Abstract
BackgroundAndrogen 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.MethodsSix 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.ResultsEighty-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).ConclusionsThe 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.
Highlights
The present biomarker blinded study enrolled 84 patients undergoing to first-line abiraterone or enzalutamide and collected plasma samples at baseline, demonstrating that the double positivity for Androgen receptor (AR) gain and AR splice variant 7 (AR-V7) at baseline is associated with shorter progression-free survival (PFS) and overall survival (OS)
14.3% and 36% of men with metastatic castration resistance prostate cancer (mCRPC) were AR gain or AR-V7 positive at baseline on Circulating free DNA (cfDNA) and exosomes, respectively, suggesting that AR assessment in liquid biopsy may address up to 50% of AR therapy resistance, allowing that other mechanisms of resistance to treatment arise
An indirect comparison of CTCs versus exosomes-derived AR-V7 demonstrates that patients positive for the AR-V7 detected by the two methods have different PFS: 2.2 vs 6.2 mo for CTCs [8] and 3 vs 20 months for exosomes [15] or 5.4 vs 24.3 months
Summary
This study is aimed to evaluate the role of AR in liquid biopsy to predict clinical outcome to AR signaling inhibitors in mCRPC patients
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