The Detection of Androgen Receptor Splice Variant 7 in Plasma-derived Exosomal RNA Strongly Predicts Resistance to Hormonal Therapy in Metastatic Prostate Cancer Patients
The Detection of Androgen Receptor Splice Variant 7 in Plasma-derived Exosomal RNA Strongly Predicts Resistance to Hormonal Therapy in Metastatic Prostate Cancer Patients
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DOI：
10.1016/j.eururo.2016.08.012
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发表时间：
2017-04-01
期刊：
影响因子：
23.4
通讯作者：
Danesi, Romano
中科院分区：
文献类型：
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作者：
Del Re, Marzia;Biasco, Elisa;Danesi, Romano
背景：雄激素受体剪接变异体7(AR-V7)与去势耐受前列腺癌(CRPC)对激素治疗的抵抗有关。由于现有AR-V7分析方法的局限性，确定一种可靠的检测方法可能有助于这一生物标志物在临床实践中的使用。目的：确认AR-V7是激素治疗抵抗的预测因子，并开发一种新的方法，通过高灵敏的数字液滴聚合酶链式反应(DdPCR)在血浆来源的胞外RNA中评估AR-V7。设计、背景和对象：36例CRPC患者在开始二线激素治疗之前采集了血浆样本。分离外切体，提取RNA，经ddPCR分析AR-V7基因。结果测量和统计分析：ddPCR测定以每毫升拷贝数(Copies/ml)为单位的绝对靶基因浓度。统计分析采用SPSS软件(IBM Corp.，Armonk，NY，USA)。结果与限制：共26例患者接受阿比特龙治疗，10例接受苯扎鲁胺治疗，39%的患者AR-V7阳性(AR-V7(+))。AR-V7阴性(AR-V7(-))患者的中位无进展生存期显著长于AR-V7(+)患者(20vs3mo；p<；0.001)。AR-V7(+)患者的总生存期显著短于AR-V7(-)患者(8个月比未达0.001个月；p<；0.001)。结论：本研究证明血浆来源的外体核糖核酸是一种可靠的AR-V7来源，可用直接聚合酶链式反应检测AR-V7。我们还发现AR-V7可以预测激素治疗的耐药性，使其成为一个临床相关的生物标志物。患者摘要：我们首次报道了一种检测从血液中释放的癌细胞囊泡提取的RNA中雄激素受体剪接变异体7(AR-V7)的方法。结果证实AR-V7作为激素治疗抵抗的预测生物标志物的作用。我们的试验表明，囊泡是AR-V7 RNA的可靠来源，该方法快速、高度敏感和负担得起。(C)2016年欧洲泌尿外科协会。爱思唯尔出版，版权所有。
Background: The androgen receptor splice variant 7 (AR-V7) is associated with resistance to hormonal therapy in castration-resistant prostate cancer (CRPC). Due to limitations of the methods available for AR-V7 analysis, the identification of a reliable detection method may facilitate the use of this biomarker in clinical practice.Objective: To confirm AR-V7 as a predictor of resistance to hormonal therapy and develop a new approach to assess AR-V7 by highly sensitive digital droplet polymerase chain reaction (ddPCR) in plasma-derived exosomal RNA.Design, setting, and participants: Plasma samples were collected from 36 CRPC patients before they began second-line hormonal treatment. Exosomes were isolated and RNA extracted for analysis of AR-V7 by ddPCR.Outcome measurements and statistical analysis: The absolute target gene concentration as copies per milliliter (copies/ml) was determined by ddPCR. Statistical analyses were performed with SPSS software (IBM Corp., Armonk, NY, USA).Results and limitations: A total of 26 patients received abiraterone and 10 enzalutamide; 39% of patients were found to be AR-V7 positive (AR-V7(+)). Median progression-free survival was significantly longer in AR-V7 negative (AR-V7(-)) versus AR-V7(+) patients (20 vs 3 mo; p < 0.001). Overall survival was significantly shorter in AR-V7(+) participants at baseline compared with AR-V7(-) participants (8 mo vs not reached; p < 0.001).Conclusions: This study demonstrates that plasma-derived exosomal RNA is a reliable source of AR-V7 that can be detected sensitively by ddPCR assay. We also showed that resistance to hormonal therapy may be predicted by AR-V7, making it a clinically relevant biomarker.Patient summary: We report a first study on a method for androgen receptor splice variant 7 (AR-V7) detection in RNA extracted from cancer cell vesicles released in blood. Results confirmed the role of AR-V7 as a predictive biomarker of resistance to hormonal therapy. Our assay showed that vesicles are a reliable source of AR-V7 RNA and that the method is fast, highly sensitive, and affordable. (C) 2016 European Association of Urology. Published by Elsevier B.V. All rights reserved.