Journal
EUROPEAN UROLOGY
Volume 70, Issue 4, Pages 599-608Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.eururo.2016.03.049
Keywords
Androgen receptor; Androgen receptor variant-7; Castration-resistant prostate cancer; Metastatic biopsy; Treatment resistance; Predictor of outcome
Categories
Funding
- Department of Defence (DoD) [UWSC7395]
- Movember/Prostate Cancer UK [CEO013-2-002]
- Prostate Cancer Foundation
- Experimental Cancer Medical Centre (ECMC) grant from Cancer Research UK
- Department of Health [C51/A7401]
- Academy of Medical Sciences (AMS) [SGL014\\1015] Funding Source: researchfish
- Medical Research Council [MR/M018318/1] Funding Source: researchfish
- National Institute for Health Research [CL-2014-22-001] Funding Source: researchfish
- MRC [MR/M018318/1] Funding Source: UKRI
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Background: The androgen receptor splice variant-7 (AR-V7) has been implicated in the development of castration-resistant prostate cancer (CRPC) and resistance to abiraterone and enzalutamide. Objective: To develop a validated assay for detection of AR-V7 protein in tumour tissue and determine its expression and clinical significance as patients progress from hormone -sensitive prostate cancer (HSPC) to CRPC. Design, setting, and participants: Following monoclonal antibody generation and validation, we retrospectively identified patients who had HSPC and CRPC tissue available for AR-V7 immunohistochemical (IHC) analysis. Outcome measurements and statistical analysis: Nuclear AR-V7 expression was determined using IHC H score (HS) data. The change in nuclear AR-V7 expression from HSPC to CRPC and the association between nuclear AR-V7 expression and overall survival (OS) was determined. Results and limitations: Nuclear AR-V7 expression was significantly lower in HSPC (median HS 50, interquartile range [IQR] 17.5-90) compared to CRPC (HS 135, IQR 80-157.5; p < 0.0001), and in biopsy tissue taken before (HS 80, IQR 30-136.3) compared to after (HS 140, IQR 105-167.5; p = 0.007) abiraterone or enzalutamide treatment. Lower nuclear AR-V7 expression at CRPC biopsy was associated with longer OS (hazard ratio 1.012, 95% confidence interval 1.004-1.020; p = 0.003). While this monoclonal antibody primarily binds to AR-V7 in PC biopsy tissue, it may also bind to other proteins. Conclusions: We provide the first evidence that nuclear AR-V7 expression increases with emerging CRPC and is prognostic for OS, unlike antibody staining for the AR N terminal domain. These data indicate that AR-V7 is important in CRPC disease biology; agents targeting AR splice variants are needed to test this hypothesis and further improve patient outcome from CRPC. Patient summary: In this study we found that levels of the protein AR-V7 were higher in patients with advanced prostate cancer. A higher level of AR-V7 identifies a group of patients who respond less well to certain prostate cancer treatments and live for a shorter period of time. (C) 2016 European Association of Urology. Published by Elsevier B.V.
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