AR-V7 in Peripheral Whole Blood of Patients with Castration-resistant Prostate Cancer: Association with Treatment-specific Outcome Under Abiraterone and Enzalutamide

Eur Urol. 2017 Nov;72(5):828-834. doi: 10.1016/j.eururo.2017.07.024. Epub 2017 Aug 14.

Abstract

Background: It has been demonstrated that androgen receptor splice variant 7 (AR-V7) expression in circulating tumor cells (CTCs) predicts poor treatment response in metastatic castration-resistant prostate cancer (mCRPC) patients treated with abiraterone or enzalutamide.

Objective: To develop a practical and robust liquid profiling approach for direct quantification of AR-V7 in peripheral whole blood without the need for CTC capture and to determine its potential for predicting treatment response in mCRPC patients.

Design, setting, and participants: Whole blood samples from a prospective biorepository of 85 mCRPC patients before treatment initiation with abiraterone (n=56) or enzalutamide (n=29) were analyzed via droplet digital polymerase chain reaction.

Outcome measurements and statistical analysis: The association of AR-V7 status with prostate-specific antigen (PSA) response defined by PSA decline ≥50% and with PSA-progression-free survival (PSA-PFS), clinical PFS, and overall survival (OS) was assessed.

Results and limitations: High AR-V7 expression levels in whole blood were detectable in 18% (15/85) of patients. No patient with high AR-V7 expression achieved a PSA response, and AR-V7 status was an independent predictor of PSA response in multivariable logistic regression analysis (p=0.03). High AR-V7 expression was associated with shorter PSA-PFS (median 2.4 vs 3.7 mo; p<0.001), shorter clinical PFS (median 2.7 vs 5.5 mo; p<0.001), and shorter OS (median 4.0 vs. 13.9 mo; p<0.001). On multivariable Cox regression analysis, high AR-V7 expression remained an independent predictor of shorter PSA-PFS (hazard ratio [HR] 7.0, 95% confidence interval [CI] 2.3-20.7; p<0.001), shorter clinical PFS (HR 2.3, 95% CI 1.1-4.9; p=0.02), and shorter OS (HR 3.0, 95% CI 1.4-6.3; p=0.005).

Conclusions: Testing of AR-V7 mRNA levels in whole blood is a simple and promising approach to predict poor treatment outcome in mCRPC patients receiving abiraterone or enzalutamide.

Patient summary: We established a method for determining AR-V7 status in whole blood. This test predicted treatment resistance in patients with metastatic castration-resistant prostate cancer undergoing treatment with abiraterone or enzalutamide. Prospective validation is needed before application to clinical practice.

Keywords: Androgen receptor splice variant; Castration-resistant prostate cancer; Droplet digital polymerase chain reaction; Liquid profiling; Resistance.

Publication types

  • Validation Study

MeSH terms

  • Aged
  • Androstenes / therapeutic use*
  • Antineoplastic Agents / therapeutic use*
  • Benzamides
  • Biomarkers, Tumor / blood*
  • Biomarkers, Tumor / genetics
  • Disease-Free Survival
  • Drug Resistance, Neoplasm
  • Humans
  • Kallikreins / blood
  • Liquid Biopsy
  • Logistic Models
  • Male
  • Multivariate Analysis
  • Neoplastic Cells, Circulating / chemistry*
  • Neoplastic Cells, Circulating / drug effects*
  • Neoplastic Cells, Circulating / pathology
  • Nitriles
  • Odds Ratio
  • Phenylthiohydantoin / analogs & derivatives*
  • Phenylthiohydantoin / therapeutic use
  • Polymerase Chain Reaction
  • Predictive Value of Tests
  • Proportional Hazards Models
  • Prostate-Specific Antigen / blood
  • Prostatic Neoplasms, Castration-Resistant / blood*
  • Prostatic Neoplasms, Castration-Resistant / drug therapy*
  • Prostatic Neoplasms, Castration-Resistant / genetics
  • Prostatic Neoplasms, Castration-Resistant / mortality
  • Protein Isoforms
  • RNA, Messenger / blood
  • RNA, Messenger / genetics
  • Receptors, Androgen / blood*
  • Receptors, Androgen / genetics
  • Reproducibility of Results
  • Retrospective Studies
  • Risk Factors
  • Time Factors
  • Treatment Outcome

Substances

  • AR protein, human
  • Androstenes
  • Antineoplastic Agents
  • Benzamides
  • Biomarkers, Tumor
  • Nitriles
  • Protein Isoforms
  • RNA, Messenger
  • Receptors, Androgen
  • Phenylthiohydantoin
  • enzalutamide
  • KLK3 protein, human
  • Kallikreins
  • Prostate-Specific Antigen
  • abiraterone