Branched chain RNA in situ hybridization for androgen receptor splice variant AR-V7 as a prognostic biomarker for metastatic castration-sensitive prostate cancer

The androgen receptor (AR) mRNA splice variant AR-V7 has emerged as a predictive biomarker for response to AR targeted therapies. There are currently no commercially available assays to detect AR splice variants. The branched chain RNA in situ hybridization (ISH) platform enables the highly sensitive detection of RNA transcripts in formalin-fixed, paraffin-embedded (FFPE) tissues.

We designed a branched chain RNA ISH probe to target the unique cryptic exon CE3 of AR-V7 using multiple tiling probes. This automated ISH assay was applied to tumor tissue from two distinct clinical cohorts that we hypothesized would differ in AR-V7 status.

We detected AR-V7 in all tumor samples from men with metastatic castration-resistant prostate cancer with tissue obtained after disease progression despite at least one subsequent line of hormonal therapy (abiraterone, enzalutamide, or bicalutamide; n=12). We detected AR-V7 in just one tumor from men who had undergone prostatectomy for localized adenocarcinoma (n=30; Gleason 4+5=9 in the AR-V7 positive sample). Given the apparent distinction between the above groups by AR-V7 signal, we analyzed pre-treatment AR-V7 status as a predictive and prognostic biomarker in men with treatment-naive metastatic disease. Patients with metastases but without detectable AR-V7 RNA at baseline had significantly longer overall survival (logrank P = 0.044) and a trend toward superior progression-free survival (logrank P = 0.055).

Within an institutional cohort, the RNA ISH assay identified AR-V7 within FFPE tissue and may have prognostic value in metastatic castration-sensitive prostate cancer. These preliminary findings warrant further study in larger cohorts.

Clinical cancer research : an official journal of the American Association for Cancer Research. 2016 Jul 20 [Epub ahead of print]

Philip J Saylor, Richard J Lee, Kshitij S Arora, Vikram Deshpande, Rong Hu, Kara Olivier, Erika Meneely, Miguel N Rivera, David T Ting, Chin-Lee Wu, David T Miyamoto

Division of Hematology-Oncology, Massachusetts General Hospital ., Cancer Center, Massachusetts General Hospital Cancer Center and Harvard Medical School., Surgery, Massachusetts General Hospital., Pathology, Massachusetts General Hospital., Pathology, Massachusetts General Hospital., Cancer Center, Massachusetts General Hospital., Cancer Center, Massachusetts General Hospital., Pathology, Massachusetts General Hospital., Department of Medicine, Massachusetts General Hospital and Harvard Medical School., Department of Pathology, Massachusetts General Hospital and Harvard Medical School., Radiation Oncology, Massachusetts General Hospital, Harvard Medical School.


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