The evidence base for the existence of androgen receptor (AR)-“indifferent” cell states in some prostate tumors is growing stronger, according to Ana Aparicio, MD, an associate professor at the University of Texas MD Anderson Cancer Center in Houston.

Dr Aparicio will speak on the case for AR-indifferent disease as part of a panel on prostate tumor evolution and progression at the 2017 ASCO Genitourinary Cancers Symposium in Orlando, Florida.

Over recent years, serial biopsy samples from the same individuals have shown that prostate tumors frequently undergo evolution during treatment, with AR-indifferent cell states emerging in some adenocarcinomas during AR-directed therapy.1

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“We know that there is a subset of prostate cancers that are morphologically small-cell carcinomas that are predominately AR-negative,” Dr Aparicio told Cancer Therapy Advisor. “These are diseases that do not respond to hormonal therapy, as one would expect in the absence of AR expression, and have atypical clinical behaviors compared to regular adenocarcinoma prostate cancer.”

Whereas prostate cancers typically spread to lymph nodes after prolonged responses to AR therapy, small-cell prostate carcinomas often metastasize instead to the viscera, such as the liver, quite early after short-lived responses to chemotherapy. These tumors do not respond to AR therapies.

Small-cell carcinomas are rare at presentation but “appear to manifest during the evolution of castrate-resistant progression of the disease,” Dr Aparicio said. “Approximately 20% of men that die of castration-resistant prostate cancer have this morphology but the small-cell is most often mixed with AR-positive cells, so I think the value of thinking of AR-indifferent disease is in the search for additional therapeutic targets — and importantly, combinatorial approaches to eradicating the disease.

“But we have to be careful. We went through decades of saying the disease was hormone-independent, and that turned out not to be.”