Nørgaard Maibritt, Bjerre Marianne T, Fredsøe Jacob, Vang Søren, Jensen Jørgen B, De Laere Bram, Grönberg Henrik, Borre Michael, Lindberg Johan, Sørensen Karina D
Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark.
Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.
Clin Chem. 2023 Apr 3;69(4):386-398. doi: 10.1093/clinchem/hvac224.
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.
转移性去势抵抗性前列腺癌（mCRPC）有多种治疗方法，包括雄激素受体信号抑制剂（ARSI）恩杂鲁胺和阿比特龙，但治疗耐药仍然是一个主要的临床障碍。我们研究了循环肿瘤DNA（ctDNA）的低深度全基因组测序（LPWGS）在mCRPC预后评估中的临床应用价值。
对143例mCRPC患者在一线ARSI治疗开始时（基线）和治疗结束时（n = 57，配对）收集的共200份血浆样本进行LPWGS分析（中位数：0.50X），以获取ctDNA百分比和拷贝数改变（CNA）模式。以最佳确认的前列腺特异性抗原（PSA）反应（≥50%下降[PSA50]）、PSA无进展生存期（PFS）和总生存期（OS）作为终点。为进行外部验证，我们使用了来自70例接受一线ARSI治疗的mCRPC患者独立队列的血浆LPWGS数据。
在发现队列中，基线ctDNA百分比范围为≤3.0%至73%（中位数：6.6%），CNA负担范围为0%至82%（中位数：13.1%）。基线时高ctDNA百分比和高CNA负担与不良的PSA50反应（P = 0.0123/0.0081）、不良的PFS（P < 0.0001）和不良的OS（P < 0.0001）相关。在32.7%和42.3%的患者中，PSA进展时的ctDNA百分比和CNA负担高于基线。在验证队列中，基线时高ctDNA百分比和高CNA负担也与不良的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。利用LPWGS数据，我们表明在2个独立队列中，基线时高ctDNA百分比和CNA负担与较短的PFS和OS相关。
