Refined Stratification Based on Baseline Concomitant Mutations and Longitudinal Circulating Tumor DNA Monitoring in Advanced EGFR-Mutant Lung Adenocarcinoma Under Gefitinib Treatment
Jianchun Duan, JiaChen Xu, Zhijie Wang, Hua Bai, Ying Cheng, Tongtong An, Hongjun Gao, Kai Wang, Qing Zhou, Yanping Hu, Yong Song, Cuimin Ding, Feng Peng, Li Liang, Yi Hu, Cheng Huang, Caicun Zhou, Yuankai Shi, Jiefei Han, Di Wang, Yanhua Tian, Zhenlin Yang, Li Zhang, Shaokun Chuai, Junyi Ye, Guanshan Zhu, Junhui Zhao, Yi-Long Wu, Jie Wang, Jianchun Duan, JiaChen Xu, Zhijie Wang, Hua Bai, Ying Cheng, Tongtong An, Hongjun Gao, Kai Wang, Qing Zhou, Yanping Hu, Yong Song, Cuimin Ding, Feng Peng, Li Liang, Yi Hu, Cheng Huang, Caicun Zhou, Yuankai Shi, Jiefei Han, Di Wang, Yanhua Tian, Zhenlin Yang, Li Zhang, Shaokun Chuai, Junyi Ye, Guanshan Zhu, Junhui Zhao, Yi-Long Wu, Jie Wang
Abstract
Introduction: The optimal treatment for EGFR-mutant lung adenocarcinoma (LUAD) remains challenging because of intratumor heterogeneity. We aimed to explore a refined stratification model based on the integrated analysis of circulating tumor DNA (ctDNA) tracking.
Methods: ctDNA was prospectively collected at baseline and at every 8 weeks in patients with advanced treatment-naive EGFR-mutant LUAD under gefitinib treatment enrolled in a phase 2 trial and analyzed using next-generation sequencing of a 168-gene panel.
Results: Three subgroups categorized by baseline comutations-EGFR-sensitizing mutations (59, 32.8%), EGFR-sensitizing mutations with tumor suppressor mutations (97, 53.9%), and EGFR-sensitizing mutations with other driver mutations (24, 13.3%)-exhibited distinct progression-free survival (13.2 [11.3-15.2] versus 9.3 [7.6-10.5] versus 4.0 [2.4-9.3] months) and overall survival (32.0 [29.2-41.5] versus 21.7 [19.3-27.0] versus 15.5 [10.5-33.7] months, respectively), providing evidence for initial stratification. A total of 63.7% of the patients achieved week 8 ctDNA clearance, with significant difference noted among the three subgroups (74.5% versus 64.0% versus 29.4%, respectively, p = 0.004, Fisher's exact test). Patients without week 8 ctDNA clearance had worse progression-free survival (clearance versus nonclearance 11.2 [9.9-13.2] versus 7.4 [5.6-9.6] months, p = 0.016, Cox regression], especially in the second subgroup [5.8 (5.6-11.5) months], suggesting the necessity of adaptive stratification during treatment. During follow-up, 56.0% and 20.8% of the patients eventually harbored p.T790M and non-p.T790M mutations, respectively, with a significant difference in non-p.T790M mutations among the three subgroups (7.5% versus 15.7% versus 80.0%, respectively, p < 0.001, Fisher's exact test), giving clues to postline treatment.
Conclusions: The patients with baseline comutations and ctDNA nonclearance at first visit might require combined therapy because of the limited survival benefit of EGFR tyrosine kinase inhibitor monotherapy. We proposed a refined stratification mode for the whole-course management of EGFR-mutant LUAD.
Keywords: Comutations; Epidermal growth factor receptor; Lung adenocarcinoma; Refined stratification; ctDNA monitoring.
Copyright © 2020. Published by Elsevier Inc.
Source: PubMed