Abstract A024: Prostate cancer neoadjuvant intensive androgen deprivation therapy selects for tumor foci with diverse oncogenic alterations
Authors: Sowalsky Adam G. , Ye Huihui , Bhasin Manoj , Allen Eliezer M. Van , Loda Massimo , Lis Rosina T. , Montaser Laleh , Calagua Carla , Ma Fen , Russo Joshua W. , Schaefer Rachel J. , Voznesensky Olga S. , Zhang Zhenwei , Bubley Glenn J. , Montgomery Robert B. , Mostaghel Elahe A. , Nelson Peter S. , Taplin Mary-Ellen , Balk Steven P. 
Published: February 2019

Abstract
Based on the hypothesis that early use of androgen deprivation therapy (ADT) may improve outcomes, we conducted a phase 2 trial of neoadjuvant leuprolide for 24 weeks in combination with abiraterone acetate plus prednisone (referred to subsequently as leuprolide plus AAP) for 12 or 24 weeks prior to radical prostatectomy (RP). As reported recently, we confirmed that the addition of AAP further markedly reduced intraprostatic androgen levels and appeared to improve responses relative to historical controls using single-agent GnRH agonists. Nonetheless, residual prostate cancer (PCa) was found in the majority of patients, with only a small number of patients demonstrating complete pathologic responses. Moreover, substantial nuclear and cytoplasmic AR expression was detected by immunohistochemistry in most cases, suggesting that AR activity still may persist and contribute to residual disease. Residual PCa foci in RPs from 18 men treated with neoadjuvant intensive androgen deprivation therapy (leuprolide plus AAP) were microdissected and analyzed for resistance mechanisms. Transcriptome profiling showed reduced but persistent androgen receptor (AR) activity in residual tumors, with no increase in neuroendocrine differentiation. Unexpectedly, proliferation was negatively correlated with AR activity, but positively correlated with decreased RB1 expression, and whole-exome sequencing (WES) further showed enrichment for RB1 genomic loss. In 14 cases where two tumor foci were microdissected, WES confirmed a common origin, but identified multiple oncogenic alterations unique to one focus. Primary PCa can have extensive microheterogeneity, but its contribution to the later emergence of metastatic castration-resistant PCa (mCRPC) has not been clear. These findings indicate that neoadjuvant intense androgen deprivation therapy selects for subclonal genomic alterations, including RB1 loss, which may be the origin for metastatic castration-resistant PCa. 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 on adjuvant strategies to prevent the emergence of mCRPC.
Citation Format: Adam G. Sowalsky, Huihui Ye, Manoj Bhasin, Eliezer M. Van Allen, Massimo Loda, Rosina T. Lis, Laleh Montaser, Carla Calagua, Fen Ma, Joshua W. Russo, Rachel J. Schaefer, Olga S. Voznesensky, Zhenwei Zhang, Glenn J. Bubley, Robert B. Montgomery, Elahe A. Mostaghel, Peter S. Nelson, Mary-Ellen Taplin, Steven P. Balk. Prostate cancer neoadjuvant intensive androgen deprivation therapy selects for tumor foci with diverse oncogenic alterations [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr A024.