Clinical significance of EGFR mutation subtypes in lung adenocarcinoma : A multi-center Korean study v1

Background: Adenocarcinoma is the most common type of non-small cell lung cancer (NSCLC). Some causative genomicalterations, including deletion of exon (E) 19 and point mutation of E 21, are known to have a favourable prognoses due to sensitivity to tyrosine kinase inhibitors (TKIs); however, the prognoses of other uncommon mutations are unclear. The goal of this study was to analyse the clinical significance of epidermal growth factor receptor (EGFR)mutation subtypes in lung adenocarcinoma. Methods: We retrospectively reviewed 1,020 subjects (mean age: 66.8 years, female: 41.7%) who were diagnosed with advanced (stage III–IV) lung adenocarcinoma, had EGFR mutation data, and did not undergo surgery from five medical institutes between 2010 and 2016. Subjects were classified according to EGFR mutation status, particularly for exon-specific mutations. It was defined to EGFR positivity for the presence of mutation or insertion/deletion and EGFR negativity for wild type EGFR. Results: The median follow-up period was 13.3 months. EGFR positivity was 38.0%, with the incidence of mutations in E 18, 19, 20, and 21 being 3.6%, 51.0%, 3.4%, and 42.0%, respectively. The EGFR positive group survived significantly longer than the negative group (p<0.001), and there was a significant difference in survival among the four EGFR subtypes (p=0.003): univariate and multivariate analysis showed that E 19 deletion was the only significant factor that lowered mortality (HR:0.678, p=0.002), while mutations in E 21 was the poorer prognostic factor that increased mortality (HR:1.365, p=0.015). Amongst EGFR-positive cases, the proportion of E19 deletion in TKI responders was significantly higher than that of non-responders, and the proportion of E21 mutations was significantly lower. Conclusion: In advanced EGFR-mutant lung adenocarcinoma, E 19 deletion predicts a good prognosis, while mutations in E 21 significantly increase mortality. Unlike previous reports, mutations in E 18 and 20 were not worse factors than mutations in E 21 L858R.