Overexpression of nuclear AR-V7 protein in primary prostate cancer is an independent negative prognostic marker in men with high-risk disease receiving adjuvant therapy.

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.

• Authors: Xin Chen, Christof Bernemann, Yuri Tolkach, Martina Heller, Cathleen Nientiedt, Michael Falkenstein, Esther Herpel, Maximilian Jenzer, Carsten Grüllich, Dirk Jäger, Holger Sültmann, Anette Duensing, Sven Perner, Marcus V Cronauer, Carsten Stephan, Jürgen Debus, Andres Jan Schrader, Glen Kristiansen, Markus Hohenfellner, Stefan Duensing
• Journal: Urologic oncology (Urol Oncol) Vol. 36 Issue 4 Pg. 161.e19-161.e30 (04 2018) ISSN: 1873-2496 [Electronic] United States
• PMID: 29198908 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2017 Elsevier Inc. All rights reserved.

Chemical References

• AR protein, human
• Androgen Antagonists
• Antineoplastic Agents
• Biomarkers, Tumor
• Protein Isoforms
• RNA, Messenger
• Receptors, Androgen
• KLK3 protein, human
• Kallikreins
• Prostate-Specific Antigen

Topics

• Aged
• Androgen Antagonists (therapeutic use)
• Antineoplastic Agents (therapeutic use)
• Biomarkers, Tumor (genetics, metabolism)
• Cell Nucleus (metabolism)
• Chemotherapy, Adjuvant (methods)
• Disease-Free Survival
• Humans
• Kallikreins (blood)
• Lymph Nodes (pathology)
• Lymphatic Metastasis
• Male
• Middle Aged
• Neoplasm Recurrence, Local (blood, mortality)
• Prognosis
• Prostate (pathology, surgery)
• Prostate-Specific Antigen (blood)
• Prostatectomy
• Prostatic Neoplasms, Castration-Resistant (blood, mortality, pathology, therapy)
• Protein Isoforms (metabolism)
• RNA, Messenger (metabolism)
• Receptors, Androgen (genetics, metabolism)
• Retrospective Studies
• Survival Analysis