Background:Epidermal growth factor receptor(EGFR) mutations,including a known exon 19 deletion(19 del) and exon 21 L858 R point mutation(L858R mutation),are strong predictors of the response to EGFR tyrosine kinase inhibitor(EGFR-TKI) treatment in lung adenocarcinoma.However,whether patients carrying EGFR 19 del and L858 R mutations exhibit different responsiveness to EGFR-TKls and what are the potential mechanism for this difference remain controversial.This study aimed to investigate the clinical outcomes of EGFR-TKI treatment in patients with EGFR 19 del and L858 R mutations and explore the genetic heterogeneity of tumors with the two mutation subtypes.Methods:Of 1127 patients with advanced lung adenocarcinoma harboring EGFR 19 del or L858 R mutations,532 received EGFR-TKI treatment and were included in this study.EGFR 19 del and L858 R mutations were detected by using denaturing high-performance liquid chromatography(DHPLC).T790 M mutation,which is a common resistant mutation on exon 20 of EGFR,was detected by amplification refractory mutation system(ARMS).Next-generation sequencing(NGS) was used to explore the genetic heterogeneity of tumors with EGFR 19 del and L858 R mutations.Results:Of the 532 patients,319(60.0%) had EGFR 19 del,and 213(40.0%) had L858 R mutations.The patients with EGFR 19 del presented a significantly higher overall response rate(ORR) for EGFR-TKI treatment(55.2%vs.43.7%,P = 0.017) and had a longer progression-free survival(PFS) after first-line EGFR-TKI treatment(14.4 vs.11.4 months,P = 0.034) compared with those with L858 R mutations.However,no statistically significant difference in overall survival(OS) was observed between the two groups of patients.T790 M mutation status was analyzed in 88 patients before EGFR-TKI treatment and 134 after EGFR-TKI treatment,and there was no significant difference in the co-existence of T790 M mutation with EGFR 19 del and L858 R mutations before EGFR-TKI treatment(5.6%vs.8.8%,P = 0.554)or after treatment(24.4%vs.35.4%,P = 0.176).In addition,24 patients with EGFR 19 del and 19 with L858 R mutations were analyzed by NGS,and no significant difference in the presence of multiple somatic mutations was observed between the two genotypes.Conclusions:Patients with EGFR 19 del exhibit longer PFS and higher ORR compared with those with L858 R mutations.Whether the heterogeneity of tumors with EGFR 19 del and L858 R mutations contribute to a therapeutic response difference needs further investigation. Background: Epidermal growth factor receptor (EGFR) mutations, including a known exon 19 deletion (19 del) and exon 21 L858 R point mutation (L858R mutation), are strong predictors of the response to EGFR tyrosine kinase inhibitor (EGFR-TKI) treatment in lung adenocarcinoma. Despite patients carrying EGFR 19 del and L858 R mutations exhibit different responsiveness to EGFR-TKls and what are the potential mechanisms for this difference remain controversial. This study aims to investigate the clinical outcomes of EGFR-TKI treatment in patients with EGFR 19 del and L858 R mutations and explore the genetic heterogeneity of tumors with the two mutation subtypes. Methods: Of 1127 patients with advanced lung adenocarcinoma harboring EGFR 19 del or L858 R mutations, 532 received EGFR-TKI treatment and were included in this study. EGFR 19 del and L858 R mutations were detected by using denaturing high-performance liquid chromatography (DHPLC). T790 M mutation, which is a common resistant mutation on ex on 20 of EGFR, was detected by amplification refractory mutation system (ARMS) .Next-generation sequencing (NGS) was used to explore the genetic heterogeneity of tumors with EGFR 19 del and L858 R mutations. Results: Of the 532 patients, 319 60.0% had had EGFR 19 del and 213 (40.0%) had L858 R mutations. These patients with EGFR 19 del presented a significant higher overall response rate (ORR) for EGFR-TKI treatment (55.2% vs. 43.7%, P = 0.017) and had a longer progression-free survival (PFS) after first-line EGFR-TKI treatment (14.4 vs.11.4 months, P = 0.034) compared with those with L858 R mutations. OS) was observed between the two groups of patients. T790 M mutation status was analyzed in 88 patients before EGFR-TKI treatment and 134 after EGFR-TKI treatment, and there was no significant difference in the co-existence of T790 M mutation with EGFR 19 del and L858 R mutations before EGFR-TKI treatment (5.6% vs.8.8%, P = 0.554) or after treatment (24.4% vs.35.4%, P = 0.176) .In addition, 24 patients with EGFR 19 del and 19 with L858 R mutations were analyzed by NGS, and no significant difference in the presence of multiple somatic mutations was observed between the two genotypes. Patients with EGFR 19 del exhibit longer PFS and higher ORR compared with those with L858 R mutations. Hether the heterogeneity of tumors with EGFR 19 del and L858 R mutations contribute to a therapeutic response difference needs further investigation.