AR-V7 detection in plasma-derived exosomal RNA strongly predicts resistance to hormonal therapy in metastatic prostate cancer

Abstract

Background: The androgen receptor splice variant 7 (AR-V7) is associated with resistance to hormonal therapy in castration resistant prostate cancer (CRPC). Due to the limitations of methods available for AR-V7 analysis, the identification of a reliable detection method may facilitate the use of this biomarker in clinical practice. In order to provide a reliable laboratory approach to AR-V7 assessment, the present study was conducted to: 1) confirm the role of AR-V7 in prediction of resistance to hormonal therapy; 2) develop a new methodological approach to reliably and easily assess AR-V7 by a digital droplet PCR in exosomal-derived RNA from plasma samples and 3) provide new data to address the correlation between exosomal-derived AR-V7 RNA and resistance, being the translation CTC to exosomes not obvious. Methods: Two ml of plasma samples were collected from 36 CRPC patients before the beginning of second-line hormonal treatment. Exosomes were isolated and RNA extracted for analysis of AR-V7 by digital droplet PCR. Results: 39% of patients were found carriers of the AR-V7 transcript. Twenty-six patients received abiraterone and 10 enzalutamide. The median clinical or radiographic progression free survival was significantly longer in AR-V7 negative compared to positive patients (20 vs 3 months; P < 0.001). Overall survival was significantly shorter in men with detectable AR-V7 at baseline compared to those with undetectable AR-V7 (median 8 months vs. not reached) (P < 0.001). In the AR-V7-positive patients, the PSA response rates was 7% (1 out of 14 men), while in the AR-V7 negative patients the PSA response rate was 64% (14 of 22 men). The AR-V7 positive subjects were more likely to be younger, Gleason Score at least 8, visceral metastases, higher PSA levels, and prior docetaxel treatment than AR-V7 negative patients. Conclusions: The present study demonstrates that plasma-derived exosomal RNA is a reliable source of AR-V7 and its detection predicts resistance to anti-hormonal therapy. The method is sensitive, fast and represents a convenient alternative to other potentially more expensive and less sensitive approaches, i.e., circulating tumor cells.