TY - JOUR
T1 - Novel Junction-specific and Quantifiable In Situ Detection of AR-V7 and its Clinical Correlates in Metastatic Castration-resistant Prostate Cancer
AU - Zhu, Yezi
AU - Sharp, Adam
AU - Anderson, Courtney M.
AU - Silberstein, John L.
AU - Taylor, Maritza
AU - Lu, Changxue
AU - Zhao, Pei
AU - De Marzo, Angelo M.
AU - Antonarakis, Emmanuel S.
AU - Wang, Mindy
AU - Wu, Xingyong
AU - Luo, Yuling
AU - Su, Nan
AU - Nava Rodrigues, Daniel
AU - Figueiredo, Ines
AU - Welti, Jonathan
AU - Park, Emily
AU - Ma, Xiao Jun
AU - Coleman, Ilsa
AU - Morrissey, Colm
AU - Plymate, Stephen R.
AU - Nelson, Peter S.
AU - de Bono, Johann S.
AU - Luo, Jun
N1 - Publisher Copyright:
© 2017 European Association of Urology
PY - 2018/5
Y1 - 2018/5
N2 - 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.
AB - 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.
KW - AR-V7
KW - Androgen receptor
KW - RNA in situ hybridization
KW - Splice variant
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U2 - 10.1016/j.eururo.2017.08.009
DO - 10.1016/j.eururo.2017.08.009
M3 - Article
C2 - 28866255
AN - SCOPUS:85028507741
SN - 0302-2838
VL - 73
SP - 727
EP - 735
JO - European Urology
JF - European Urology
IS - 5
ER -