Xin Chen1, Christof Bernemann2, Yuri Tolkach3, Martina Heller1, Cathleen Nientiedt4, Michael Falkenstein1, Esther Herpel5, Maximilian Jenzer4, Carsten Grüllich6, Dirk Jäger6, Holger Sültmann7, Anette Duensing8, Sven Perner9, Marcus V Cronauer10, Carsten Stephan11, Jürgen Debus12, Andres Jan Schrader2, Glen Kristiansen3, Markus Hohenfellner13, Stefan Duensing14. 1. Department of Urology, Molecular Urooncology, University of Heidelberg School of Medicine, Heidelberg, Germany. 2. Department of Urology, University of Münster School of Medicine, Münster, Germany. 3. Institute of Pathology, University of Bonn School of Medicine, Bonn, Germany. 4. Department of Urology, Molecular Urooncology, University of Heidelberg School of Medicine, Heidelberg, Germany; Department of Medical Oncology, University of Heidelberg School of Medicine, National Center for Tumor Diseases (NCT), Heidelberg, Germany. 5. Institute of Pathology, University of Heidelberg School of Medicine, Heidelberg, Germany; Tissue Bank of the National Center for Tumor Diseases (NCT), Heidelberg, Germany. 6. Department of Medical Oncology, University of Heidelberg School of Medicine, National Center for Tumor Diseases (NCT), Heidelberg, Germany. 7. Cancer Genome Research, National Center for Tumor Diseases, German Cancer Research Center and German Cancer Consortium (DKTK), Heidelberg, Germany. 8. Cancer Therapeutics Program, University of Pittsburgh Cancer Institute, Hillman Cancer Center, Pittsburgh, PA. 9. Institute of Pathology, University Medical Center Schleswig-Holstein, Lübeck, Germany; Research Center Borstel, Leibniz Center for Medicine and Biosciences, Borstel, Germany. 10. Department of Urology, University Medical Center Schleswig-Holstein, Lübeck, Germany. 11. Department of Urology, Charité-University Medical Center Berlin and Berlin Institute for Urologic Research, Berlin, Germany. 12. Department of Radiation Oncology, University of Heidelberg School of Medicine, Heidelberg, Germany. 13. Department of Urology, University of Heidelberg School of Medicine, Heidelberg, Germany. 14. Department of Urology, Molecular Urooncology, University of Heidelberg School of Medicine, Heidelberg, Germany; Department of Urology, University of Heidelberg School of Medicine, Heidelberg, Germany. Electronic address: stefan.duensing@med.uni-heidelberg.de.
Abstract
BACKGROUND: Overexpression of the androgen receptor (AR) splice variant 7 (AR-V7) has recently been reported to be associated with resistance to antihormonal therapy. Herein, we address the question whether tumor cells with AR-V7 expression can be detected at the time of radical prostatectomy, that is, before long-term hormonal manipulation and castration resistance, and what the potential prognostic impact on the biochemical recurrence (BCR)-free survival may be. METHODS: An anti-AR-V7 antibody was first validated in a training set of prostate cancer specimens by a comparison of AR-V7 protein to AR-V7 mRNA expression. We then analyzed nuclear AR-V7 protein expression in the primary tumors and lymph node metastases from 163 predominantly high-risk patients (cohort I) as well as the primary tumors from patients of a second, consecutive patient cohort (n = 238, cohort II) not selected for any clinicopathological features. Staining results were correlated to patient characteristics and BCR-free patient survival. RESULTS: High nuclear AR-V7 protein expression was detected in approximately 30%-40% of patients in cohort I and II at the time of radical prostatectomy. High baseline expression of nuclear AR-V7 protein was associated with an unfavorable BCR-free survival in the high-risk patient cohort I but not in the unselected consecutive cohort II. Remarkably, AR-V7 was an independent negative prognostic factor in high-risk prostate cancer patients of cohort I who were selected to receive adjuvant treatment. CONCLUSIONS: Prostate cancer cells with high nuclear AR-V7 protein expression can be detected in a substantial proportion of tumors at the time of radical prostatectomy. The presence of AR-V7-positive tumor cells is associated with an unfavorable prognosis for BCR-free survival in a high-risk patient cohort including a subgroup of patients selected to receive adjuvant therapy, in which AR-V7 was an independent negative prognosticator. Overexpression of nuclear AR-V7 protein hence identifies a subset of tumors with remarkably aggressive growth characteristics among clinically and histologically high-risk patients at the time of radical prostatectomy.
BACKGROUND: Overexpression of the androgen receptor (AR) splice variant 7 (AR-V7) has recently been reported to be associated with resistance to antihormonal therapy. Herein, we address the question whether tumor cells with AR-V7 expression can be detected at the time of radical prostatectomy, that is, before long-term hormonal manipulation and castration resistance, and what the potential prognostic impact on the biochemical recurrence (BCR)-free survival may be. METHODS: An anti-AR-V7 antibody was first validated in a training set of prostate cancer specimens by a comparison of AR-V7 protein to AR-V7 mRNA expression. We then analyzed nuclear AR-V7 protein expression in the primary tumors and lymph node metastases from 163 predominantly high-risk patients (cohort I) as well as the primary tumors from patients of a second, consecutive patient cohort (n = 238, cohort II) not selected for any clinicopathological features. Staining results were correlated to patient characteristics and BCR-free patient survival. RESULTS: High nuclear AR-V7 protein expression was detected in approximately 30%-40% of patients in cohort I and II at the time of radical prostatectomy. High baseline expression of nuclear AR-V7 protein was associated with an unfavorable BCR-free survival in the high-risk patient cohort I but not in the unselected consecutive cohort II. Remarkably, AR-V7 was an independent negative prognostic factor in high-risk prostate cancerpatients of cohort I who were selected to receive adjuvant treatment. CONCLUSIONS:Prostate cancer cells with high nuclear AR-V7 protein expression can be detected in a substantial proportion of tumors at the time of radical prostatectomy. The presence of AR-V7-positive tumor cells is associated with an unfavorable prognosis for BCR-free survival in a high-risk patient cohort including a subgroup of patients selected to receive adjuvant therapy, in which AR-V7 was an independent negative prognosticator. Overexpression of nuclear AR-V7 protein hence identifies a subset of tumors with remarkably aggressive growth characteristics among clinically and histologically high-risk patients at the time of radical prostatectomy.
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