T790M and Acquired Resistance of Epidermal Growth Factor Receptor to Tyrosine Kinase Inhibitors in Patients with Lung Adenocarcinoma.

Abstract

Background: Activating mutations in the epidermal growth factor receptor (EGFR) are initially responsive to tyrosine kinase inhibitors (TKIs), but responses to TKIs is not permanent and drug resistance eventually happens for almost all patients. Subsequent studies found different resistance mechanisms, among which (EGFR) T790M mutation is the most important mechanism of TKI treatment failure. Using cell-free DNA (cfDNA) is a new way for diagnosing resistance mutations in EGFR. The aim of present study is to determine cfDNA-identified recurrence mutation rate and their association with clinical outcome in lung Adenocarcinoma patients.

Materials and methods: Patients who were diagnosed with metastatic adenocarcinoma of the lung and acquired resistance to TKIs were enrolled. The incidence of T790M positivity, overall survival (OS) and median duration of TKI treatment before progression was calculated. Polymerase chain reaction (PCR) and sequencing were used to identify the T790M mutation in cfDNA.

Results: The incidence of T790M mutations was higher in men, younger cases (<59 years), in patients with L858R primary mutation and never smokers although they were not significantly different (P-values= 041, 0.316, 0.316 and 0.158, respectively). There was significant longer OS in the Del19 subgroup than the L858R subgroup (p = 0.014). In multivariable analysis, significant longer OS was associated with younger age (<59 years) and primary EGFR mutation exon 19 (P-values= 0.028 and 0.050, respectively).

Conclusion: T790M mutations frequency may differ by ethnicity, genetic factors and EGFR primary mutations. Detecting T790M mutations in plasma is considered as an indicator of treatment with third generation EGFR-TKIs.