Novel Junction-specific and Quantifiable In Situ Detection of AR-V7 and its Clinical Correlates in Metastatic Castration-resistant Prostate Cancer.
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Authors
Zhu, Y
Sharp, A
Anderson, CM
Silberstein, JL
Taylor, M
Lu, C
Zhao, P
De Marzo, AM
Antonarakis, ES
Wang, M
Wu, X
Luo, Y
Su, N
Nava Rodrigues, D
Figueiredo, I
Welti, J
Park, E
Ma, X-J
Coleman, I
Morrissey, C
Plymate, SR
Nelson, PS
de Bono, JS
Luo, J
Sharp, A
Anderson, CM
Silberstein, JL
Taylor, M
Lu, C
Zhao, P
De Marzo, AM
Antonarakis, ES
Wang, M
Wu, X
Luo, Y
Su, N
Nava Rodrigues, D
Figueiredo, I
Welti, J
Park, E
Ma, X-J
Coleman, I
Morrissey, C
Plymate, SR
Nelson, PS
de Bono, JS
Luo, J
Document Type
Journal Article
Date
2018-05-01
Date Accepted
2017-08-09
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.
Citation
European Urology, 2018, 73 (5), pp. 727 - 735
Source Title
European Urology
Publisher
ELSEVIER SCIENCE BV
ISSN
0302-2838
eISSN
1873-7560
Collections
Research Team
Translational Therapeutic
Sarcoma Mol Pathol
Cancer Biomarkers
PrCa Targeted Therapy
Sarcoma Mol Pathol
Cancer Biomarkers
PrCa Targeted Therapy