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Androgen receptor splice variant, AR-V7, and resistance to enzalutamide and abiraterone in men with metastatic castration-resistant prostate cancer (mCRPC).
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2014
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Androgen ReceptorPathologyPharmacotherapyTumor BiologyEndocrine OncologyPsa Response RatesGenitourinary CancerMetronomic TherapyClinical OutcomesMolecular OncologyCancer ResearchMedicineCancer TreatmentProstatic DiseasePharmacologyEndocrine-related CancerPrognostic BiomarkersUrologyOncology
5001 Background: Androgen receptor splice variant-7 (AR-V7) is a truncated form of the androgen receptor that lacks the ligand-binding domain, the target of enzalutamide and abiraterone, but remains constitutively active as a transcription factor. We hypothesized that detection of AR-V7 in circulating tumor cells (CTCs) from men with mCRPC may be associated with primary resistance to enzalutamide and abiraterone. Methods: We used quantitative reverse-transcription PCR (qRT-PCR) to interrogate CTCs for the presence or absence of AR-V7 from prospectively enrolled patients with mCRPC initiating treatment with enzalutamide or abiraterone. We examined associations between AR-V7 status and PSA response rates, PSA progression-free survival (PSA-PFS), and clinical/radiographic progression-free survival (PFS). Multivariable Cox regression analyses were performed to determine the independent effect of AR-V7 status on these clinical outcomes. 30 men (per cohort) were required to detect a difference in PSA response rates from 10% (in AR-V7–positive men) to 60% (in AR-V7–negative men), using a 2-sided α=0.10 and β=0.15. Results: 31 enzalutamide-treated patients and 31 abiraterone-treated patients were enrolled, of which 38.7% and 19.4% had detectable AR-V7 from CTCs, respectively. Among men receiving enzalutamide, AR-V7–positive patients had inferior PSA response rates (0% vs 52.6%, P=0.004), PSA-PFS (median 1.4 vs 5.9 months, P<0.001), and PFS (median 2.1 vs 6.1 months, P<0.001) compared to AR-V7–negative patients. Similarly, among men receiving abiraterone, AR-V7–positive patients had inferior PSA response rates (0% vs 68.0%, P=0.004), PSA-PFS (median 1.3 months vs not reached, P<0.001), and PFS (median 2.3 months vs not reached, P<0.001). The negative prognostic impact of AR-V7 was maintained after adjusting for full-length AR expression levels. Conclusions: Detection of AR-V7 in CTCs from men with mCRPC is associated with resistance to enzalutamide and abiraterone. AR-V7 status may be used as a biomarker to predict resistance to AR-targeting agents, facilitate treatment selection, and fuel the development AR N-terminal domain inhibitors.