Pretreatment epidermal growth factor receptor (EGFR) T790M mutation predicts shorter EGFR tyrosine kinase inhibitor response duration in patients with non-small-cell lung cancer.
OBJECTIVE
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.


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).


CONCLUSIONS
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.
Institute of Statistical Science, Academia Sinica, Taipei, Taiwan.
Kang-Yi
KY
Su
Hsuan-Yu
HY
Chen
Ker-Chau
KC
Li
Min-Liang
ML
Kuo
James Chih-Hsin
JC
Yang
Wing-Kai
WK
Chan
Bing-Ching
BC
Ho
Gee-Chen
GC
Chang
Jin-Yuan
JY
Shih
Sung-Liang
SL
Yu
Pan-Chyr
PC
Yang
D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics*; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics; D008297:Male; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D016896:Treatment Outcome
D047428:Protein Kinase Inhibitors; D066246:ErbB Receptors