Dr. Ana Aparicio is an Associate Professor in the Department of Genitourinary Medical Oncology at the University of Texas MD Anderson Cancer Center in Houston, Texas.
Prostatepedia spoke with her about rare but highly aggressive forms of prostate cancer.
Are small-cell and aggressive variant prostate cancers discovered in men who are newly diagnosed or in those whose cancers recur after treatment?
Dr. Aparicio: There is a lot of discussion about that in the field. For the most part, small-cell carcinoma morphology emerges during the progression of the disease on hormone therapy. It is more common for us to find them after men have started therapy. Whether the underlying program that results in small-cell cancer was already there or if it’s induced by the hormone therapy is not clear.
So then it is unclear whether small-cell and aggressive variant prostate cancers are there from the beginning or whether there is something about hormonal therapy treatment that induces this more aggressive form of prostate cancer?
Dr. Aparicio: Right. I can tell you that from our data and our various clinical trials it is looking more and more like the program was already there. The small-cell cancers, as I mentioned earlier, do not respond well to hormonal therapies so they are categorized as androgen-indifferent tumors. Androgen-indifferent small-cell cancers may show some minor response to a hormonal therapy, but the response is short-lived and unsatisfying, if you will.
The aggressive variants that we define clinically are also considered androgen-indifferent. Whether that program of androgen indifference is present at diagnosis is the question. Our data from clinical trials and from people with metastatic disease at initial diagnosis suggest that a large proportion of those are androgen indifferent from the get-go. That androgen indifference —that primary resistance—to the androgen receptor inhibitors and the AR-targeted therapies like Zytiga (abiraterone) and Xtandi (enzalutamide) is present from the beginning. But we know that people who are treated with Zytiga (abiraterone), Xtandi (enzalutamide), or any of the other AR-inhibitory drugs that we have, eventually develop resistance in those tumors. They might not be primarily resistant to those drugs, but they become secondarily resistant to those drugs.
This group of secondarily resistant prostate cancers is heterogeneous. Not all secondary resistances to the AR-targeted therapies are the same, but a subset of those secondarily resistant tumors are probably very similar to the primarily resistant ones.
Is anyone able to predict which of these people will be resistant?
Dr. Aparicio: Through various analyses, we arrived at a molecular signature for the androgen-indifferent tumors that consist of combined tumor suppressor defects. You have to have at least two of three alterations in p53, RB1, or PTEN. If you have two out of those three altered tumor suppressor defects, you have a tumor that has the molecular signature we have identified as aggressive variance. Some recent papers look at genetically engineered mouse models and have confirmed the signature—confirmed that alterations in p53 and RB plus or minus PTEN are linked to androgen indifference.
Are they now developing tests to see if people have two of these three alterations?
Dr. Aparicio: Yes.
And if a man does have two of these three alterations, would you then choose a different treatment for him based on that result?
Dr. Aparicio: That’s the goal: it allows us to pick the right treatment. Although, like I said, we’re already pretty good at telling who has aggressive disease. But this test is important because one of the problems in prostate cancer has been that we’ve treated the disease like it’s all one disease. Look at leukemia as an example.
If we treated chronic myelogenous leukemia, which is currently treated with a pill, the same way that we treat acute myelogenous leukemia, which requires multiple chemotherapies, that would be a problem. And yet when we do Phase III clinical trials for prostate cancer, we lump together the chronic and the acute, which have different biologies.
Because of this, we may have overlooked drugs or treatments that might have been beneficial for the acute diseases or vice versa. We just weren’t able to show the benefit because we’ve mixed acute and chronic diseases. A case in point: Yervoy (ipilimumab), a checkpoint inhibitor, missed the Phase III trial’s primary endpoint in prostate cancer by a hair. That may have been due in part to the fact that a number of tumors included in those clinical trials were of the aggressive variant flavor and those don’t benefit, but it is still possible that men with garden-variety prostate cancer might have benefitted from Yervoy (ipilimumab). That’s the hypothesis.
So you’re saying we can then better stratify patients going into clinical trials?
Dr. Aparicio: Exactly.