The Detection of Androgen Receptor Splice Variant 7 in Plasma-derived Exosomal RNA Strongly Predicts Resistance to Hormonal Therapy in Metastatic Prostate Cancer Patients

Eur Urol. 2017 Apr;71(4):680-687. doi: 10.1016/j.eururo.2016.08.012. Epub 2016 Oct 10.

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 limitations of the methods available for AR-V7 analysis, the identification of a reliable detection method may facilitate the use of this biomarker in clinical practice.

Objective: To confirm AR-V7 as a predictor of resistance to hormonal therapy and develop a new approach to assess AR-V7 by highly sensitive digital droplet polymerase chain reaction (ddPCR) in plasma-derived exosomal RNA.

Design, setting, and participants: Plasma samples were collected from 36 CRPC patients before they began second-line hormonal treatment. Exosomes were isolated and RNA extracted for analysis of AR-V7 by ddPCR.

Outcome measurements and statistical analysis: The absolute target gene concentration as copies per milliliter (copies/ml) was determined by ddPCR. Statistical analyses were performed with SPSS software (IBM Corp., Armonk, NY, USA).

Results and limitations: A total of 26 patients received abiraterone and 10 enzalutamide; 39% of patients were found to be AR-V7 positive (AR-V7+). Median progression-free survival was significantly longer in AR-V7 negative (AR-V7-) versus AR-V7+ patients (20 vs 3 mo; p<0.001). Overall survival was significantly shorter in AR-V7+ participants at baseline compared with AR-V7- participants (8 mo vs not reached; p<0.001).

Conclusions: This study demonstrates that plasma-derived exosomal RNA is a reliable source of AR-V7 that can be detected sensitively by ddPCR assay. We also showed that resistance to hormonal therapy may be predicted by AR-V7, making it a clinically relevant biomarker.

Patient summary: We report a first study on a method for androgen receptor splice variant 7 (AR-V7) detection in RNA extracted from cancer cell vesicles released in blood. Results confirmed the role of AR-V7 as a predictive biomarker of resistance to hormonal therapy. Our assay showed that vesicles are a reliable source of AR-V7 RNA and that the method is fast, highly sensitive, and affordable.

Keywords: AR-V7; Digital droplet PCR; Exosomes; Hormonal therapy; Pharmacogenetics; Prostate cancer; Resistance.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / drug therapy
  • Adenocarcinoma / genetics*
  • Adenocarcinoma / metabolism
  • Adenocarcinoma / secondary
  • Aged
  • Aged, 80 and over
  • Androstenes / therapeutic use
  • Antineoplastic Agents, Hormonal / therapeutic use
  • Disease-Free Survival
  • Drug Resistance, Neoplasm / genetics*
  • Humans
  • Male
  • Middle Aged
  • Neoplasm Metastasis
  • Phenylthiohydantoin / analogs & derivatives
  • Phenylthiohydantoin / therapeutic use
  • Prostatic Neoplasms, Castration-Resistant / drug therapy
  • Prostatic Neoplasms, Castration-Resistant / genetics*
  • Prostatic Neoplasms, Castration-Resistant / metabolism
  • Prostatic Neoplasms, Castration-Resistant / pathology
  • Protein Isoforms / genetics
  • RNA / blood
  • Receptors, Androgen / genetics*
  • Receptors, Androgen / metabolism

Substances

  • Androstenes
  • Antineoplastic Agents, Hormonal
  • MDV 3100
  • Protein Isoforms
  • Receptors, Androgen
  • Phenylthiohydantoin
  • RNA
  • abiraterone