Ma Li, Li Haoyang, Wang Dongpo, Hu Ying, Yu Mengjun, Zhang Quan, Qin Na, Zhang Xinyong, Li Xi, Zhang Hui, Wu Yuhua, Lv Jialin, Yang Xinjie, Yu Ruoying, Zhang Shucai, Wang Jinghui
Department of Medical Oncology, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing Chest Hospital, Capital Medical University, Beijing, China.
Department of Radiology, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing Chest Hospital, Capital Medical University, Beijing, China.
Front Oncol. 2021 Mar 25;11:643199. doi: 10.3389/fonc.2021.643199. eCollection 2021.
Circulating cell-free DNA (cfDNA) level has been demonstrated to be associated with efficacy in first generation EGFR TKIs in non-small cell lung cancer (NSCLC). However, the role of dynamic cfDNA analysis using next-generation sequencing (NGS) in patients with subsequent third-generation EGFR TKIs remains unclear.
From 2016 to 2019, 81 NSCLC patients with T790M mutation either in tissue or plasma who received third-generation EGFR TKIs treatment were enrolled. CfDNA were sequenced by NGS with a 425-gene panel. The association of clinical characteristics, pretreatment, dynamic cfDNA and T790M level with outcomes in patients treated with the third-generation TKIs were analyzed.
In univariate analysis, the median PFS of patients with undetectable cfDNA level during treatment was significantly longer than those with detectable cfDNA (16.97 . 6.10 months; HR 0.2109; < 0.0001). The median PFS of patients with undetectable T790M level during treatment was significantly longer than those with detectable T790M (14.1 . 4.4 months; HR 0.2192; < 0.001). Cox hazard proportion model showed that cfDNA clearance was an independent predictor for longer PFS (HR 0.3085; < 0.001) and longer OS (HR 0.499; = 0.034). The most common resistant mutations of the third-generation TKIs were C797S (24%). CNV, , D761N, Q791H, V843I, and mutation genes may possibly be new resistant mechanisms.
Patients with undetectable cfDNA during the third-generation EGFR TKI treatment have superior clinical outcomes, and dynamic cfDNA analysis by NGS is valuable to explore potential resistant mechanisms.
循环游离DNA（cfDNA）水平已被证明与非小细胞肺癌（NSCLC）患者使用第一代表皮生长因子受体酪氨酸激酶抑制剂（EGFR TKIs）的疗效相关。然而，使用下一代测序（NGS）进行动态cfDNA分析在后续使用第三代EGFR TKIs的患者中的作用仍不清楚。
2016年至2019年，纳入81例组织或血浆中存在T790M突变且接受第三代EGFR TKIs治疗的NSCLC患者。使用包含425个基因的检测板通过NGS对cfDNA进行测序。分析临床特征、治疗前情况、动态cfDNA和T790M水平与接受第三代TKIs治疗患者结局之间的关联。
单因素分析显示，治疗期间cfDNA水平不可检测的患者的中位无进展生存期（PFS）显著长于cfDNA可检测的患者（16.97对6.10个月；风险比[HR]0.2109；P<0.0001）。治疗期间T790M水平不可检测的患者的中位PFS显著长于T790M可检测的患者（14.1对4.4个月；HR 0.2192；P<0.001）。Cox风险比例模型显示，cfDNA清除是更长PFS（HR 0.3085；P<0.001）和更长总生存期（OS，HR 0.499；P=0.034）的独立预测因素。第三代TKIs最常见的耐药突变是C797S（24%）。拷贝数变异（CNV）、D761N、Q791H、V843I和其他突变基因可能是新的耐药机制。
在第三代EGFR TKI治疗期间cfDNA不可检测的患者具有更好的临床结局，并且通过NGS进行动态cfDNA分析对于探索潜在的耐药机制具有重要价值。
