title: KRAS mutations are associated with inferior clinical outcome in patients with metastatic colorectal cancer, but are not predictive for benefit with cediranib.
abstract: OBJECTIVE
  The prognostic potential of KRAS mutations in advanced colorectal cancer (CRC) patients and the impact of KRAS mutation status on the effectiveness of chemotherapy or vascular endothelial growth factor (VEGF) signalling inhibitor therapy remain unclear. KRAS mutation status was evaluated retrospectively as a potential prognostic/predictive marker of clinical outcomes using tumour samples from patients with metastatic CRC receiving cediranib or placebo plus FOLFOX/XELOX in a Phase III trial (HORIZON II; NCT00399035).
  
  
  METHODS
  KRAS codon 12 and 13 mutation analyses were performed using a commercially available, allele-specific, amplification refractory mutation system (ARMS)-based polymerase chain reaction (PCR) assay. Retrospective analyses of progression-free survival (PFS) and overall survival (OS) according to KRAS mutation status were performed for patients randomised to cediranib 20mg or placebo.
  
  
  RESULTS
  KRAS status was determined in 599/1076 patients (cediranib 20mg, n=285/502; cediranib 30 mg, n=110/216; placebo, n=204/358). Baseline characteristics were similar across KRAS mutant (n=258; 24.0%), wild-type (n=341; 31.7%) and status unknown (n=477; 44.3%) groups. There was a trend towards improved PFS and OS in the wild-type versus mutant subgroups independent of treatment (cediranib 20 mg and placebo: PFS hazard ratio (HR)=0.85 [median PFS: wild-type=8.5 months; mutant=8.3 months]; OS HR=0.71 [median OS: wild-type=20.9 months; mutant=16.9 months]). Treatment effects were similar between KRAS subgroups for cediranib 20mg versus placebo (PFS: wild-type HR=0.78, mutant HR=0.82; OS: wild-type HR=0.92, mutant HR=1.01).
  
  
  CONCLUSIONS
  Data from this large randomised Phase III study show that KRAS codon 12/13 mutations have negative prognostic value in metastatic CRC patients receiving treatment with FOLFOX/XELOX, but KRAS mutation status is not predictive of treatment benefit with cediranib, using PFS or OS.
authors.affiliation: Former AstraZeneca (RDG), Macclesfield, UK.
authors.forename: John C
authors.initials: JC
authors.lastname: Smith
authors.forename: Laura
authors.initials: L
authors.lastname: Brooks
authors.forename: Paulo M
authors.initials: PM
authors.lastname: Hoff
authors.forename: Gael
authors.initials: G
authors.lastname: McWalter
authors.forename: Simon
authors.initials: S
authors.lastname: Dearden
authors.forename: Shethah R
authors.initials: SR
authors.lastname: Morgan
authors.forename: David
authors.initials: D
authors.lastname: Wilson
authors.forename: Jane D
authors.initials: JD
authors.lastname: Robertson
authors.forename: Juliane M
authors.initials: JM
authors.lastname: Jürgensmeier
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017326:Clinical Trials, Phase III as Topic; D003062:Codon / Q000235:genetics; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D004252:DNA Mutational Analysis; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009362:Neoplasm Metastasis; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras); D011799:Quinazolines / Q000008:administration & dosage; D016032:Randomized Controlled Trials as Topic; D012189:Retrospective Studies; D016896:Treatment Outcome; D018631:ras Proteins / Q000235:genetics*; D007211:Indoles
chemical_list: D003062:Codon; D011518:Proto-Oncogene Proteins; D016283:Proto-Oncogene Proteins p21(ras); D011799:Quinazolines; D018631:ras Proteins; C117307:KRAS protein, human; C500926:cediranib; D007211:Indoles