ABSTRACT
INTRODUCTION: Prostate cancer is a highly heterogeneous disease, with remarkably different prognosis across all stages. Increased circulating tumor cell (CTC) count (≥ 5) using the CellSearch assay has been identified as one of the markers that can be used to predict survival, with added value beyond currently available prognostic factors. Recently, androgen receptor splice variant 7 (AR-V7) detection has been associated with worse outcomes for patients with castration-resistant prostate cancer (CRPC) treated with novel androgen receptor-signaling (ARS) inhibitors such as abiraterone and enzalutamide but not taxane chemotherapies. Areas covered: In this manuscript, the authors review the available biomarkers in CRPC and discuss emerging data on the value of CTC-derived AR-V7 status to assess prognosis and its potential role to guide treatment selection for patients with advanced prostate cancer. Expert commentary: Current evidence supports AR-V7 status as a prognostic biomarker and also as a potential predictive biomarker for patients with mCRPC. The authors expect that the incorporation of AR-V7 status and other biomarkers (e.g. AR mutations) in the sequential assessment of patients with advanced prostate cancer will lead to a more rational use of available and future therapies, with significant improvements in outcomes for our patients.
Subject(s)
Alternative Splicing , Biomarkers, Tumor , Neoplastic Cells, Circulating/metabolism , Prostatic Neoplasms/diagnosis , Prostatic Neoplasms/genetics , Receptors, Androgen/genetics , Androgen Antagonists/pharmacology , Androgen Antagonists/therapeutic use , Antineoplastic Agents, Hormonal/pharmacology , Antineoplastic Agents, Hormonal/therapeutic use , Humans , Male , Mutation , Neoplasm Staging , Neoplastic Cells, Circulating/pathology , Prognosis , Prostatic Neoplasms/blood , Prostatic Neoplasms/drug therapy , Prostatic Neoplasms, Castration-Resistant/blood , Prostatic Neoplasms, Castration-Resistant/diagnosis , Prostatic Neoplasms, Castration-Resistant/drug therapy , Prostatic Neoplasms, Castration-Resistant/genetics , Signal Transduction/drug effectsABSTRACT
PURPOSE: Androgen receptor (AR) splice variant 7 (AR-V7) has been related with both a higher risk of prostate cancer (PC) progression and differential responsiveness to hormonal agents versus chemotherapy. The objective of this study was to investigate the feasibility of a novel capillary nano-immunoassay in assessing AR-V7 in plasma from PC patients. METHODS: Patients with either localized or advanced PC were included in the study. Assessment of AR-V7 in plasma was performed through a capillary nano-immunoassay platform. Correlation with clinical data, stem cell biomarkers (such as CD133+), AR amplification and PTEN status was identified. RESULTS: The study included 72 PC patients. AR-V7 signal was detected in 21 (29%) patients: 17 (81%) had a Gleason score ≥7, 15 (71%) castration-resistant prostate cancer (CRPC), 18 (86%) metastatic disease and PSA (median) high than AR-V7 negative (p < 0.05). CD133 was expressed in 69 (96%) patients. The median CD133+ expression in circulating tumor cells CTCs was higher among the 21 AR-V7 positive cases versus AR-V7 negative (7 vs. 3). Androgen Receptor and PTEN fluorescence in situ hybridization (FISH) on CD133+ captured cells were performed: 37 cases showed ≥four CD133+ CTCs, of which 81% showed an increased AR copy number. This percentage was similar in both AR-V7-positive and AR-V7-negative patients. A total of 68% of the cases showed deletion of PTEN: 70% were ARV-7 positive vs. 67%, which were AR-V7 negative. CONCLUSIONS: Assessing the presence of AR-V7 in plasma from PC patients is feasible by a novel capillary nano-immunoassay. AR-V7 was observed in 29% of the tumors and is more frequent in aggressive tumors.
Subject(s)
AC133 Antigen/metabolism , Alternative Splicing , Biomarkers, Tumor/blood , Neoplastic Cells, Circulating/metabolism , Prostatic Neoplasms/blood , Receptors, Androgen/genetics , Biomarkers, Tumor/genetics , Follow-Up Studies , Humans , Immunoassay , Male , Nanomedicine , Neoplastic Cells, Circulating/pathology , Pilot Projects , Prognosis , Prostatic Neoplasms/genetics , Prostatic Neoplasms/pathologyABSTRACT
Major advances have been achieved recently in the treatment of metastatic castration-resistant prostate cancer, resulting in significant improvements in quality of life and survival with the use of several new agents, including the next-generation androgen receptor (AR)-targeted drugs abiraterone and enzalutamide. However, virtually all patients will eventually progress on these therapies and most will ultimately die of treatment-refractory metastatic disease. Recently, several mechanisms of resistance to AR-directed therapies have been uncovered, including the AR splice variant 7 (AR-V7), which is a ligand-independent constitutionally-active form of the AR that has been associated with poor outcomes to abiraterone and enzalutamide. Galeterone, a potent anti-androgen with three modes of action (CYP17 lyase inhibition, AR antagonism, and AR degradation), is a novel agent under clinical development that could potentially target both full-length AR and aberrant AR, including AR-V7. In this manuscript, we will first discuss the biological mechanisms of action of galeterone and then review the safety and efficacy data from Phase I and II clinical studies of galeterone in patients with metastatic castration-resistant prostate cancer. A Phase III study of galeterone (compared against enzalutamide) in AR-V7-positive patients is currently underway, and represents the first pivotal trial using a biomarker-selection design in this disease.