Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark.
Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.
Clin Cancer Res. 2023 Apr 14;29(8):1582-1591. doi: 10.1158/1078-0432.CCR-22-3250.
To investigate the use of plasma and urine DNA mutation analysis for predicting neoadjuvant chemotherapy (NAC) response and oncological outcome in patients with muscle-invasive bladder cancer.
Whole-exome sequencing of tumor and germline DNA was performed for 92 patients treated with NAC followed by radical cystectomy (RC). A custom NGS-panel capturing approximately 50 mutations per patient was designed and used to track mutated tumor DNA in plasma and urine. A total of 447 plasma samples, 281 urine supernatants, and 123 urine pellets collected before, during, and after treatment were analyzed. Patients were enrolled from 2013 to 2019, with a median follow-up time of 41.3 months after RC.
We identified tumor DNA before NAC in 89% of urine supernatants, 85% of urine pellets, and 43% of plasma samples. Tumor DNA levels were higher in urine supernatants and urine pellets compared with plasma samples (P < 0.001). In plasma, detection of circulating tumor DNA (ctDNA) before NAC was associated with a lower NAC response rate (P < 0.001). Detection of tumor DNA after NAC was associated with lower response rates in plasma, urine supernatant, and urine pellet (P < 0.001, P = 0.03, P = 0.002). Tumor DNA dynamics during NAC was predictive of NAC response and outcome in urine supernatant and plasma (P = 0.006 and P = 0.002). A combined measure from plasma and urine supernatant tumor DNA dynamics stratified patients by outcome (P = 0.003).
Analysis of tumor DNA in plasma and urine samples both separately and combined has a potential to predict treatment response and outcome.
研究血浆和尿液 DNA 突变分析在预测接受新辅助化疗（NAC）的肌层浸润性膀胱癌患者的化疗反应和肿瘤学结局中的作用。
对 92 例接受 NAC 后行根治性膀胱切除术（RC）的患者的肿瘤和种系 DNA 进行全外显子组测序。设计了一个约每个患者捕获 50 个突变的定制 NGS 面板，并用于跟踪治疗前后血浆和尿液中的突变肿瘤 DNA。共分析了 447 份血浆样本、281 份尿液上清液和 123 份尿液沉淀物，这些样本分别在治疗前、治疗中和治疗后采集。患者于 2013 年至 2019 年期间入组，RC 后中位随访时间为 41.3 个月。
我们在 89%的尿液上清液、85%的尿液沉淀物和 43%的血浆样本中检测到 NAC 前的肿瘤 DNA。尿液上清液和尿液沉淀物中的肿瘤 DNA 水平明显高于血浆样本（P < 0.001）。在血浆中，NAC 前循环肿瘤 DNA（ctDNA）的检测与较低的 NAC 反应率相关（P < 0.001）。NAC 后检测到肿瘤 DNA 与血浆、尿液上清液和尿液沉淀物中较低的反应率相关（P < 0.001、P = 0.03、P = 0.002）。NAC 期间肿瘤 DNA 的动态变化可预测 NAC 反应和尿液上清液及血浆中的结局（P = 0.006 和 P = 0.002）。来自血浆和尿液上清液肿瘤 DNA 动态变化的联合指标按结局对患者进行分层（P = 0.003）。
血浆和尿液样本中肿瘤 DNA 的单独和联合分析具有预测治疗反应和结局的潜力。
