BACKGROUND

It has been reported that the structure-based approach for defining functional groups of epidermal growth factor receptor () 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 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 mutations identified in next-generation sequencing (NGS) testing were recruited. Both exon-based and structure-based groupings of 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 mutations were identified in the 1,012 NSCLC patients, of whom 84.39% harbored a single  mutation and 15.61% harbored complex mutations. As expected, L858R was more common than 19del in our population (39.33% . 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 mutations was identified in the AIS cohort than in the stage I-III NSCLC cohort (33.33% . 21.66%, P0.03). According to the structure-based classification of mutations, 86.07%, 7.11%, 5.04%, and 1.78% of the 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 mutations was different between patients <65 and ≥65 years (P0.0267) but similar between patients with AIS and stage I-III NSCLC (P0.1436). However, a higher percentage of Ex20ins occurred in younger (<65 years) patients, nonsmoking patients, and patients with AIS (6.7% . 2.5%, P0.003; 5.8% . 0.8%, P0.0107; and 10.6% . 4.7%, P0.0423, respectively).

CONCLUSIONS

This large cross-sectional study delineated the structure-based classification of mutations in patients with operable NSCLC. While the traditional exon-based 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.