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

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.

Biophysical technologies for understanding circulating tumor cell biology and metastasis

“…These findings support the use of AR-V7 as a predictive biomarker for response failure to treatment with AR signaling inhibitors (54). HD-CTC has been lesser studied in the predictive setting for NSCLC, but in a small series of patients with NSCLC, detection of ALK rearrangement by FISH on peripheral blood CTCs using the Epic platform demonstrated modest sensitivity and specificity (55).…”

Heterogeneity of advanced prostate cancer: clinical implications of genomics

“…6 In a further retrospective analysis, Scher et al have demonstrated that patients positive for AR-V7, as detected by anti-AR-V7 on circulating tumour cells, had a better overall survival if treated with a taxane compared to hormonal therapy (HR 0.24; 95% CI 0.10-0.57; p=0.035), and that the presence of AR-V7 increased with more exposure to systemic therapy. 7 Separately, Welti et al demonstrated in intra-patient paired tissue biopsies that the expression of AR-V7 increased between the hormone-sensitive and castration-resistant prostate cancer samples, and that high AR-V7 predicts for worse overall survival. 8 Significantly, they also demonstrated that the AR-V7 antibody used (epitope aa630-645, the AR-V7 cryptic region) for both the Scher and Welti studies also detected as yet unidentified off-target proteins that could limit the potential utility of this antibody in future studies.…”

Piecing the puzzle together: Docetaxel cycles and current considerations in the treatment of metastatic castration-resistant prostate cancer

“…15 One splice variant in particular, AR-V7, is associated with resistance to anti-androgens and has recently been identified as a possible resistance biomarker. 16,17 Patients expressing AR-V7 in circulating tumor cells showed improved survival when treated with taxanes, indicating that the AR-V7 status of a patient could be helpful in treatment decisions. 17 In a study of Chinese patients with newly diagnosed (cohort 1), metastatic (cohort 2), and CRPC (cohort 3), 18 AR-V7 was predictive of disease progression, yet was inversely correlated with serum PSA at diagnosis or surgery.…”

“…16,17 Patients expressing AR-V7 in circulating tumor cells showed improved survival when treated with taxanes, indicating that the AR-V7 status of a patient could be helpful in treatment decisions. 17 In a study of Chinese patients with newly diagnosed (cohort 1), metastatic (cohort 2), and CRPC (cohort 3), 18 AR-V7 was predictive of disease progression, yet was inversely correlated with serum PSA at diagnosis or surgery. The disagreement between AR-V7 and serum PSA may show that AR-V7 has more predictive value for progressed disease.…”