Assessment of Androgen Receptor Splice Variant-7 as a Biomarker of Clinical Response in Castration-Sensitive Prostate Cancer.
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Date
2022-08-15Author
Sowalsky, AG
Figueiredo, I
Lis, RT
Coleman, I
Gurel, B
Bogdan, D
Yuan, W
Russo, JW
Bright, JR
Whitlock, NC
Trostel, SY
Ku, AT
Patel, RA
True, LD
Welti, J
Jimenez-Vacas, JM
Rodrigues, DN
Riisnaes, R
Neeb, A
Sprenger, CT
Swain, A
Wilkinson, S
Karzai, F
Dahut, WL
Balk, SP
Corey, E
Nelson, PS
Haffner, MC
Plymate, SR
de Bono, JS
Sharp, A
Type
Journal Article
Metadata
Show full item recordAbstract
PURPOSE: 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. EXPERIMENTAL DESIGN: 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. RESULTS: 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 with 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 was associated neither with time to development of castration resistance nor with overall survival, and intense neoadjuvant androgen-deprivation therapy did not lead to significant AR-V7 mRNA or staining following treatment. Neither pre- nor posttreatment AR-V7 levels were associated with volumes of residual disease after therapy. CONCLUSIONS: This study demonstrates that further analytical validation and clinical qualification are required before AR-V7 can be considered for clinical use in CSPC as a predictive biomarker.
Collections
Subject
Androgen Antagonists
Biomarkers
Castration
Humans
Male
Prostatic Neoplasms, Castration-Resistant
Protein Isoforms
RNA, Messenger
Receptors, Androgen
Research team
Cancer Biomarkers
PrCa Targeted Therapy
Language
eng
Date accepted
2022-06-08
License start date
2022-08-15
Citation
Clinical Cancer Research, 2022, 28 (16), pp. 3509 - 3525
Publisher
AMER ASSOC CANCER RESEARCH