title: Analysis of tumor specimens at the time of acquired resistance to EGFR-TKI therapy in 155 patients with EGFR-mutant lung cancers.
abstract: OBJECTIVE
  All patients with EGF receptor (EGFR)-mutant lung cancers eventually develop acquired resistance to EGFR tyrosine kinase inhibitors (TKI). Smaller series have identified various mechanisms of resistance, but systematic evaluation of a large number of patients to definitively establish the frequency of various mechanisms has not been conducted.
  
  
  METHODS
  Patients with lung adenocarcinomas and acquired resistance to erlotinib or gefitinib enrolled onto a prospective biopsy protocol and underwent a rebiopsy after the development of acquired resistance. Histology was reviewed. Samples underwent genotyping for mutations in EGFR, AKT1, BRAF, ERBB2, KRAS, MEK1, NRAS and PIK3CA, and FISH for MET and HER2.
  
  
  RESULTS
  Adequate tumor samples for molecular analysis were obtained in 155 patients. Ninety-eight had second-site EGFR T790M mutations [63%; 95% confidence interval (CI), 55%-70%] and four had small cell transformation (3%, 95% CI, 0%-6%). MET amplification was seen in 4 of 75 (5%; 95% CI, 1%-13%). HER2 amplification was seen in 3 of 24 (13%; 95% CI, 3%-32%). We did not detect any acquired mutations in PIK3CA, AKT1, BRAF, ERBB2, KRAS, MEK1, or NRAS (0 of 88, 0%; 95% CI, 0%-4%). Overlap among mechanisms of acquired resistance was seen in 4%.
  
  
  CONCLUSIONS
  This is the largest series reporting mechanisms of acquired resistance to EGFR-TKI therapy. We identified EGFR T790M as the most common mechanism of acquired resistance, whereas MET amplification, HER2 amplification, and small cell histologic transformation occur less frequently. More comprehensive methods to characterize molecular alterations in this setting are needed to improve our understanding of acquired resistance to EGFR-TKIs.
authors.affiliation: Thoracic Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: Helena A
authors.initials: HA
authors.lastname: Yu
authors.forename: Maria E
authors.initials: ME
authors.lastname: Arcila
authors.forename: Natasha
authors.initials: N
authors.lastname: Rekhtman
authors.forename: Camelia S
authors.initials: CS
authors.lastname: Sima
authors.forename: Maureen F
authors.initials: MF
authors.lastname: Zakowski
authors.forename: William
authors.initials: W
authors.lastname: Pao
authors.forename: Mark G
authors.initials: MG
authors.lastname: Kris
authors.forename: Vincent A
authors.initials: VA
authors.lastname: Miller
authors.forename: Marc
authors.initials: M
authors.lastname: Ladanyi
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Riely
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001706:Biopsy; D019002:CD56 Antigen / Q000032:analysis; D004252:DNA Mutational Analysis / Q000379:methods; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics; D000069347:Erlotinib Hydrochloride; D005260:Female; D000077156:Gefitinib; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D053208:Kaplan-Meier Estimate; D019394:Ki-67 Antigen / Q000032:analysis; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics; D011799:Quinazolines / Q000627:therapeutic use; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics
chemical_list: D019002:CD56 Antigen; D066246:ErbB Receptors; D000069347:Erlotinib Hydrochloride; D000077156:Gefitinib; D019394:Ki-67 Antigen; D047428:Protein Kinase Inhibitors; D019859:Proto-Oncogene Proteins c-met; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; C508053:ERBB2 protein, human; C491743:MET protein, human