title: Molecular characteristics predict clinical outcomes: prospective trial correlating response to the EGFR tyrosine kinase inhibitor gefitinib with the presence of sensitizing mutations in the tyrosine binding domain of the EGFR gene.
abstract: OBJECTIVE
  To determine if tumor regression following treatment with gefitinib correlates with the presence of sensitizing mutations in epidermal growth factor receptor (EGFR).
  
  
  METHODS
  Patients with resectable stage I and II non-small cell lung cancer (NSCLC) enriched for the likelihood of EGFR mutation (≤ 15 pack-year cigarette smoking history and/or a component of bronchioloalveolar carcinoma) received preoperative gefitinib for 21 days. Tumor specimens were analyzed for EGFR and KRAS mutations and EGFR protein expression and amplification. Patients with 25% or more reduction in tumor size measured bidimensionally at 3 weeks and/or patients with an EGFR mutation received adjuvant gefitinib for 2 years postoperatively.
  
  
  RESULTS
  Fifty patients with stage I/II NSCLC were treated. After 21 days of preoperative gefitinib a response of 25% or more was observed in 21 of 50 (42%) patients. Seventeen of 21 patients with a response had an EGFR mutation and 4 of 21 patients with a response did not (P = 0.0001). Twenty-five of 50 patients were eligible to receive adjuvant gefitinib. With a median follow-up of 44.1 months, 2-year disease free survival for EGFR mutant patients and for those who received adjuvant gefitinib was not statistically different than those who were EGFR wild-type and those who did not receive adjuvant gefitinib. The median disease free and overall survivals have not been reached.
  
  
  CONCLUSIONS
  The presence of sensitizing EGFR mutations correlates with radiographic response. A short course of preoperative treatment serves a platform for evaluating activity of new agents and assures sufficient tumor availability for correlative analyses.
authors.affiliation: Thoracic Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan-Kettering Cancer Center and Weill Medical College of Cornell University, New York, New York 10021, USA. rizvin@mskcc.org
authors.forename: Naiyer A
authors.initials: NA
authors.lastname: Rizvi
authors.forename: Valerie
authors.initials: V
authors.lastname: Rusch
authors.forename: William
authors.initials: W
authors.lastname: Pao
authors.forename: Jamie E
authors.initials: JE
authors.lastname: Chaft
authors.forename: Marc
authors.initials: M
authors.lastname: Ladanyi
authors.forename: Vincent A
authors.initials: VA
authors.lastname: Miller
authors.forename: Lee M
authors.initials: LM
authors.lastname: Krug
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Azzoli
authors.forename: Manjit
authors.initials: M
authors.lastname: Bains
authors.forename: Robert
authors.initials: R
authors.lastname: Downey
authors.forename: Raja
authors.initials: R
authors.lastname: Flores
authors.forename: Bernard
authors.initials: B
authors.lastname: Park
authors.forename: Bhuvanesh
authors.initials: B
authors.lastname: Singh
authors.forename: Maureen
authors.initials: M
authors.lastname: Zakowski
authors.forename: Robert T
authors.initials: RT
authors.lastname: Heelan
authors.forename: Ronglai
authors.initials: R
authors.lastname: Shen
authors.forename: Mark G
authors.initials: MG
authors.lastname: Kris
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002289:Carcinoma, Non-Small-Cell Lung / Q000175:diagnosis* / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality; D020134:Catalytic Domain / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics; D005260:Female; D000077156:Gefitinib; D018773:Genes, erbB-1 / Q000235:genetics* / Q000502:physiology; D006801:Humans; D008175:Lung Neoplasms / Q000175:diagnosis* / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000502:physiology; D011379:Prognosis; D011485:Protein Binding / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D011799:Quinazolines / Q000627:therapeutic use*; D016019:Survival Analysis; D016896:Treatment Outcome; D014443:Tyrosine / Q000378:metabolism
chemical_list: D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D014443:Tyrosine; D066246:ErbB Receptors; D000077156:Gefitinib