Distinct epidemiology and clinical consequence of classic versus rare EGFR mutations in lung adenocarcinoma.

Abstract

INTRODUCTION:: While classic sensitizing mutations of epidermal growth factor receptor (EGFR) are positive predictive markers for EGFR tyrosine kinase inhibitors (TKIs) in lung adenocarcinoma, there are rare EGFR mutations with unknown epidemiology and influence on prognosis and TKI response. METHODS:: 814 lung adenocarcinoma patients with KRAS and/or EGFR mutation analyses for TKI therapy indication were identified. 645 patients were included in the epidemiological analysis. The clinical outcome was analyzed in 419 advanced stage patients with follow-up data. RESULTS:: 480 (59%) KRAS/EGFR double wild-type, 216 (27%) KRAS mutant, 42 (5%) classic, 49 (6%) rare and 27 (3%) synonymous EGFR mutant cases were identified. 20 previously unpublished non-synonymous mutations were found. Rare EGFR mutations were significantly associated with smoking (vs classic EGFR mutations; P=.0062). Classic EGFR mutations but not rare ones were independent predictors of increased overall survival (HR, 0.45; 95% CI, 0.25-0.82; P=.009). TKI therapy response rate (RR) of patients harboring classic EGFR mutations was significantly higher (vs rare EGFR mutations; 71% vs 37%; P=.039). Patients with classic or sensitizing rare (G719x and L861Q) EGFR mutations had significantly longer progression-free survival when compared to the remaining rare mutation cases (12 vs 6.2 months; P=.048). CONCLUSIONS:: The majority of rare EGFR mutations was associated with smoking, shorter overall survival and decreased TKI response when compared to classic EGFR mutations. However, studies characterizing the TKI sensitizing effect of individual rare mutations are indispensable to prevent the exclusion of patients with sensitizing rare EGFR mutations who may benefit from anti-EGFR therapy.