High-Risk Mutations in Oligometastatic Prostate Cancer Patients

Matthew Deek, MD, Department of Radiation Oncology, Rutgers Cancer Institute, New Brunswick, NJ, shares with us what “high-risk mutation” signified in his study, what classified patients with “high-risk mutation,” and how patients with and without “high-risk mutation” should be treated.

Can you describe what “high-risk mutation” signified in your study? What classified patients with “high-risk mutation?”

Dr. Deek: A little background on that is that if you look at the paper, these were both what we call positive trials. So patients who had radiation had a longer time until their tumor grew back compared to people who were just receiving observation. And so, a positive trial, that means that this type of treatment worked for a lot of patients. But if you look at the nitty gritty and you look at the curves, you’ll notice that unfortunately, there are some patients that really quickly developed; their tumor grew back very quickly after getting treatment. So while we know that in a large group of patients, if you group them all together, there’s a benefit to this treatment, not everyone benefits equally. And so the idea behind classifying these patients into high-risk or not having high-risk mutations is to say, can we identify patients who maybe are not responding optimally to this treatment?

And can we use genetics to do that? And then using that information in the future to come up with new treatment paradigms. And so based on some other work within prostate cancer, we identified five mutations that we felt were high risk for having disease progression following metastasis-directed therapy. And these were pathogenic mutations in ATM, BRCA1, BRCA2, retinoblastoma, and TP53. And so that’s how we classify patients into being either high-risk or not high-risk. And then when we started to look into how do patients with these mutations respond to the treatment, what we saw was that these five mutations were strongly prognostic, meaning that patients who did not have a mutation appeared to have longer times until their tumor grew back, compared to patients who did have a mutation. And in addition to that, if you sort of did a little bit more higher level analyses, it appears that these biomarkers could potentially be predictive.

And so a predictive biomarker helps you decide, does a patient benefit from this treatment? And the caveat here is that these were a little bit lower numbers of patients, and so this has to be evaluated in a much larger study, but it appeared that actually the magnitude of benefits for integrating radiation into patients who had a high-risk mutation was a lot larger than those who didn’t have a high-risk mutation. Sort of suggesting that being aggressive with your treatment in patients who have these high-risk mutations might differentially benefit them, compared to those who don’t have a high-risk mutation. So there’s a lot that can come out of this and we’re hoping to move it forward in the future.

How should “high-risk mutation” direct treatment decisions for patients? How should patients with and without “high-risk mutation” be treated?

Dr. Deek: I think that that’s going to have to be the next step in this process, to understand that better. But I suspect that these patients with high-risk mutations are going to need more aggressive treatment course than patients who don’t have a high-risk mutation. So, potentially someone who doesn’t have a high-risk mutation, what we saw was that the percentage of patients that really had no relapse of their disease or no increase in their PSA was a lot higher when you didn’t have a high-risk mutation than when you did have a high-risk mutation. So potentially, you could say, well, if you don’t have a high-risk mutation, this might be a patient who really benefits from just using radiation alone. And maybe you don’t need any other treatments upfront. You can see how you respond to radiation and see if that can prolong the time that you have to start hormone therapy.

As opposed to these patients who do have a high-risk mutation, maybe these are the ones that are going to need an intensification of treatment and have more than one treatment thing. They’re going to need radiation, they’re going to need some other treatment that’s integrated into that, in addition to the radiation. And so that’s to be determined, but I think that’s the course that this is going to go down, that patients with a high-risk mutation represent more aggressive disease and they need more treatment than those who don’t have a high-risk mutation.

View Dr. Deek’s other comments on oligometastatic prostate cancer, including MDT in the ORIOLE and STOMP Trials, PSMA Imaging, and The Future of Personalized Care.