Assessment of Androgen Receptor splice variant-7 as a biomarker of clinical response in castration-sensitive prostate cancer.

Therapies targeting the androgen receptor (AR) have improved the outcome for patients with castration-sensitive prostate cancer (CSPC). Expression of the constitutively active AR splice variant-7 (AR-V7) has shown clinical utility as a predictive biomarker of AR-targeted therapy resistance in castration-resistant prostate cancer (CRPC), but its importance in CSPC remains understudied.

We assessed different approaches to quantify AR-V7 mRNA and protein in prostate cancer cell lines, patient-derived xenograft (PDX) models, publicly available cohorts, and independent institutional clinical cohorts, to identify reliable approaches for detecting AR-V7 mRNA and protein and its association with clinical outcome.

In CSPC and CRPC cohorts, AR-V7 mRNA was much less abundant when detected using reads across splice boundaries than when considering isoform-specific exonic reads. The RM7 AR-V7 antibody had increased sensitivity and specificity for AR-V7 protein detection by immunohistochemistry (IHC) in CRPC cohorts but rarely identified AR-V7 protein reactivity in CSPC cohorts, when compared to the EPR15656 AR-V7 antibody. Using multiple CRPC PDX models, we demonstrated that AR-V7 expression was exquisitely sensitive to hormonal manipulation. In CSPC institutional cohorts, AR-V7 protein quantification by either assay associated neither with time to development of castration-resistance nor overall survival, and intense neoadjuvant androgen-deprivation therapy did not lead to significant AR-V7 mRNA or staining following treatment. Neither pre- nor post-treatment AR-V7 levels associated with volumes of residual disease after therapy.

This study demonstrates that further analytical validation and clinical qualification is required before AR-V7 can be considered for clinical use in CSPC as a predictive biomarker.

Clinical cancer research : an official journal of the American Association for Cancer Research. 2022 Jun 13 [Epub ahead of print]

Adam G Sowalsky, Ines Figueiredo, Rosina T Lis, Ilsa Coleman, Bora Gurel, Denisa Bogdan, Wei Yuan, Joshua W Russo, John R Bright, Nichelle C Whitlock, Shana Y Trostel, Anson T Ku, Radhika A Patel, Lawrence D True, Jonathan Welti, Juan M Jimenez-Vacas, Daniel Nava Rodrigues, Ruth Riisnaes, Antje Neeb, Cynthia T Sprenger, Amanda Swain, Scott Wilkinson, Fatima Karzai, William L Dahut, Steven P Balk, Eva Corey, Peter S Nelson, Michael C Haffner, Stephen R Plymate, Johann S de Bono, Adam Sharp

National Cancer Institute, Bethesda, MD, United States., Institute of Cancer Research, Sutton, Surrey, United Kingdom., Fred Hutchinson Cancer Research Center, Seattle, WA, United States., Institute of Cancer Research, London, United Kingdom., Institute of Cancer Research, Sutton, United Kingdom., Beth Israel Deaconess Medical Center, Boston, MA, United States., National Cancer Institute, Bethesda, Maryland, United States., National Institutes of Health, BETHESDA., University of Washington, Seattle, WA, United States., Royal Free London NHS Foundation Trust, United Kingdom., Institute of Cancer Research, Sutton, London, United Kingdom., University of Washington, Seattle, Washington, United States., Bethesda, MD, Bethesda, MARYLAND, United States., University of Washington, SEATTLE, WA, United States., Fred Hutchinson Cancer Research Center, Seattle, United States.

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