Pretreatment Epidermal Growth Factor Receptor (EGFR) T790M mutation predicts shorter EGFR tyrosine kinase inhibitor response duration in patients with non-small-cell lung cancer
Journal
Journal of Clinical Oncology
Journal Volume
30
Journal Issue
4
Pages
433-440
Date Issued
2012
Author(s)
Chen H.-Y.
Li K.-C.
Kuo M.-L.
Chan W.-K.
Ho B.-C.
Chang G.-C.
Abstract
Purpose: Patients with non-small-cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR)-activating mutations have excellent response to EGFR tyrosine kinase inhibitors (TKIs), but T790M mutation accounts for most TKI drug resistance. This study used highly sensitive methods to detect T790M before and after TKI therapy and investigated the association of T790M and its mutation frequencies with clinical outcome. Patients and Methods: Direct sequencing, matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) and next-generation sequencing (NGS) were used to assess T790M in the following two cohorts of patients with NSCLC: TKI-naive patients (n = 107) and TKI-treated patients (n = 85). Results were correlated with TKI treatment response and survival. Results: MALDI-TOF MS was highly sensitive in detecting and quantifying the frequency of EGFR-activating mutations and T790M (detection limits, 0.4% to 2.2%). MALDI-TOF MS identified more T790M than direct sequencing in TKI-naive patients with NSCLC (27 of 107 patients, 25.2% v three of 107 patients, 2.8%, respectively; P < .001) and in TKI-treated patients (before TKI: 23 of 73 patients, 31.5% v two of 73 patients, 2.7%, respectively; P < .001; and after TKI: 10 of 12 patients, 83.3% v four of 12 patients, 33.3%, respectively; P = .0143). The EGFR mutations and their frequencies were confirmed by NGS. T790M was an independent predictor of decreased progression-free survival (PFS) in patients with NSCLC who received TKI treatment (P < .05, multivariate Cox regression). Conclusion: T790M may not be a rare event before or after TKI therapy in patients with NSCLC with EGFR-activating mutations. The pretreatment T790M mutation was associated with shorter PFS with EGFR TKI therapy in patients with NSCLC. ? 2012 by American Society of Clinical Oncology.
SDGs
Other Subjects
epidermal growth factor receptor; protein tyrosine kinase inhibitor; article; controlled study; direct sequencing; female; gene frequency; gene mutation; gene sequence; human; human cell; lung non small cell cancer; major clinical study; male; matrix assisted laser desorption ionization time of flight mass spectrometry; next generation sequencing; priority journal; progression free survival; sensitivity and specificity; treatment duration; treatment response; Carcinoma, Non-Small-Cell Lung; Female; Humans; Lung Neoplasms; Male; Mutation; Protein Kinase Inhibitors; Receptor, Epidermal Growth Factor; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Treatment Outcome
Type
journal article