Novel Junction-specific and Quantifiable In Situ Detection of AR-V7 and its Clinical Correlates in Metastatic Castration-resistant Prostate Cancer

Yezi Zhu, Adam Sharp, Courtney M. Anderson, John L. Silberstein, Maritza Taylor, Changxue Lu, Pei Zhao, Angelo M. De Marzo, Emmanuel S. Antonarakis, Mindy Wang, Xingyong Wu, Yuling Luo, Nan Su, Daniel Nava Rodrigues, Ines Figueiredo, Jonathan Welti, Emily Park, Xiao Jun Ma, Ilsa Coleman, Colm MorrisseyStephen R. Plymate, Peter S. Nelson, Johann S. de Bono, Jun Luo

Research output: Contribution to journalArticle

Abstract

Background: Androgen receptor splice variant 7 (AR-V7) has been implicated in resistance to abiraterone and enzalutamide treatment in men with metastatic castration-resistant prostate cancer (mCRPC). Tissue- or cell-based in situ detection of AR-V7, however, has been limited by lack of specificity. Objective: To address current limitations in precision measurement of AR-V7 by developing a novel junction-specific AR-V7 RNA in situ hybridization (RISH) assay compatible with automated quantification. Design, setting, and participants: We designed a RISH method to visualize single splice junctions in cells and tissue. Using the validated assay for junction-specific detection of the full-length AR (AR-FL) and AR-V7, we generated quantitative data, blinded to clinical data, for 63 prostate tumor biopsies. Outcome measurements and statistical analysis: We evaluated clinical correlates of AR-FL/AR-V7 measurements, including association with prostate-specific antigen progression-free survival (PSA-PFS) and clinical and radiographic progression-free survival (PFS), in a subset of patients starting treatment with abiraterone or enzalutamide following biopsy. Results and limitations: Quantitative AR-FL/AR-V7 data were generated from 56 of the 63 (88.9%) biopsy specimens examined, of which 44 were mCRPC biopsies. Positive AR-V7 signals were detected in 34.1% (15/44) mCRPC specimens, all of which also co-expressed AR-FL. The median AR-V7/AR-FL ratio was 11.9% (range 2.7–30.3%). Positive detection of AR-V7 was correlated with indicators of high disease burden at baseline. Among the 25 CRPC biopsies collected before treatment with abiraterone or enzalutamide, positive AR-V7 detection, but not higher AR-FL, was significantly associated with shorter PSA-PFS (hazard ratio 2.789, 95% confidence interval 1.12–6.95; p = 0.0081). Conclusions: We report for the first time a RISH method for highly specific and quantifiable detection of splice junctions, allowing further characterization of AR-V7 and its clinical significance. Patient summary: Higher AR-V7 levels detected and quantified using a novel method were associated with poorer response to abiraterone or enzalutamide in prostate cancer. We developed and evaluated a novel method for splice junction–specific detection of the full-length AR (AR-FL) and splice variant AR-V7. Using this method, higher AR-V7, but not higher AR-FL, was associated with reduced clinical benefit to abiraterone or enzalutamide.

Original languageEnglish (US)
Pages (from-to)727-735
Number of pages9
JournalEuropean Urology
Volume73
Issue number5
DOIs
StatePublished - May 2018

Keywords

  • AR-V7
  • Androgen receptor
  • RNA in situ hybridization
  • Splice variant

ASJC Scopus subject areas

  • Urology

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    Zhu, Y., Sharp, A., Anderson, C. M., Silberstein, J. L., Taylor, M., Lu, C., Zhao, P., De Marzo, A. M., Antonarakis, E. S., Wang, M., Wu, X., Luo, Y., Su, N., Nava Rodrigues, D., Figueiredo, I., Welti, J., Park, E., Ma, X. J., Coleman, I., ... Luo, J. (2018). Novel Junction-specific and Quantifiable In Situ Detection of AR-V7 and its Clinical Correlates in Metastatic Castration-resistant Prostate Cancer. European Urology, 73(5), 727-735. https://doi.org/10.1016/j.eururo.2017.08.009