Early Detection of Metastatic Relapse and Monitoring of Therapeutic Efficacy by Ultra-Deep Sequencing of Plasma Cell-Free DNA in Patients With Urothelial Bladder Carcinoma
Early Detection of Metastatic Relapse and Monitoring of Therapeutic Efficacy by Ultra-Deep Sequencing of Plasma Cell-Free DNA in Patients With Urothelial Bladder Carcinoma
复制标题
DOI：
10.1200/jco.18.02052
复制
发表时间：
2019-06-20
影响因子：
45.3
通讯作者：
Dyrskjot, Lars
中科院分区：
文献类型：
--
作者：
Christensen, Emil;Birkenkamp-Demtroder, Karin;Dyrskjot, Lars
目的早期发现复发和监测疗效的新的敏感方法可能会对膀胱癌患者的风险分层、治疗和最终结果产生巨大影响。我们探讨了超深测序在膀胱切除术前后和化疗期间对患者预后和预测的影响。通过全外显子组测序鉴定患者特定的体细胞突变，通过血浆DNA的超深测序(中位数为105,000倍)来评估循环肿瘤DNA(CtDNA)。血浆样本(n=656)在诊断时、化疗期间、膀胱切除术前和监测期间采集。结果在化疗前诊断时，ctDNA的存在具有很高的预后(风险比，29.1；P=.001)。在膀胱切除术后，ctDNA分析在疾病监测期间正确地识别了所有转移复发的患者(100%的敏感性，98%的特异性)。观察到放射成像的中位提前时间为96天。此外，对于高危患者(治疗前或治疗中ctDNA阳性)，化疗期间ctDNA的动态变化与疾病复发有关(P=0.023)，而病理分期下降与疾病复发无关。以肿瘤为中心的生物标记物的分析表明，突变过程(签名5)与病理分级有关(P=.024)；然而，没有观察到肿瘤亚型、DNA损伤反应突变和其他生物标记物之间的显著相关性。结论ctDNA分析用于膀胱癌的早期危险分层、治疗监测和早期复发检测是可行的，并为临床研究评估早期治疗干预措施提供了依据。(C)2019年美国临床肿瘤学会
PURPOSE Novel sensitive methods for early detection of relapse and for monitoring therapeutic efficacy may have a huge impact on risk stratification, treatment, and ultimately outcome for patients with bladder cancer. We addressed the prognostic and predictive impact of ultra-deep sequencing of cell-free DNA in patients before and after cystectomy and during chemotherapy.PATIENTS AND METHODS We included 68 patients with localized advanced bladder cancer. Patient-specific somatic mutations, identified by whole-exome sequencing, were used to assess circulating tumor DNA (ctDNA) by ultra-deep sequencing (median, 105,000x) of plasma DNA. Plasma samples (n = 656) were procured at diagnosis, during chemotherapy, before cystectomy, and during surveillance. Expression profiling was performed for tumor subtype and immune signature analyses.RESULTS Presence of ctDNA was highly prognostic at diagnosis before chemotherapy (hazard ratio, 29.1; P = .001). After cystectomy, ctDNA analysis correctly identified all patients with metastatic relapse during disease monitoring (100% sensitivity, 98% specificity). A median lead time over radiographic imaging of 96 days was observed. In addition, for high-risk patients (ctDNA positive before or during treatment), the dynamics of ctDNA during chemotherapy was associated with disease recurrence (P = .023), whereas pathologic downstaging was not. Analysis of tumor-centric biomarkers showed that mutational processes (signature 5) were associated with pathologic downstaging (P = .024); however, no significant correlation for tumor subtypes, DNA damage response mutations, and other biomarkers was observed. Our results suggest that ctDNA analysis is better associated with treatment efficacy compared with other available methods.CONCLUSION ctDNA assessment for early risk stratification, therapy monitoring, and early relapse detection in bladder cancer is feasible and provides a basis for clinical studies that evaluate early therapeutic interventions. (C) 2019 by American Society of Clinical Oncology