title: Primary resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in patients with non-small-cell lung cancer harboring TKI-sensitive EGFR mutations: an exploratory study.
abstract: BACKGROUND
  The mechanism of primary resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in EGFR-mutant non-small-cell lung cancer (NSCLC) has not been clearly understood.
  
  
  METHODS
  Eleven patients exhibiting primary resistance (disease progression <3 months) were identified among 197 consecutive NSCLC patients with TKI-sensitive EGFR mutations who received EGFR TKIs at Seoul National University Hospital. Treatment-naïve tumors were examined for concurrent genetic alterations using fluorescence in situ hybridization and targeted deep sequencing of cancer-related genes. Deletion polymorphism of Bcl-2-interacting mediator of cell death (BIM) gene was examined to validate its predictive role for TKI outcome.
  
  
  RESULTS
  The median progression-free survival (PFS) for patients receiving EGFR TKIs was 11.9 months, and the response rate 78.8%. Among the 11 patients exhibiting primary resistance, a de novo T790M mutation was identified in one patient, and two exhibited mesenchymal-epithelial transition amplification and anaplastic lymphoma kinase fusion. Targeted deep sequencing identified no recurrent, coexistent drivers of NSCLC. Survival analysis revealed that patients with recurrent disease after surgery had a longer PFS than those with initial stage IV disease. However, BIM deletion polymorphism, line of treatment, EGFR genotype, and smoking were not predictive of PFS for EGFR TKIs.
  
  
  CONCLUSIONS
  We identified coexistent genetic alterations of cancer-related genes that could explain primary resistance in a small proportion of patients. Our result suggests that the mechanism of primary resistance might be heterogeneous.
authors.affiliation: Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea.
authors.forename: J K
authors.initials: JK
authors.lastname: Lee
authors.forename: J-Y
authors.initials: JY
authors.lastname: Shin
authors.forename: S
authors.initials: S
authors.lastname: Kim
authors.forename: S
authors.initials: S
authors.lastname: Lee
authors.forename: C
authors.initials: C
authors.lastname: Park
authors.forename: J-Y
authors.initials: JY
authors.lastname: Kim
authors.forename: Y
authors.initials: Y
authors.lastname: Koh
authors.forename: B
authors.initials: B
authors.lastname: Keam
authors.forename: H S
authors.initials: HS
authors.lastname: Min
authors.forename: T M
authors.initials: TM
authors.lastname: Kim
authors.forename: Y-K
authors.initials: YK
authors.lastname: Jeon
authors.forename: D-W
authors.initials: DW
authors.lastname: Kim
authors.forename: D H
authors.initials: DH
authors.lastname: Chung
authors.forename: D S
authors.initials: DS
authors.lastname: Heo
authors.forename: S-H
authors.initials: SH
authors.lastname: Lee
authors.forename: J-I
authors.initials: JI
authors.lastname: Kim
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D051017:Apoptosis Regulatory Proteins / Q000235:genetics; D001483:Base Sequence; D000072224:Bcl-2-Like Protein 11; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics; D054338:Cell Transdifferentiation / Q000235:genetics; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics*; D000069347:Erlotinib Hydrochloride; D005260:Female; D000077156:Gefitinib; D005838:Genotype; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D008875:Middle Aged; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011518:Proto-Oncogene Proteins / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D011799:Quinazolines / Q000627:therapeutic use; D017422:Sequence Analysis, DNA; D017384:Sequence Deletion / Q000235:genetics
chemical_list: D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; D008565:Membrane Proteins; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011799:Quinazolines; D000069347:Erlotinib Hydrochloride; C512478:EGFR protein, human; D066246:ErbB Receptors; D000077156:Gefitinib
keywords: epidermal growth factor receptor mutation; erlotinib; gefitinib; primary resistance