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. 2018 Sep 1;4(9):1179-1186.
doi: 10.1001/jamaoncol.2018.1621.

Assessment of the Validity of Nuclear-Localized Androgen Receptor Splice Variant 7 in Circulating Tumor Cells as a Predictive Biomarker for Castration-Resistant Prostate Cancer

Howard I Scher  1   2 , Ryon P Graf  3 , Nicole A Schreiber  1 , Anuradha Jayaram  4   5 , Eric Winquist  6   7 , Brigit McLaughlin  1 , David Lu  3 , Martin Fleisher  8 , Sarah Orr  3 , Lori Lowes  6   7 , Amanda Anderson  3 , Yipeng Wang  3 , Ryan Dittamore  3 , Alison L Allan  6   7 , Gerhardt Attard  4   5 , Glenn Heller  9
Affiliations

Assessment of the Validity of Nuclear-Localized Androgen Receptor Splice Variant 7 in Circulating Tumor Cells as a Predictive Biomarker for Castration-Resistant Prostate Cancer

Howard I Scher et al. JAMA Oncol. .

Abstract

Importance: A blood test to determine whether to treat patients with metastatic castration-resistant prostate cancer (mCRPC) with an androgen receptor signaling (ARS) inhibitor or taxane is an unmet medical need.

Objective: To determine whether a validated assay for the nuclear-localized androgen receptor splice variant 7 (AR-V7) protein in circulating tumor cells can determine differential overall survival among patients with mCRPC treated with taxanes vs ARS inhibitors.

Design, setting, and participants: This blinded correlative study conducted from December 31, 2012, to September 1, 2016, included 142 patients with histologically confirmed mCRPC and who were treated at Memorial Sloan Kettering Cancer Center, The Royal Marsden, or the London Health Sciences Centre. Blood samples were obtained prior to administration of ARS inhibitors or taxanes as a second-line or greater systemic therapy for progressing mCRPC.

Main outcomes and measures: Overall survival after treatment with an ARS inhibitor or taxane in relation to pretherapy AR-V7 status.

Results: Among the 142 patients in the study (mean [SD] age, 69.5 [9.6] years), 70 were designated as high risk by conventional prognostic factors. In this high-risk group, patients positive for AR-V7 who were treated with taxanes had superior overall survival relative to those treated with ARS inhibitors (median overall survival, 14.3 vs 7.3 months; hazard ratio, 0.62; 95% CI, 0.28-1.39; P = .25). Patients negative for AR-V7 who were treated with ARS inhibitors had superior overall survival relative to those treated with taxanes (median overall survival, 19.8 vs 12.8 months; hazard ratio, 1.67; 95% CI, 1.00-2.81; P = .05).

Conclusions and relevance: This study suggests that nuclear-localized AR-V7 protein in circulating tumor cells can identify patients who may live longer with taxane chemotherapy vs ARS inhibitor treatment.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Scher reported receiving institutional financial support from Janssen and Medivation; receiving personal fees from Astellas, Sanofi Aventis, and Clovis; and receiving research funding from Janssen Diagnostics, Janssen Pharmaceuticals, and Innocrin. Dr Allan reported receiving nonfinancial support from Janssen Diagnostics, and receiving research funding from Pfizer. Dr Attard reported being on the Institute of Cancer Research list of rewards to inventors for abiraterone; receiving honoraria, consulting fees, or travel support from Astellas, Medivation, Janssen, Millennium Pharmaceuticals, Ipsen, Ventana, ESSA Pharmaceuticals, and Sanofi-Aventis; and receiving grant support from Janssen, AstraZeneca, and Arno. Dr Heller reported receiving grant funding from Janssen. Drs Graf, Lu, Anderson, and Wang, Ms Orr, and Mr Dittamore are employees of Epic Sciences. The Institute of Cancer Research developed abiraterone and therefore has a commercial interest in this agent. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Distribution of Patient Samples in the Training Cohort and Validation Cohort
CONSORT diagram showing the breakdown and relationship of blood samples analyzed in the previous training cohort and for this validation study. Second-line and greater line samples from a study by Scher et al were analyzed as the training cohort, from which the risk stratification method was developed for this validation study. AR-V7 indicates androgen receptor splice variant 7; ARSi, androgen receptor signaling inhibitors; and mCRPC, metastatic castration-resistant prostate cancer.
Figure 2.
Figure 2.. Association Between Patient Risk, Androgen Receptor Splice Variant 7 (AR-V7) Status, and Therapy
A, Overall survival is shown for all 4 treatment-biomarker result groups using the Kaplan-Meier method not stratified by overall patient risk. B, Smoothed median estimates of overall survival as a function of patient risk and the 4 treatment-biomarker groups are shown. Censored patients are indicated by “o,” and deceased patients are indicated by “x.” Six observations (beyond 36 months) are attenuated by the graph axes. ARSi indicates androgen receptor signaling inhibitors.
Figure 3.
Figure 3.. Androgen Receptor Splice Variant 7 (AR-V7), Therapy, and Overall Survival
A, Overall survival for low risk only for all 4 treatment-biomarker result groups. B, Overall survival for high risk only for all 4 treatment-biomarker result groups. Six observations (beyond 36 months) are attenuated by the graph axes. C, Forest plot of hazard ratios derived from Cox model. ARSi indicates androgen receptor signaling inhibitors.
Figure 4.
Figure 4.. Treatment Selection With Androgen Receptor Splice Variant 7 (AR-V7)
A, Recommended decision guide for use of AR-V7 test result with risk score. B, Recommended decision guide for use of AR-V7 test result without risk score. ARSi indicates androgen receptor signaling inhibitors; mCRPC, metastatic castration-resistant prostate cancer; and OS, overall survival.
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