Neoadjuvant-intensive androgen deprivation therapy selects for prostate tumor foci with diverse subclonal oncogenic alterations

Primary prostate cancer (PCa) can have extensive microheterogeneity, but its contribution to the later emergence of metastatic castration-resistant PCa (mCRPC) remains unclear. In this study, we microdissected residual PCa foci in radical prostatectomies from 18 men treated with neoadjuvant intensive androgen deprivation therapy (leuprolide, abiraterone acetate, and prednisone) and analyzed them for resistance mechanisms. Transcriptome profiling showed reduced but persistent androgen receptor (AR) activity in residual tumors with no increase in neuroendocrine differentiation. Proliferation correlated negatively with AR activity but positively with decreased RB1 expression, and whole exome sequencing (WES) further showed enrichment for RB1 genomic loss. In 15 cases where 2 or 3 tumor foci were microdissected, WES confirmed a common clonal origin but identified multiple oncogenic alterations unique to each focus. These findings show that subclones with oncogenic alterations found in mCRPC are present in primary PCa and are selected for by neoadjuvant-intense androgen deprivation therapy. In particular, this study indicates that subclonal RB1 loss may be more common than previously appreciated in intermediate- to high-risk primary PCa and may be an early event, independent of neuroendocrine differentiation, in the development of mCRPC. Comprehensive molecular analyses of primary PCa may detect aggressive subclones and possibly inform adjuvant strategies to prevent recurrence.

https://ift.tt/2tjxTk5