a Department of Respiratory Medicine , Center for Molecular Medicine, Xiangya Hospital , Central South University , Changsha , China.
b Department of Respiratory Medicine, First Affiliated Hospital , Guangzhou Medical University , Guangzhou , China.
Cancer Biol Ther. 2019;20(8):1097-1104. doi: 10.1080/15384047.2019.1595280. Epub 2019 Apr 16.
Literatures regarding the prevalence and clinical significance of compound EGFR mutations are limited. Until now, none of retrospective or prospective research has focused on compound mutations except case reports. In this study, we screened a cohort of 3,000 treatment-naïve Chinese advanced NSCLC patients using capture-based ultra-deep targeted sequencing to evaluate the prevalence of compound mutations and the efficacy of EGFR-TKI in this population. Of the 3,000 patients screened, 1,266 (42.2%) had mutation; among them, 15 patients (1.2%) harborin compound mutations, with 10 patients carrying L858R in combination with a rare mutation and five patients carrying two rare mutations. No patient with 19del was observed. Interestingly, no configuration was identified in this cohort. All of the patients harborin compound mutations were non-smokers, histologically diagnosed with adenocarcinoma and received first-generation EGFR-TKI. Furthermore, our data also revealed that patients with compound mutations exhibit comparable PFS to first generation EGFR-TKI comparing to patients with single activating mutation. This observation was further supported by molecular modeling analyses which demonstrated compound mutations do not alter the ATP-binding pocket of , thus having no effect on the interaction between gefitinib and .
关于复合 EGFR 突变的流行率和临床意义的文献有限。到目前为止，除了病例报告外，没有回顾性或前瞻性研究专门针对复合突变。在这项研究中，我们使用基于捕获的超深度靶向测序筛选了 3000 名未经治疗的中国晚期 NSCLC 患者队列，以评估复合突变的流行率以及在该人群中 EGFR-TKI 的疗效。在筛选的 3000 名患者中，有 1266 名（42.2%）存在 突变；其中，15 名患者（1.2%）携带复合 突变，其中 10 名患者携带 L858R 与罕见突变的组合，5 名患者携带两种罕见的 突变。没有观察到 19del 的患者。有趣的是，在该队列中未发现 配置。所有携带复合 突变的患者均为不吸烟者，组织学诊断为腺癌，并接受了第一代 EGFR-TKI 治疗。此外，我们的数据还表明，与携带单一激活 突变的患者相比，携带复合 突变的患者的 PFS 与第一代 EGFR-TKI 相当。分子建模分析进一步支持了这一观察结果，该分析表明复合突变不会改变 的 ATP 结合口袋，因此不会影响吉非替尼与 的相互作用。
