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Original Investigation
November 2016

Association of AR-V7 on Circulating Tumor Cells as a Treatment-Specific Biomarker With Outcomes and Survival in Castration-Resistant Prostate Cancer

Author Affiliations
  • 1Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
  • 2Department of Medicine, Weill Cornell Medical College, New York, New York
  • 3Epic Sciences, La Jolla, California
  • 4Body Imaging Service, Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York
  • 5Department of Radiology, Weill Cornell Medical College, New York, New York
  • 6Cancer Services, Department of Medical Oncology, Cork University Hospital, Wilton, Cork, Ireland
  • 7Biostatistics Service, Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York
  • 8Clinical Chemistry Service, Department of Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
JAMA Oncol. 2016;2(11):1441-1449. doi:10.1001/jamaoncol.2016.1828
Key Points

Question  Can the measurement of the nuclear androgen-receptor splice variant 7 (AR-V7) protein in circulating tumor cells (CTCs) be a treatment-specific biomarker in metastatic castration-resistant prostate cancer (mCRPC) at therapeutic decision points in the first-line, second-line, or third or greater line setting?

Findings  In this cross-sectional cohort study, mCRPC patients with pre-androgen receptor signaling (ARS) inhibitor AR-V7–positive CTCs had resistant prostate-specific antigen responses, shorter time on therapy, shorter radiographic progression-free survival, and inferior overall survival. In a multivariable model incorporating line of therapy and other clinical features, AR-V7 status showed significant treatment-specific interaction with taxane administration.

Meaning  Pretherapy CTC nuclear expression of AR-V7 protein in men with mCRPC is a treatment-specific biomarker predicting superior overall survival for taxane therapy over ARS inhibitors in a clinical practice setting, warranting prospective validation.

Abstract

Importance  A critical decision in the management of metastatic castration-resistant prostate cancer (mCRPC) is when to administer an androgen receptor signaling (ARS) inhibitor or a taxane.

Objective  To determine if pretherapy nuclear androgen-receptor splice variant 7 (AR-V7) protein expression and localization on circulating tumor cells (CTCs) is a treatment-specific marker for response and outcomes between ARS inhibitors and taxanes.

Design, Setting, and Participants  For this cross-sectional cohort study at Memorial Sloan Kettering Cancer Center, 265 men with progressive mCRPC undergoing a change in treatment were considered; 86 were excluded because they were not initiating ARS or taxane therapy; and 18 were excluded for processing time constraints, leaving 161 patients for analysis. Between December 2012 and March 2015, blood was collected and processed from patients with progressive mCRPC immediately prior to new line of systemic therapy. Patients were followed up to 3 years.

Main Outcomes and Measures  Prostate-specific antigen (PSA) response, time receiving therapy, radiographic progression-free survival (rPFS), and overall survival (OS).

Results  Overall, of 193 prospectively collected blood samples from 161 men with mCRPC, 191 were evaluable (128 pre-ARS inhibitor and 63 pretaxane). AR-V7–positive CTCs were found in 34 samples (18%), including 3% of first-line, 18% of second-line, and 31% of third- or greater line samples. Patients whose samples had AR-V7–positive CTCs before ARS inhibition had resistant posttherapy PSA changes (PTPC), shorter rPFS, shorter time on therapy, and shorter OS than those without AR-V7–positive CTCs. Overall, resistant PTPC were seen in 65 of 112 samples (58%) without detectable AR-V7–positive CTCs prior to ARS inhibition. There were statistically significant differences in OS but not in PTPC, time on therapy, or rPFS for patients with or without pretherapy AR-V7–positive CTCs treated with a taxane. A multivariable model adjusting for baseline factors associated with survival showed superior OS with taxanes relative to ARS inhibitors when AR-V7–positive CTCs were detected pretherapy (hazard ratio, 0.24; 95% CI, 0.10-0.57; P = .035).

Conclusions and Relevance  The results validate CTC nuclear expression of AR-V7 protein in men with mCRPC as a treatment-specific biomarker that is associated with superior survival on taxane therapy over ARS-directed therapy in a clinical practice setting. Continued examination of this biomarker in prospective studies will further aid clinical utility.

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