title: Pooled analysis of the prognostic and predictive effects of KRAS mutation status and KRAS mutation subtype in early-stage resected non-small-cell lung cancer in four trials of adjuvant chemotherapy.
abstract: OBJECTIVE
  We undertook this analysis of KRAS mutation in four trials of adjuvant chemotherapy (ACT) versus observation (OBS) to clarify the prognostic/predictive roles of KRAS in non-small-cell lung cancer (NSCLC).
  
  
  METHODS
  KRAS mutation was determined in blinded fashion. Exploratory analyses were performed to characterize relationships between mutation status and subtype and survival outcomes using a multivariable Cox model.
  
  
  RESULTS
  Among 1,543 patients (763 OBS, 780 ACT), 300 had KRAS mutations (codon 12, n = 275; codon 13, n = 24; codon 14, n = 1). In OBS patients, there was no prognostic difference for overall survival for codon-12 (mutation v wild type [WT] hazard ratio [HR] = 1.04; 95% CI, 0.77 to 1.40) or codon-13 (HR = 1.01; 95% CI, 0.47 to 2.17) mutations. No significant benefit from ACT was observed for WT-KRAS (ACT v OBS HR = 0.89; 95% CI, 0.76 to 1.04; P = .15) or codon-12 mutations (HR = 0.95; 95% CI, 0.67 to 1.35; P = .77); with codon-13 mutations, ACT was deleterious (HR = 5.78; 95% CI, 2.06 to 16.2; P < .001; interaction P = .002). There was no prognostic effect for specific codon-12 amino acid substitution. The effect of ACT was variable among patients with codon-12 mutations: G12A or G12R (HR = 0.66; P = .48), G12C or G12V (HR = 0.94; P = .77) and G12D or G12S (HR = 1.39; P = .48; comparison of four HRs, including WT, interaction P = .76). OBS patients with KRAS-mutated tumors were more likely to develop second primary cancers (HR = 2.76, 95% CI, 1.34 to 5.70; P = .005) but not ACT patients (HR = 0.66; 95% CI, 0.25 to 1.75; P = .40; interaction, P = .02).
  
  
  CONCLUSIONS
  KRAS mutation status is not significantly prognostic. The potential interaction in patients with codon-13 mutations requires validation. At this time, KRAS status cannot be recommended to select patients with NSCLC for ACT.
authors: Department of Medical Oncology and Hematology, Princess Margaret Hospital, Room 5-103, 610 University Ave, Toronto, Ontario, Canada. frances.shepherd@uhn.on.ca
authors: Frances A
authors: FA
authors: Shepherd
authors: Caroline
authors: C
authors: Domerg
authors: Pierre
authors: P
authors: Hainaut
authors: Pasi A
authors: PA
authors: Jänne
authors: Jean-Pierre
authors: JP
authors: Pignon
authors: Stephen
authors: S
authors: Graziano
authors: Jean-Yves
authors: JY
authors: Douillard
authors: Elizabeth
authors: E
authors: Brambilla
authors: Thierry
authors: T
authors: Le Chevalier
authors: Lesley
authors: L
authors: Seymour
authors: Abderrahmane
authors: A
authors: Bourredjem
authors: Gwénaël
authors: G
authors: Le Teuff
authors: Robert
authors: R
authors: Pirker
authors: Martin
authors: M
authors: Filipits
authors: Rafael
authors: R
authors: Rosell
authors: Robert
authors: R
authors: Kratzke
authors: Bizhan
authors: B
authors: Bandarchi
authors: Xiaoli
authors: X
authors: Ma
authors: Marzia
authors: M
authors: Capelletti
authors: Jean-Charles
authors: JC
authors: Soria
authors: Ming-Sound
authors: MS
authors: Tsao
mesh_terms: D000368:Aged; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D017024:Chemotherapy, Adjuvant; D005788:Gene Pool; D011905:Genes, ras; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D009154:Mutation; D009367:Neoplasm Staging; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D016032:Randomized Controlled Trials as Topic; D018631:ras Proteins / Q000235:genetics; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins
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