title: Role of KRAS and EGFR as biomarkers of response to erlotinib in National Cancer Institute of Canada Clinical Trials Group Study BR.21.
abstract: OBJECTIVE
  To evaluate the effect of KRAS and epidermal growth factor receptor (EGFR) genotype on the response to erlotinib treatment in the BR.21, placebo-controlled trial.
  
  
  METHODS
  We analyzed 206 tumors for KRAS mutation, 204 tumors for EGFR mutation, and 159 tumors for EGFR gene copy by fluorescent in situ hybridization (FISH). We reanalyzed EGFR deletion/mutation using two highly sensitive techniques that detect abnormalities in samples with 5% to 10% tumor cellularity. KRAS mutation was analyzed by direct sequencing.
  
  
  RESULTS
  Thirty patients (15%) had KRAS mutations, 34 (17%) had EGFR exon 19 deletion or exon 21 L858R mutations, and 61 (38%) had high EGFR gene copy (FISH positive). Response rates were 10% for wild-type and 5% for mutant KRAS (P = .69), 7% for wild-type and 27% for mutant EGFR (P = .03), and 5% for EGFR FISH-negative and 21% for FISH-positive patients (P = .02). Significant survival benefit from erlotinib therapy was observed for patients with wild-type KRAS (hazard ratio [HR] = 0.69, P = .03) and EGFR FISH positivity (HR = 0.43, P = .004) but not for patients with mutant KRAS (HR = 1.67, P = .31), wild-type EGFR (HR = 0.74, P = .09), mutant EGFR (HR = 0.55, P = .12), and EGFR FISH negativity (HR = 0.80, P = .35). In multivariate analysis, only EGFR FISH-positive status was prognostic for poorer survival (P = .025) and predictive of differential survival benefit from erlotinib (P = .005).
  
  
  CONCLUSIONS
  EGFR mutations and high copy number are predictive of response to erlotinib. EGFR FISH is the strongest prognostic marker and a significant predictive marker of differential survival benefit from erlotinib.
authors.affiliation: FRCPC, Princess Margaret Hospital, 610 University Ave, Toronto, Ontario, Canada M5G 2M9; Ming.Tsao@uhn.on.ca.
authors.forename: Chang-Qi
authors.initials: CQ
authors.lastname: Zhu
authors.forename: Gilda
authors.initials: G
authors.lastname: da Cunha Santos
authors.forename: Keyue
authors.initials: K
authors.lastname: Ding
authors.forename: Akira
authors.initials: A
authors.lastname: Sakurada
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Cutz
authors.forename: Ni
authors.initials: N
authors.lastname: Liu
authors.forename: Tong
authors.initials: T
authors.lastname: Zhang
authors.forename: Paula
authors.initials: P
authors.lastname: Marrano
authors.forename: Marlo
authors.initials: M
authors.lastname: Whitehead
authors.forename: Jeremy A
authors.initials: JA
authors.lastname: Squire
authors.forename: Suzanne
authors.initials: S
authors.lastname: Kamel-Reid
authors.forename: Lesley
authors.initials: L
authors.lastname: Seymour
authors.forename: Frances A
authors.initials: FA
authors.lastname: Shepherd
authors.forename: Ming-Sound
authors.initials: MS
authors.lastname: Tsao
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002170:Canada; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D000069347:Erlotinib Hydrochloride; D005260:Female; D018773:Genes, erbB-1 / Q000235:genetics*; D005838:Genotype; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011237:Predictive Value of Tests; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras); D011799:Quinazolines / Q000627:therapeutic use*; D016019:Survival Analysis; D018631:ras Proteins / Q000235:genetics*
chemical_list: D000970:Antineoplastic Agents; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D011799:Quinazolines; D000069347:Erlotinib Hydrochloride; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins