多种治疗方法可用于转移后的去势抵抗性前列腺癌（mCRPC），包括雄激素受体信号抑制剂（ARSI）恩扎鲁胺和阿比特龙，但治疗耐药性仍然是一个主要的临床障碍。我们检查了周转肿瘤DNA（ctDNA）的低通全基因组测序（LPWGS）在mCRPC预后中的临床实用性。共分析了143名mCRPC患者在第一线ARSI治疗（基线）开始时和治疗结束时（n = 57，相匹配）收集的200个血浆样本的LPWGS（中位数：0.50X），以获得ctDNA％和拷贝数变化（CNA）模式。最佳确认血清前列腺特异性抗原（PSA）反应（≥50％下降[PSA50]），PSA进展无病生存期（PFS）和总生存期（OS）用作终点。外部验证中，我们使用第一线ARSI接受的70名mCRPC患者的血浆LPWGS数据。在探索队列中，基线ctDNA％范围为≤3.0％至73％（中位数：6.6％），CNA负担为0％至82％（中位数：13.1％）。高基线ctDNA％和高CNA负担与较差的PSA50反应（P = 0.0123 / 0.0081），较差的PFS（P <0.0001）和较差的OS（P <0.0001）相关联。在32.7％和42.3％的患者中，PSA进展时的ctDNA％和CNA负担高于基线。验证队列中，高基线ctDNA％和高CNA负担也与较差的PFS和OS相关（P ≤0.0272）。 ctDNA的LPWGS为mCRPC患者的肿瘤基因组提供了临床相关信息。使用LPWGS数据，我们表明高基线ctDNA％和CNA负担与两个独立队列中的短期PFS和OS相关。牛津大学出版社或美国临床化学协会2023。

Multiple treatments are available for metastatic castration-resistant prostate cancer (mCRPC), including androgen receptor signaling inhibitors (ARSI) enzalutamide and abiraterone, but therapy resistance remains a major clinical obstacle. We examined the clinical utility of low-pass whole-genome sequencing (LPWGS) of circulating tumor DNA (ctDNA) for prognostication in mCRPC.A total of 200 plasma samples from 143 mCRPC patients collected at the start of first-line ARSI treatment (baseline) and at treatment termination (n = 57, matched) were analyzed by LPWGS (median: 0.50X) to access ctDNA% and copy number alteration (CNA) patterns. The best confirmed prostate specific antigen (PSA) response (≥50% decline [PSA50]), PSA progression-free survival (PFS), and overall survival (OS) were used as endpoints. For external validation, we used plasma LPWGS data from an independent cohort of 70 mCRPC patients receiving first-line ARSI.Baseline ctDNA% ranged from ≤3.0% to 73% (median: 6.6%) and CNA burden from 0% to 82% (median: 13.1%) in the discovery cohort. High ctDNA% and high CNA burden at baseline was associated with poor PSA50 response (P = 0.0123/0.0081), poor PFS (P < 0.0001), and poor OS (P < 0.0001). ctDNA% and CNA burden was higher at PSA progression than at baseline in 32.7% and 42.3% of the patients. High ctDNA% and high CNA burden at baseline was also associated with poor PFS and OS (P ≤ 0.0272) in the validation cohort.LPWGS of ctDNA provides clinically relevant information about the tumor genome in mCRPC patients. Using LPWGS data, we show that high ctDNA% and CNA burden at baseline is associated with short PFS and OS in 2 independent cohorts.Oxford University Press OR American Association for Clinical Chemistry 2023.