title: Clinical outcome according to the level of preexisting epidermal growth factor receptor T790M mutation in patients with lung cancer harboring sensitive epidermal growth factor receptor mutations.
abstract: BACKGROUND
  Epidermal growth factor receptor (EGFR) T790M mutation drives acquired drug resistance to EGFR tyrosine kinase inhibitors (EGFR-TKIs) in patients with EGFR-mutant lung cancer. However, it was reported that this mutation may exist before drug exposure. The objective of the current study was to evaluate whether the clinical outcomes are affected by the percentage of preexisting T790M mutations within a tumor.
  
  
  METHODS
  Pretreatment tissues were collected from 124 patients with advanced non-small cell lung cancer with sensitizing EGFR mutations that were detected by direct sequencing. Genotyping for EGFR T790M mutation was further performed using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Patients who were positive for the T790M mutation were divided to 2 subgroups according to T790M mutant signal frequency.
  
  
  RESULTS
  The T790M mutation was found in 31 patients (25.0%). The T790M mutation frequency at which the risk of disease progression after therapy with EGFR-TKIs begins to increase was estimated to be 3.2%. The patients with T790M-positive tumors had a shorter time to disease progression after treatment with EGFR-TKIs (median, 6.3 months vs 11.5 months; P < .001) and overall survival (median, 16.1 months vs 26.5 months; P = .065) compared with those with T790M-negative tumors. Among the T790M-positive patients, the patients with high T790M frequency (9 patients) were found to have a shorter time to disease progression (median, 2.4 months vs 6.7 months; P = .009) and overall survival (median, 9.1 months vs 18.7 months; P = .018) compared with those with low T790M frequency (22 patients).
  
  
  CONCLUSIONS
  A preexisting EGFR T790M mutation was noted in 25% of patients with EGFR-mutant lung cancer. Patients with a high T790M mutation frequency had worse clinical outcomes to EGFR-TKIs than patients with a low T790M mutation frequency.
authors.affiliation: Lung Cancer Branch, Research Institute and Hospital, National Cancer Center, Goyang, Republic of Korea; Department of Medicine, Graduate School, Yonsei University, Seoul, Republic of Korea.
authors.forename: Youngjoo
authors.initials: Y
authors.lastname: Lee
authors.forename: Geon Kook
authors.initials: GK
authors.lastname: Lee
authors.forename: Yeon-Su
authors.initials: YS
authors.lastname: Lee
authors.forename: Wenji
authors.initials: W
authors.lastname: Zhang
authors.forename: Jung-Ah
authors.initials: JA
authors.lastname: Hwang
authors.forename: Byung-Ho
authors.initials: BH
authors.lastname: Nam
authors.forename: Seok Hyun
authors.initials: SH
authors.lastname: Kim
authors.forename: Joo-Hang
authors.initials: JH
authors.lastname: Kim
authors.forename: Tak
authors.initials: T
authors.lastname: Yun
authors.forename: Ji-Youn
authors.initials: JY
authors.lastname: Han
authors.forename: Heung Tae
authors.initials: HT
authors.lastname: Kim
authors.forename: Jin Soo
authors.initials: JS
authors.lastname: Lee
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D044466:Asian People / Q000235:genetics* / Q000706:statistics & numerical data; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000235:genetics*; D005260:Female; D000077156:Gefitinib; D005838:Genotype; D006801:Humans; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology; D008297:Male; D008715:Methionine; D008875:Middle Aged; D009154:Mutation; D009367:Neoplasm Staging; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011799:Quinazolines / Q000008:administration & dosage; D056910:Republic of Korea / Q000453:epidemiology; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D013912:Threonine; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured
chemical_list: D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D013912:Threonine; D008715:Methionine; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases; D000077156:Gefitinib
keywords: EGFR mutation; drug resistance; drug sensitivity; epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor; non-small cell lung cancer; sequencing