EGF+61 A'G polymorphism does not predict response to first-generation EGFR tyrosine kinase inhibitors in lung cancer patients

Abstract

Epidermal growth factor (EGF) and its receptor (EGFR) play a paramount role in lung carcinogenesis. The polymorphism in the EGF promoter region EGF+61A'G (rs4444903) has been associated with cancer susceptibility, but its role in lung cancer patients treated with tyrosine kinase inhibitors (TKIs) remains unknown. Here, we aimed to evaluate the predictive and prognostic role of EGF+61A'G SNP in lung cancer from Brazilian EGFR-mutated TKI-treated patients. Herein, patients carrying EGFR-sensitizing mutations submitted to TKI treatment (gefitinib/erlotinib) were analyzed (n = 111) for EGF+61A'G genotype by TaqMan genotyping assay. TKI treatment was classified as partial response (PR), stable disease (SD), and disease progression (DP), according to RECIST1.1. Association analysis was assessed by chi-square and Fisher's test (univariate) and multinomial model (multivariate) and survival analysis by Kaplan-Meier method and log-rank test. The EGF+61A'G genotype frequencies observed were: AA = 31.5% (n = 35), AG = 49.6% (n = 55) and GG = 18.9% (n = 21). The allelic frequencies were 56.3% for A, and 43.7% for G and the population was in Hardy-Weinberg equilibrium (P = 0.94). EGF+61A'G codominant model (AA vs. AG vs. GG) was associated with a response to TKIs (P = 0.046), as well as a recessive model (AA vs. AG + GG; P = 0.023). The multinomial regression showed an association between the codominant model (AG) and recessive model (AG + GG) with SD compared with DP (P = 0.01;OR = 0.08; 95% CI = 0.01–0.60 and P = 0.02;OR = 0.12; 95% CI = 0.20–0.72, respectively). No association between genotypes and progression-free or overall survival was observed. In conclusion, the EGF+61 polymorphism (AG and AG + GG) was independently associated with stable disease in lung cancer patients although it was not associated with the overall response rate to first-generation TKIs or patient outcome.