Abstract: PD65-12
Sources of Funding: Prostate Cancer Canada and McGill Urology Research Funds

Introduction

Prostate cancer (PCa) is a leading cause of cancer deaths in USA. There is no cure for advanced disease; patients failing surgery or radiations invariably fail androgen-deprivation therapy (ADT) and further progress once castrate-resistant (CRPC). Studies point to anomalies in the androgen/androgen receptor (AR) axis in advanced PCa. We reported on the Fer tyrosine kinase directly activating AR on Y223 in PCa cells and becoming its partner in the tumor cell nucleus of CRPC patients (Rocha et al 2013). We aimed to assess the pY223AR fate in PCa._x000D_

Methods

Sections of human prostate tissues and metastases were stained using pY223AR antibodies (Abs) we raised, and N- and C- terminal Abs to detect all AR forms vs wild-type, respectively. Results were expressed in percentages (%) and H scores. The cohort included 450 cases ranging from healthy men to benign hyperplasia, prostatectomies, neo-adjuvant hormone therapy, advanced on ADT, primary/lymph nodes, bone metastases and seminal vesicles. _x000D_

Results

AR and pY223AR-negative tumor cells constituted up to 15% in ADT/CRPC cases. In AR positive epithelial cells of normal and benign cases, the AR staining was mainly nuclear but negative for pY223AR. In primary tumors, the AR intensity and H scores increased with Gleason (p<0.01), being most elevated in ADT/CRPC. A shift in intensity from 1+ to +3 and +2 was observed with progression when all forms of AR were detected, whereas wild-type nuclear AR remained at 1+. Similar observations were made for all forms and wild-type AR in seminal vesicles, lymph nodes and bone metastases. Nuclear AR levels (all forms and wild-type) did not correlate with patient outcome. The nuclear intensity and H score of pY223AR also increased with Gleason of primary tumors (p<0.01), being most elevated in ADT/CRPC. Again, the pY223AR shifted from 1+ to +3 and +2 in the cell nucleus of primary tumors and metastases. Of interest, nuclear pY223AR correlated with biochemical recurrence (BCR) (Kaplan-Meier; log rank, p<0.0001 at H score?160). In univariate and multivariate analyses, pY223AR H scores predicted BCR (p<0.0001), PCa specific death (p=0.002) and overall survival (p=0.0002), independently of Gleason, stage and PSA. Also, combining pY223AR H score with PSA, GS and stages improved prognostication (ROC curves).

Conclusions

These findings suggest that activation of Y223 in all forms of AR is key for progression. Also, pY223AR represents a novel biomarker predicting outcome of prostate cancer._x000D_

Funding

Prostate Cancer Canada and McGill Urology Research Funds