Structure-based classification of EGFR mutations in operable pre-invasive and invasive non-small cell lung cancer: a cross-sectional study

Abstract

Background: It has been reported that the structure-based approach for defining functional groups of epidermal growth factor receptor (EGFR) mutations predicts the efficacy of EGFR inhibitors better than the traditional exon-based approach in the advanced stage. However, less is known about this structure-based classification of EGFR mutations in operable early-stage lung adenocarcinoma. Methods: Non-small cell lung cancer (NSCLC) patients with pathological stage I–III or adenocarcinoma in situ (AIS) who had EGFR mutations identified in next-generation sequencing (NGS) testing were recruited. Both exon-based and structure-based groupings of EGFR mutations were compared between the AIS and stage I–III patients using Fisher’s exact test. Results: In total 1,012 patients including 66 AIS and 946 stage I–III patients were analyzed in the study. A total of 1185 EGFR mutations were identified in the 1,012 NSCLC patients, of whom 84.39% harbored a single EGFR mutation and 15.61% harbored complex EGFR mutations. As expected, L858R was more common than 19del in our population (39.33% vs. 35.67%). Interestingly, concurrent L858R and 19del mutations were identified in 9 patients (0.89%), and all these patients were diagnosed with multiple primary lung cancer. A higher percentage of atypical EGFR mutations was identified in the AIS cohort than in the stage I–III NSCLC cohort (33.33% vs. 21.66%, P=0.03). According to the structure-based classification of EGFR mutations, 86.07%, 7.11%, 5.04%, and 1.78% of the EGFR mutations were classified as classical-like, P-loop and α C-helix compressing (PACC), exon 20 insertions (Ex20ins), and T790M-like mutations, respectively. The composition of EGFR mutations was different between patients <65 and ≥65 years (P=0.0267) but similar between patients with AIS and stage I–III NSCLC (P=0.1436). However, a higher percentage of Ex20ins occurred in younger (<65 years) patients, nonsmoking patients, and patients with AIS (6.7% vs. 2.5%, P=0.003; 5.8% vs. 0.8%, P=0.0107; and 10.6% vs. 4.7%, P=0.0423, respectively). Conclusions: This large cross-sectional study delineated the structure-based classification of EGFR mutations in patients with operable NSCLC. While the traditional exon-based EGFR grouping showed difference between AIS and stage I–III NSCLC cohort, no difference was identified in the structural approach. Which approach had better prediction of targeted therapy efficacy in adjuvant settings warrants further investigation.