title: The prognostic impact of KRAS, its codon and amino acid specific mutations, on survival in resected stage I lung adenocarcinoma.
abstract: BACKGROUND
  Despite complete surgical resection, patients with stage I non-small-cell lung cancer (NSCLC) are at risk for disease recurrence. The impact of common oncogenic driver mutations on prognosis in stage I NSCLC is limited. The pure prognostic value of KRAS mutational status was explored in resected stage I lung adenocarcinoma.
  
  
  METHODS
  Mutation status was tested in patients who had complete resection of stage I lung adenocarcinoma without any adjuvant therapy, using a multiplex polymerase chain reaction)-based assay. Disease-free survival (DFS) and overall survival (OS) were compared between patients with KRAS-mutant (KRAS-MUT), KRAS-MUT subtypes, and KRAS wild-type (KRAS-WT) tumors.
  
  
  RESULTS
  A total of 312 patients were included in this analysis; 127 harbored KRAS mutations and 185 had KRAS-WT tumors. When compared with KRAS-WT, KRAS-MUT was associated with significantly shorter OS (hazard ratio 4.36, 95% confidence interval 2.09-9.07; p < 0.0001) and DFS (hazard ratio 3.62, 95% confidence interval 2.11-6.22; p < 0.0001). When stratifying KRAS-WT patients based on EGFR status, KRAS-MUT patients had worse OS (p = 0.0001) and DFS (p < 0.0001) than patients with EGFR-MUT and EGFR-WT/KRAS-WT (WT/WT). Patients with codon 12 mutations had superior DFS (p = 0.0314), but there were no differences in OS compared with mutations found in codons 13 and 61 (p = 0.1772). We observed better DFS associated with G12C/G12V mutations compared with other amino acid specific KRAS mutations (p = 0.0271) with a trend towards improved OS (p = 0.0636). Multivariate analysis identified KRAS mutation as independent predictor of worse OS (p = 0.001) and DFS (p < 0.0001).
  
  
  CONCLUSIONS
  KRAS is an independent prognostic marker in resected stage I lung adenocarcinoma. Differential outcomes are associated with codon and amino acid specific KRAS mutations.
authors.affiliation: *Division of Hematology/Oncology, Department of Medicine; †Division of Thoracic Surgery; ‡Biostatistics Center; §Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston,Massachusetts; and ‖Department of Thoracic Surgery, Guangdong General Hospital, Southern Medical University, Guangdong, China.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Izar
authors.forename: Haiyu
authors.initials: H
authors.lastname: Zhou
authors.forename: Rebecca S
authors.initials: RS
authors.lastname: Heist
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Azzoli
authors.forename: Alona
authors.initials: A
authors.lastname: Muzikansky
authors.forename: Emily E F
authors.initials: EE
authors.lastname: Scribner
authors.forename: Lindsay A
authors.initials: LA
authors.lastname: Bernardo
authors.forename: Dora
authors.initials: D
authors.lastname: Dias-Santagata
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Iafrate
authors.forename: Michael
authors.initials: M
authors.lastname: Lanuti
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D000077192:Adenocarcinoma of Lung; D000368:Aged; D016001:Confidence Intervals; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm / Q000235:genetics*; D018572:Disease-Free Survival; D005260:Female; D005500:Follow-Up Studies; D005838:Genotype; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D008297:Male; D008404:Massachusetts / Q000453:epidemiology; D009154:Mutation; D009364:Neoplasm Recurrence, Local / Q000401:mortality* / Q000473:pathology; D009367:Neoplasm Staging; D011013:Pneumonectomy; D016133:Polymerase Chain Reaction; D011379:Prognosis; D016016:Proportional Hazards Models; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras); D012189:Retrospective Studies; D015996:Survival Rate / Q000639:trends; D018631:ras Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D004273:DNA, Neoplasm; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins