefully important, in this study is that we were able to have about 300 and some individuals of the self-identified black race, in addition to about 1,100 individuals of the self-identified white race. Since our study has come out, there have been some other studies looking at individuals of African genetic ancestry. But when we started, there was really not a lot of data in that space as well.

So we decided to do germline genetic sequencing in the lab for the genes for which there is olaparib approval. And then looked at the rate of those mutations in intermediate and low-risk patients, versus our high and high-risk patients. And so what was interesting to us at least, is that we found that, in fact, yes, the mutation rate does go up in high and very high-risk patients, compared to our intermediate-risk patients. Overall, the mutation rate is actually pretty low in localized prostate cancer. So we feel that our results do suggest that that stratification that was suggested by the NCCN probably is the right way to think about who we should do genetic testing on.

Alicia Morgans: That's so helpful. I wonder, obviously, you have the results for this analysis and you know what the rates are for intermediate and for low-risk. But how does family history come into play? I'm not sure you were able to answer that, necessarily, in this data set.

Kara Maxwell: We weren't. And I think that is really the important point. We didn't have a family history as well documented as we would want in all patients. And so I do still think that there are open questions for exactly how we should tackle the vast majority, the large proportion of men, who currently are presenting with prostate cancer. And to your point, family history still remains so important. So it shouldn't be that these are taken with only pathological criteria as the reason to do testing and that family history piece still plays such a role. And I think that we need broader-based studies to look into the specific factors that predict the carriage of a mutation. I think to do that, also, this was a little bit more real-world setting in a biobank, but it's still an academic center. So I think larger sets of data and, hopefully, work that is going on within the veteran population. That may be one population, for example, that might be again, a little bit more representative to start to study this question, to figure out what factors are best to predict who we should do genetic testing on.

Alicia Morgans: Thank you. I think those are great next steps for you and your team to pursue. And so what would your take-home message be? What should clinicians be thinking about as they are considering your work?

Kara Maxwell: Yeah, I think that, for this work in general, I think it's pretty clear that high-risk, very high-risk localized patients should undergo genetic testing. I do think though that it helps to set some expectations that still, even though we say they should undergo genetic testing, the rates of mutations are pretty low. And so when you're doing the counseling for a gentleman with prostate cancer, to think about that it's probably more likely we're not going to find a mutation than we are. And I do think that's important to frame that. And it really means that when people think about prostate cancer risk in their family, there is still probably a lot we don't know in fact. But this testing could be important for not only their own treatment but for their family members. So it is still important to consider.

The next sort of take-home piece for me is more of a research question. That is, now I think what we really need are not only these large populations to figure out mutation rates overall, but in comparison to control populations. So we can start to tease about which genes are truly related to the development of prostate cancer, versus just genetic mutations that might be found incidentally, because we are finding them at the rate at which they incur in the population in general.

Alicia Morgans: I think those are great points. And I so appreciate that you're throwing in some goals for us in terms of research. Because this area of prostate cancer genetics, germline, and the implications, of course, in the somatic setting, really do impact our patients, their families, and the outcomes over time. So thank you so much for your continued work. And we really look forward to talking to you again.

Kara Maxwell: Thank you so much.