Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada.
Faculty of Medicine and Life Sciences and Biomeditech Institute, University of Tampere, Tampere, Finland.
Cancer Discov. 2018 Apr;8(4):444-457. doi: 10.1158/2159-8290.CD-17-0937. Epub 2018 Jan 24.
Primary resistance to androgen receptor (AR)-directed therapies in metastatic castration-resistant prostate cancer (mCRPC) is poorly understood. We randomized 202 patients with treatment-naïve mCRPC to abiraterone or enzalutamide and performed whole-exome and deep targeted 72-gene sequencing of plasma cell-free DNA prior to therapy. For these agents, which have never been directly compared, time to progression was similar. Defects in and were strongly associated with poor clinical outcomes independently of clinical prognostic factors and circulating tumor DNA abundance. Somatic alterations in , previously linked to reduced tumor dependency on AR signaling, were also independently associated with rapid resistance. Although detection of amplifications did not outperform standard prognostic biomarkers, gene structural rearrangements truncating the ligand binding domain were identified in several patients with primary resistance. These findings establish genomic drivers of resistance to first-line AR-directed therapy in mCRPC and identify potential minimally invasive biomarkers. Leveraging plasma specimens collected in a large randomized phase II trial, we report the relative impact of common circulating tumor DNA alterations on patient response to the most widely used therapies for advanced prostate cancer. Our findings suggest that liquid biopsy analysis can guide the use of AR-targeted therapy in general practice. .
在转移性去势抵抗性前列腺癌（mCRPC）中，对雄激素受体（AR）靶向治疗的原发性耐药机制仍不清楚。我们将 202 例初治 mCRPC 患者随机分为阿比特龙或恩扎卢胺组，并在治疗前对血浆无细胞 DNA 进行全外显子组和深度靶向 72 基因测序。对于这两种从未直接比较过的药物，进展时间相似。 和 缺陷与临床预后因素和循环肿瘤 DNA 丰度无关，与不良临床结局密切相关。先前与 AR 信号转导依赖性降低相关的 中的体细胞改变也与快速耐药独立相关。虽然检测 扩增并不能优于标准预后生物标志物，但在一些原发性耐药患者中发现了截断配体结合域的 基因结构重排。这些发现确定了 mCRPC 一线 AR 靶向治疗耐药的基因组驱动因素，并确定了潜在的微创生物标志物。利用在大型随机 II 期试验中收集的血浆标本，我们报告了常见循环肿瘤 DNA 改变对晚期前列腺癌最广泛使用的治疗方法的患者反应的相对影响。我们的研究结果表明，液体活检分析可以指导 AR 靶向治疗在一般实践中的应用。
