Persistence of androgen receptor (AR) expression in patients (pts) with small cell prostate cancer (SCPC): Preliminary results from the SU2C/PCF/AACR West Coast Prostate Cancer Dream Team (WCDT).

Abstract

288 Background: Historically, SCPC has been regarded as an AR-null subtype observed in ~ 1% of pts. In castration-resistant metastatic biopsies, we have observed a higher frequency of SCPC (~ 15%), associated with shortened survival. We sought to contrast AR signaling between adenocarcinoma and SCPC. Methods: Pts underwent a metastatic tumor biopsy of bone or soft tissue. Formalin fixed, paraffin-embedded tissue underwent pathologic review, fluorescence in situ hybridization (FISH) for assessment of AR amplification, and assessment of AR expression by immunohistochemistry (IHC). A novel AR transcriptional signature was applied to RNA sequencing data from frozen tissue. AR-V7 transcripts in biopsy tissue were quantified and compared to AR-full length (AR-FL) expression. Results: Overall, 70 of 114 biopsies were AR amplified by FISH (61%). AR amplification was seen in similar proportions of adenocarcinoma (53%) and small cell tumors (54%) (p = ns). AR expression by IHC was observed in 27/32 (84%) and 5/6 (83%) of evaluable adenocarcinoma and SCPC biopsies, respectively (p = ns). AR was localized to nucleus in 85% of biopsies and did not differ by histology. AR-V7 splice variants were detected in all evaluable biopsies. Neither the absolute AR-FL expression level nor the ratio of AR-V7/AR-FL differed by histology. AR transcriptional signature scores were lower in SCPC versus adenocarcinoma (p = 0.029); scores were not correlated with AR-V7/AR-FL transcript ratio (r = 0.16). Of the 5 pts with SCPC identified on biopsy subsequently treated with abiraterone or enzalutamide, 3 achieved PSA declines > 50%. Conclusions: Contrary to the classical description of SCPC as an AR-null phenotype, the majority of metastatic SCPC biopsies were positive for AR amplification and expression, reflecting their likely clonal origin from adenocarcinoma. AR transcriptional activity was lower in SCPC, potentially related to epigenetic or post-translational modulation of AR activity upon transdifferentiation from adenocarcinoma to SCPC. As novel therapeutic targets are identified in SCPC, continued co-targeting of the AR may be warranted.