Androgen receptor gain in circulating free DNA and splicing variant 7 in exosomes predict clinical outcome in CRPC patients treated with abiraterone and enzalutamide

Abstract

Background Androgen receptor (AR) signaling inhibitors represent the standard treatment in metastatic castration resistance prostate cancer (mCRPC) patients. However, some patients display a primary resistance, and several studies investigated the role of the AR as a predictive biomarker of response to treatment. This study is aimed to evaluate the role of AR in liquid biopsy to predict clinical outcome to AR signaling inhibitors in mCRPC patients. Methods Six milliliters of plasma samples were collected before first-line treatment with abiraterone or enzalutamide. Circulating free DNA (cfDNA) and exosome-RNA were isolated for analysis of AR gain and AR splice variant 7 (AR-V7), respectively, by digital droplet PCR. Results Eighty-four mCRPC patients received abiraterone (n = 40) or enzalutamide (n = 44) as first-line therapy. Twelve patients (14.3%) presented AR gain and 30 (35.7%) AR-V7+ at baseline. Median progression-free survival (PFS) and overall survival (OS) were significantly longer in AR-V7− vs AR-V7+ patients (24.3 vs 5.4 months, p < 0.0001; not reached vs 16.2 months, p = 0.0001, respectively). Patients carrying the AR gain had a median PFS of 4.8 vs 24.3 months for AR normal patients (p < 0.0001). Median OS was significantly longer in AR normal vs patients with AR gain (not reached vs 8.17 months, p < 0.0001). A significant correlation between AR-V7 and AR gain was observed (r = 0.28; p = 0.01). The AR gain/AR-V7 combined analysis confirmed a strong predictive effect for biomarkers combination vs patients without any AR aberration (PFS 3.8 vs 28 month, respectively; OS 6.1 vs not reached, respectively; p < 0.0001). Conclusions The present study demonstrates that cfDNA and exosome-RNA are both a reliable source of AR variants and their combined detection in liquid biopsy predicts resistance to AR signaling inhibitors.

Role of Exosomes in Prostate Cancer Metastasis

“…TMPRSS2:ERG is the predominant gene fusion in PCa where TMPRSS2 protein functions with overexpressed ERG; an ETS transcription factor thereby contributing to androgenresistance in PCa [62][63][64]. A recent study showed that AR variant, AR-V7 RNA is present in exosomes in patients treated with AR pathway inhibitors Enzalutamide and Abiraterone as a primary therapy and is predictive of resistance to AR signaling inhibitors [65].…”

AR Splicing Variants and Resistance to AR Targeting Agents

“…[41] Exosomal AR-V7 is associated with resistance to ABI and ENZ. [44,56] AR-V7 in biopsies detected by RISH is associated with a shorter PFS.…”

“…Isolated CTCs can be further analyzed by single-cell sequencing methods for more detailed DNA or RNA profiling [45,46]. AR-V7, detected from plasma-derived exosomal RNA, similarly predicts resistance to abiraterone and enzalutamide [44,56]. Such combinatorial liquid biomarkers are yet to be tested in a prospective fashion.…”

Cell-Secreted Vesicles: Novel Opportunities in Cancer Diagnosis, Monitoring and Treatment

“…Moreover, EVs which transport lncRNA SNHG14 or TGF-β1 could be used for the same function; in fact, both populations of EVs are present in non-responding patients [153,154]. In prostate cancer, the presence of Arv7 mRNA in circulating EVs predicts resistance to hormone therapy and correlates with a short OS [155].…”