Purpose: Biomarkers aiding treatment optimization in metastatic castration-resistant prostate cancer (mCRPC) are scarce. Presence or absence of androgen receptor (AR) splice variants, AR-V7 and ARv567es, in mCRPC patient circulating tumor cells (CTCs) may be associated with taxane treatment outcomes. Methods: A novel digital droplet PCR (ddPCR) assay assessed AR splice variant expression in patient CTCs receiving docetaxel or cabazitaxel in TAXYNERGY (NCT01718353). Outcomes were examined according to AR splice variant expression, including prostate-specific antigen (PSA)50 response and progression-free survival (PFS). Results: Of 54 evaluable patients, 36 (67%) were AR-V7+, 42 (78%) ARv567es+, 29 (54%) double positive and 5 (9%) double negative. PSA50 response rates at any time were numerically higher for AR-V7- vs AR-V7+ (78% vs 58%; p=0.23) and for ARv567es- vs ARv567es+ (92% vs 57%; p=0.04) patients. When AR-V mRNA status was correlated with change in nuclear AR from Cycle 1 Day 1 to 8 (n=24), AR-V7+ patients (n=16) had a 0.4% decrease vs a 12.9% and 26.7% decrease in AR-V7-/ARv567es- (n=3) and AR-V7-/ ARv567es+ (n=5) patients, respectively, suggesting a dominant role for AR-V7 over ARv567es.Median PFS was 12.02 vs 8.48 months for AR-V7- vs AR-V7+ (HR=0.38; p=0.01), and 12.71 vs 7.29 months for ARv567es- vs ARv567es+ (HR=0.37; p=0.02). For AR-V7+, AR-V7-/ARv567es+, and AR-V7-/ ARv567es- patients, median PFS was 8.48, 11.17 and 16.62 months, respectively (trend: p=0.0013). Conclusions: Detection of CTC-specific AR-V7 and ARv567es by ddPCR influenced taxane outcomes; AR-V7 primarily mediated the prognostic impact. Absence of both variants was associated with best response and PFS with taxanes.
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