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

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

Mol Oncol. 2019 Jun 10;:

Authors: Sieuwerts AM, Onstenk W, Kraan J, Beaufort CM, Van M, De Laere B, Dirix LY, Hamberg P, Beeker A, Meulenbeld HJ, Creemers GJ, van Weerden WM, Jenster GW, Nieuweboer AJM, Mathijssen RHJ, de Wit R, Martens JWM, Sleijfer S

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) versus 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-Vs by RT-qPCR. Correlations with CTC- and PSA-response to cabazitaxel as well as associations with overall survival (OS) were investigated. All AR-Vs were frequently present and co-expressed at frequencies of 31-48% at baseline and at 19-40% after 2 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.

PMID: 31180178 [PubMed – as supplied by publisher]