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 genetic mutations, 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 EGFR mutation subtypes in lung adenocarcinoma. Methods: We retrospective reviewed 1021 patients (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 2010–2016. Patients were classified according to EGFR mutation status, particularly for exon-specific mutations. Results: The median follow-up period was 13.3 months. EGFR positivity was 38.1%, with the incidence of mutations in E 18, 19, 20, and 21 being 3.6%, 51.2%, 3.3%, and 41.9%, 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=0.004): mutation in E 19 showed a better survival probability compared with the other subtypes (p<0.001), whereas mutation in E 21 showed a poorer prognosis (p=0.006). Multivariate analysis showed that mutation in E 19 was the only significant factor that lowered mortality rate (HR:0.415, p=0.001), while mutations in E 18, 20, and 21 were not significant. Amongst EGFR-positive cases, TKI non-responders had a significantly higher proportion of E 21 mutations compared with TKI-responders (p=0.047). Conclusion: In advanced EGFR-mutant lung adenocarcinoma, mutations in E 19 predict good prognoses, while the presence of mutations in E 18, 20, and 21 did not significantly affect survival. Unlike previous reports, mutations in E 18 and 20 were not worse factors than mutation in E 21.