Abstract
BackgroundEpidermal growth factor receptor (EGFR) mutations, including a known exon 19 deletion (19 del) and exon 21 L858R 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 L858R mutations exhibit different responsiveness to EGFR-TKIs 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 L858R mutations and explore the genetic heterogeneity of tumors with the two mutation subtypes.MethodsOf 1127 patients with advanced lung adenocarcinoma harboring EGFR 19 del or L858R mutations, 532 received EGFR-TKI treatment and were included in this study. EGFR 19 del and L858R mutations were detected by using denaturing high-performance liquid chromatography (DHPLC). T790M 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 L858R mutations.ResultsOf the 532 patients, 319 (60.0%) had EGFR 19 del, and 213 (40.0%) had L858R 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 L858R mutations. However, no statistically significant difference in overall survival (OS) was observed between the two groups of patients. T790M 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 T790M mutation with EGFR 19 del and L858R 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 L858R mutations were analyzed by NGS, and no significant difference in the presence of multiple somatic mutations was observed between the two genotypes.ConclusionsPatients with EGFR 19 del exhibit longer PFS and higher ORR compared with those with L858R mutations. Whether the heterogeneity of tumors with EGFR 19 del and L858R mutations contribute to a therapeutic response difference needs further investigation.
Highlights
Epidermal growth factor receptor (EGFR) mutations, including a known exon 19 deletion (19 del) and exon 21 L858R point mutation (L858R mutation), are strong predictors of the response to EGFR tyrosine kinase inhibi‐ tor (EGFR-TKI) treatment in lung adenocarcinoma
Given the co-existence of uncommon mutations of EGFR including T790M mutation and other gene mutations might influence the efficacy of EGFR-TKI between these two sensitive groups [11, 12], we deeply explored the difference in heterogeneity between tumors with the two EGFR mutation subtypes
Patient population Among 1127 patients with histologically confirmed lung adenocarcinoma possessing either the EGFR 19 del or L858R mutation treated at the Peking University Cancer Hospital between April 2004 and September 2014, 532 patients treated with EGFR-TKIs were included in this study
Summary
Epidermal growth factor receptor (EGFR) mutations, including a known exon 19 deletion (19 del) and exon 21 L858R point mutation (L858R mutation), are strong predictors of the response to EGFR tyrosine kinase inhibi‐ tor (EGFR-TKI) treatment in lung adenocarcinoma. A series of phase III randomized-controlled trials (RCTs) have shown that patients with EGFRmutated NSCLC who received EGFR-TKI treatment had a higher objective response rate (ORR), longer progressionfree survival (PFS), and better quality of life (QoL) than those who received standard chemotherapy [7,8,9]. These studies did not report an overall survival (OS) benefit of EGFR-TKI therapy in NSCLC patients
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