Clinical and Genomic Characterization of Treatment-Emergent Small-Cell Neuroendocrine Prostate Cancer - Rahul Aggarwal

May 16, 2020

Charles Ryan invites Rahul Aggarwal to discuss treatment-emergent small-cell neuroendocrine prostate cancer, an area not well characterized in the era of modern androgen receptor (AR)-targeting therapy. This study was funded by Stand Up to Cancer and the Prostate Cancer Foundation. Patients with metastatic castration-resistant prostate cancer were enrolled in which metastatic tumor biopsies were performed to understand the patterns of resistance beyond first or second-generation hormonal agents.


Rahul Aggarwal, MD Assistant Professor of Hematology/Oncology, Director of STAND Clinic, UCSF Helen Diller Family Comprehensive Cancer Center
Charles J. Ryan, MD, the President and Chief Executive Officer of The Prostate Cancer Foundation (PCF), the world’s leading philanthropic organization dedicated to funding life-saving prostate cancer research. Charles J. Ryan is an internationally recognized genitourinary (GU) oncologist with expertise in the biology and treatment of advanced prostate cancer. Dr. Ryan joined the PCF from the University of Minnesota, Minneapolis, where he served as Director of the Hematology, Oncology, and Transplantation Division in the Department of Medicine. He also served as Associate Director for Clinical Research in the Masonic Cancer Center and held the B.J. Kennedy Chair in Clinical Medical Oncology.

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Charles Ryan: Hello, I'm joined today with my friend and colleague, Rahul Aggarwal, who's an Associate Professor of Medicine at the UCSF Helen Diller Family Comprehensive Cancer Center. Dr. Aggarwal is a Medical Oncologist who specializes in prostate cancer. You published a really important paper in the Journal of Clinical Oncology last year. I think it's worth having a little conversation to get the word out a little bit on this topic, and this is treatment, small cell neuroendocrine cancer or treatment of evolved neuroendocrine cancer, the result of a long, hard fought process of collecting metastatic biopsies. Tell us a little bit about your findings.

Rahul Aggarwal: Yeah, so this was a study that is a huge team effort. This was a study that was funded by Stand Up to Cancer and Prostate Cancer Foundation. It was through a collaboration with five different centers that enrolled patients with metastatic hormone-resistant prostate cancer. We're really where we're trying to do metastatic tumor biopsies to really just understand the patterns of resistance beyond first or second generation hormonal agents such as abiraterone and enzalutamide. About three-quarters of the patients in our cohort had received either one or both of those agents. At the outset, we were just really looking to understand what were the gene expression patterns, what were some of the drivers of resistance.

What was clear as we started to do tumor biopsies, is we were seeing a pretty high prevalence of what we call small cell neuroendocrine prostate cancer, and this is an entity that's very rare at the time of diagnosis, less than 1% of all cases of prostate cancer. But clearly in the setting where patients have received hormone therapy, both primary hormone therapy, as well as abiraterone and enzalutamide, we're detecting it a lot more commonly. So in our series of patients, which was about 200 patients or so, we saw an incidence of about 17% of all biopsies showing small cell neuroendocrine cancer. That figure alone really caught our attention, and then we devoted the rest of the paper and findings to really sort of delve into what are the genes and drivers of that type of cancer, as well as we followed patients long term and have good data on outcomes and went a little bit more in detail in terms of the clinical characteristics of these patients.

Charles Ryan: Not surprisingly, these patients have a worse prognosis than those who do not have any neuroendocrine disease.

Rahul Aggarwal: Correct. I think that was one of the striking things, that even though we're biopsying only one site in a patient at one point in time, we all recognize there's a lot of heterogeneity, so it's not that these patients have neuroendocrine cancer in every single tumor in the body, at least the majority of patients. But despite that, a single biopsy at a single point in time was a negative prognostic factor in shorter survival for those patients.

Charles Ryan: There's also a huge learning curve here about simply doing a biopsy. I'm a clinician in my site and I send a patient for a metastatic biopsy to my interventional radiologist, and they do a biopsy of the pelvic bone. Is that likely to be successful? I mean, tell us about that learning curve.

Rahul Aggarwal: It is a steep learning curve. I think that was really one of the big successes, really of both Stand Up to Cancer networks, both on the east coast and west coast, is really how to learn to do this in a multicenter fashion. There definitely is a learning curve where if you just take a bone scan and CAT scan, and do a needle guided biopsy and a sclerotic bone metastasis in the pelvis, you're very likely to only get bone and no tumor. My hope is that, in terms of generalizing this to serve a broader community, is that I think that's where the next generation imaging will hopefully play a role, that if we can use and select more PET avid metabolically active lesions, that will definitely increase the yield rate, as well as training of interventional radiologists of even specifically where within a lesion to direct the needle, that makes a big impact in terms of success rate.

Charles Ryan: So your project, while very successful and very impactful, took many years and yet lots of money and lots of effort. Couldn't we just replace this by doing cell-free DNA? I mean, what are the markers that you saw in these biopsies that we could find a noninvasive way?

Rahul Aggarwal: Noninvasive detection of small cell neuroendocrine, especially of the treatment-emergent variety, I think is a huge need for the community to really make this broadly applicable, because clearly, we can't be doing biopsies in every patient. They may not have lesions that are safely accessible, there's a steep learning curve, and so that's really where we've put a lot of our efforts. I think in terms of the cell-free DNA, it's probably emerging that RB1 loss is probably the most reliable indicator. It's not a hundred percent overlap. You can see RB1 loss without neuroendocrine and vice versa. But, I think it is a fairly accurate predictor for the presence of small cell neuroendocrine cancer. So that, I think, with cell-free DNA is one utility there. There's some other efforts looking at circulating tumor cells and ways to try to characterize a neuroendocrine phenotype. Then, the other approach with noninvasively, I think, is imaging, and really trying to probably need a combination of a couple of different types of scans to try to distinguish what's the AR-independent neuroendocrine type of phenotype.

Charles Ryan: One of the most important pieces of this data, I think, is that you showed not only what neuroendocrine cancer is, but sort of what it isn't. It didn't fit the assumptions that we had that this was going to be liver metastases with low PSAs. You did a really nice analysis of PSA levels and other things. Hormone therapy.

Rahul Aggarwal: Yeah, so I mean we looked at a lot of the clinical characteristics of these patients that had small cell neuroendocrine in the prostate cancer, and we were actually surprised. The median or average PSA level for these patients was above 50. In our classic, clinical definition of small cell, we think of a patient, like you said, PSAs less than five, everyone has visceral metastases. We saw a lot of patients with bone-only prostate cancer that had small cell neuroendocrine, and I think it has impacted treatment guidelines. NCCN has sort of modified their guidelines to a little bit more broadly recommend tumor biopsies to look for neuroendocrine cancer. I think we're making headway, and that was one of the important findings of the study.

Charles Ryan: Yeah. Well, congratulations. I predict that this is going to stand out as a real landmark achievement in our understanding of this disease, especially as we layer on more and more intense treatments upfront. We're going to need to know down the road, you know, who are the patients who are getting this phenotype, what to do about it. We haven't really addressed the therapy angle. I know that that's a big challenge in terms of what to do once you've diagnosed this.

Rahul Aggarwal: Right.

Charles Ryan: Maybe next year we'll get back and talk about the therapeutic strides you're making against neuroendocrine cancer. But congratulations on this very important paper.

Rahul Aggarwal: Thank you, Chuck. Appreciate it.