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-Vs 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-Vs 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.

中文翻译：

---

去势抵抗性前列腺癌患者循环肿瘤细胞中的 AR 剪接变异：与卡巴他赛结果的关系。

循环肿瘤细胞 (CTC) 中的雄激素受体剪接变体 (AR-V) 7 是抗 AR 靶向治疗耐药的预测因子，但不能预测转移性去势抵抗性前列腺癌 (mCRPC) 中紫杉烷类化疗的耐药性。在这项研究中，我们研究了是否测量了两种组成型活性变体（AR-V3、AR-V7）和另外两种条件激活变体（AR-V1、AR-V9）与全长雄激素受体（AR-FL）的存在mCRPC 患者的 CTC 与紫杉烷卡巴他赛治疗的结果相关。在一项前瞻性 II 期试验中，在基线时和两个周期的卡巴他赛治疗后，从 118 名 mCRPC 患者中采集了卡巴他赛的血液。计数了 CellSearch 富集的 CTC，并通过逆转录定量聚合酶链反应并行表征 AR-V 的存在。研究了 CTC 和前列腺特异性抗原对卡巴他赛反应的相关性以及与总生存期 (OS) 的相关性。所有 AR-V 均频繁出现并共表达，基线时频率为 31-48%，卡巴他赛两个周期后频率为 19-40%。在治疗开始和卡巴他赛两个周期后，没有检测到测量变异的具体变化方向。没有观察到 AR-V3 和 AR-V7 的存在与卡巴他赛结果之间存在关联。虽然在基线时 AR-V9 阳性 CTC 的患者中，治疗期间 CTC 减少至 < 5 个 CTC（CTC5 反应）的情况较少见（P = 0.004），但两个周期后 AR-V1 的 CTC5 调整检测卡巴他赛是 OS 的独立预后因素 [HR 2.4 (95% CI 1.1-5.1，P = 0.03)]。这些新发现有望为 mCRPC 患者提供更个性化的治疗方法。