title: Distinct clinical course of EGFR-mutant resected lung cancers: results of testing of 1118 surgical specimens and effects of adjuvant gefitinib and erlotinib.
abstract: BACKGROUND
  EGFR and KRAS mutations are mutually exclusive and predict outcomes with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) treatment in patients with stage IV lung cancers. The clinical significance of these mutations in patients with resected stage I-III lung cancers is unclear.
  
  
  METHODS
  At our institution, resection specimens from patients with stage I-III lung adenocarcinomas are tested for the presence of EGFR or KRAS mutations during routine pathology analysis such that the results are available before consideration of adjuvant therapy. In a cohort of 1118 patients tested over 8 years, overall survival was analyzed using multivariate analysis to control for potential confounders, including age, sex, stage, and smoking history. The impact of adjuvant erlotinib or gefitinib was examined in an independent data set of patients exclusively with EGFR mutation, in which date of recurrence was recorded.
  
  
  RESULTS
  In the overall population, we identified 227 KRAS (25%) and 222 EGFR (20%) mutations. Patients with EGFR-mutant lung cancers had a lower risk of death compared with those without EGFR mutations, overall survival (OS) HR 0.51 (95% confidence interval [CI]: 0.34-0.76, p < 0.001). Patients with KRAS-mutant lung cancers had similar outcomes compared with individuals with KRAS wild-type tumors, OS HR 1.17 (95% CI: 0.87-1.57, p = 0.30). A separate data set includes only patients with EGFR-mutant lung cancers identified over 10 years (n = 286). In patients with resected lung cancers and EGFR mutation, treatment with adjuvant erlotinib or gefitinib was associated with a lower risk of recurrence or death, disease-free survival HR 0.43 (95% CI: 0.26-0.72, p = 0.001), and a trend toward improved OS.
  
  
  CONCLUSIONS
  Patients with resected stage I-III lung cancers and EGFR mutation have a lower risk of death compared with patients without EGFR mutation. This may be because of treatment with EGFR TKIs. Patients with, and without KRAS mutation have similar OS. These data support reflex testing of resected lung adenocarcinomas for EGFR mutation to provide prognostic information and identify patients for enrollment on prospective clinical trials of adjuvant EGFR TKIs.
authors.affiliation: Department of Medicine, Division of Solid Tumor Oncology, Thoracic Oncology Service, Memorial Sloan-Kettering Cancer Center and Weill Cornell Medical College, New York, New York.
authors.forename: Sandra P
authors.initials: SP
authors.lastname: D'Angelo
authors.affiliation: Department of Medicine, Division of Solid Tumor Oncology, Thoracic Oncology Service, Memorial Sloan-Kettering Cancer Center and Weill Cornell Medical College, New York, New York.
authors.forename: Yelena Y
authors.initials: YY
authors.lastname: Janjigian
authors.affiliation: Department of Medicine, Division of Solid Tumor Oncology, Thoracic Oncology Service, Memorial Sloan-Kettering Cancer Center and Weill Cornell Medical College, New York, New York.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Ahye
authors.affiliation: Department of Medicine, Division of Solid Tumor Oncology, Thoracic Oncology Service, Memorial Sloan-Kettering Cancer Center and Weill Cornell Medical College, New York, New York.
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Riely
authors.affiliation: Department of Medicine, Division of Solid Tumor Oncology, Thoracic Oncology Service, Memorial Sloan-Kettering Cancer Center and Weill Cornell Medical College, New York, New York. Electronic address: chaftj@mskcc.org.
authors.forename: Jamie E
authors.initials: JE
authors.lastname: Chaft
authors.affiliation: Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center and Weill Cornell Medical College, New York, New York.
authors.forename: Camelia S
authors.initials: CS
authors.lastname: Sima
authors.affiliation: Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center and Weill Cornell Medical College, New York, New York.
authors.forename: Ronglai
authors.initials: R
authors.lastname: Shen
authors.affiliation: Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center and Weill Cornell Medical College, New York, New York.
authors.forename: Junting
authors.initials: J
authors.lastname: Zheng
authors.affiliation: Department of Surgery, Memorial Sloan-Kettering Cancer Center and Weill Cornell Medical College, New York, New York.
authors.forename: Joseph
authors.initials: J
authors.lastname: Dycoco
authors.affiliation: Department of Medicine, Division of Solid Tumor Oncology, Thoracic Oncology Service, Memorial Sloan-Kettering Cancer Center and Weill Cornell Medical College, New York, New York.
authors.forename: Mark G
authors.initials: MG
authors.lastname: Kris
authors.affiliation: Department of Pathology, Memorial Sloan-Kettering Cancer Center and Weill Cornell Medical College, New York, New York.
authors.forename: Maureen F
authors.initials: MF
authors.lastname: Zakowski
authors.affiliation: Department of Pathology, Memorial Sloan-Kettering Cancer Center and Weill Cornell Medical College, New York, New York.
authors.forename: Marc
authors.initials: M
authors.lastname: Ladanyi
authors.affiliation: Department of Surgery, Memorial Sloan-Kettering Cancer Center and Weill Cornell Medical College, New York, New York.
authors.forename: Valerie
authors.initials: V
authors.lastname: Rusch
authors.affiliation: Department of Medicine, Division of Solid Tumor Oncology, Thoracic Oncology Service, Memorial Sloan-Kettering Cancer Center and Weill Cornell Medical College, New York, New York.
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Azzoli
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality / Q000601:surgery; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality / Q000601:surgery; D066246:ErbB Receptors / Q000235:genetics*; D000069347:Erlotinib Hydrochloride; D005260:Female; D005500:Follow-Up Studies; D000077156:Gefitinib; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality / Q000601:surgery; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009367:Neoplasm Staging; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D011799:Quinazolines / Q000008:administration & dosage; D012189:Retrospective Studies; D015996:Survival Rate; D055815:Young Adult; D018631:ras Proteins / Q000235:genetics
chemical_list: C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D011799:Quinazolines; D000069347:Erlotinib Hydrochloride; C512478:EGFR protein, human; D066246:ErbB Receptors; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins; D000077156:Gefitinib