AR splice variants in circulating tumor cells of patients with castration‐resistant prostate cancer: relation with outcome to cabazitaxel

Abstract

The androgen receptor splice variant ( AR‐V ) 7 in circulating tumor cells (CTCs) is a predictor for resistance to anti‐AR‐targeted treatment, but not to taxane‐based chemotherapy in metastatic castration‐resistant prostate cancer (mCRPC). In this study, we investigated whether the presence of two constitutively active variants ( AR‐V3, AR‐V7 ) and two other conditionally activated variants ( AR‐V1, AR‐V9 ) vs full‐length androgen receptor ( AR‐FL ) measured in CTCs from patients with mCRPC were associated with outcome to therapy with the taxane cabazitaxel. Blood was collected at baseline and after two cycles of cabazitaxel from 118 mCRPC patients starting cabazitaxel in a prospective phase II trial. CellSearch‐enriched CTCs were enumerated and in parallel characterized for the presence of the AR‐V s by reverse transcription quantitative polymerase chain reaction. Correlations with CTC and prostate‐specific antigen response to cabazitaxel as well as associations with overall survival (OS) were investigated. All AR‐V s were frequently present and co‐expressed at frequencies of 31–48% at baseline and at 19–40% after two cycles of cabazitaxel. No specific directions of change in the measured variants were detected between the start of treatment and after two cycles of cabazitaxel. No associations between the presence of AR‐V3 and AR‐V7 and outcome to cabazitaxel were observed. While a reduction in CTCs to < 5 CTCs during treatment (CTC5‐response) was less often observed in patients with AR‐V9 ‐positive CTCs at baseline ( P = 0.004), the CTC5‐adjusted detection of AR‐V1 after two cycles of cabazitaxel was an independent prognostic factor for OS [HR 2.4 (95% CI 1.1–5.1, P = 0.03)]. These novel findings are expected to contribute to more personalized treatment approaches in mCRPC patients.

Clinical implication of prognostic and predictive biomarkers for castration-resistant prostate cancer: a systematic review

“…Presence of ARV7+ and CTC+ in patients with mCRPC were associated with poorer outcomes on OS along with higher ARV7 values. However, one study reported no significant association with ARV7 [18]. Circulating tumor cells (CTCs) have emerged as a viable solution to the problem whereby patients with a variety of solid tumors, including PC, often do not have recent tumor tissue available for analysis [86].…”

“…Six studies were observed for the presence of ARVs in CTC. The presence of AR-V9-positive CTCs at baseline in mCRPC was associated with poor survival outcome to cabazitaxel treatment [18], while another study reported no association of AR-V7 with OS on treatment with cabazitaxel [19]. ARV7+ was associated with shorter OS on treatment with androgen-receptor signaling inhibitors (ARSi) [20].…”

The Prognostic Value of Androgen Receptor Splice Variant 7 in Castration-Resistant Prostate Cancer Treated With Novel Hormonal Therapy or Chemotherapy: A Systematic Review and Meta-analysis

“…AR-V7 mediates taxane resistance via several mechanisms. Previously, high expression of AR-V7 was linked to NHT resistance, but its expression level declined after chemotherapy (7,8,(16)(17)(18)(19)(20)(21). In recent years, the prognostic value and clinical utility of AR-V7 in NHT and chemotherapy are deeply investigated.…”

Prognostic Value of Androgen Receptor Splice Variant 7 in the Treatment of Metastatic Castration-Resistant Prostate Cancer: A Systematic Review and Meta-Analysis

“…The advantages and disadvantages of AR-V7 detection methods were discussed before (28). Among AR-V7 detection methods, RT-PCR-based tests are the most widely used (12,15,16,20,25,(29)(30)(31)(32)(33)(34). This method is highly sensitive, but its clinical application may be limited because of a defective reliance on the detection of circulating tumor cells (CTCs) and low levels of analytes in liquid biopsy samples.…”