title: Mutant KRAS codon 12 and 13 alleles in patients with metastatic colorectal cancer: assessment as prognostic and predictive biomarkers of response to panitumumab.
abstract: OBJECTIVE
  Panitumumab, a fully human monoclonal antibody targeting the epidermal growth factor receptor (EGFR), has demonstrated significant improvements in progression-free survival (PFS) in patients with wild-type KRAS metastatic colorectal cancer (mCRC) in studies 20050203 (first line), 20050181 (second line), and 20020408 (monotherapy). Mutations in KRAS codons 12 and 13 are recognized biomarkers that predict lack of response to anti-EGFR antibody therapies. This retrospective analysis of three randomized phase III studies assessed the prognostic and predictive impact of individual mutant KRAS codon 12 and 13 alleles.
  
  
  METHODS
  Patients were randomly assigned 1:1 to FOLFOX4 (infusional fluorouracil, leucovorin, and oxaliplatin) in study 20050203, FOLFIRI (fluorouracil, leucovorin, and irinotecan) in study 20050181, or best supportive care in study 20020408 with or without panitumumab 6.0 mg/kg once every 2 weeks. In all, 441 (20050203), 486 (20050181), and 126 (20020408) patients with mutant KRAS codon 12 or 13 alleles were included in the analysis.
  
  
  RESULTS
  No mutant KRAS allele in patients treated on the control arm emerged as a consistent prognostic factor for PFS or overall survival (OS). In addition, no mutant KRAS allele was consistently identified as a predictive factor for PFS or OS in patients receiving panitumumab treatment. Significant interactions for individual mutant KRAS alleles were observed only in study 20050203 with G13D negatively and G12V positively associated with OS in the panitumumab-containing arm. Pooled analysis indicated that only G12A was associated with a negative predictive effect on OS.
  
  
  CONCLUSIONS
  In this retrospective analysis, results across three treatment regimens suggest that patients with mutant KRAS codon 12 or 13 mCRC tumors are unlikely to benefit from panitumumab therapy. Currently, panitumumab therapy should be limited to patients with wild-type KRAS mCRC.
authors.affiliation: Department of Oncology, Antwerp University Hospital, Edegem, Belgium. Marc.Peeters@uza.be
authors.forename: Marc
authors.initials: M
authors.lastname: Peeters
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Douillard
authors.forename: Eric
authors.initials: E
authors.lastname: Van Cutsem
authors.forename: Salvatore
authors.initials: S
authors.lastname: Siena
authors.forename: Kathy
authors.initials: K
authors.lastname: Zhang
authors.forename: Richard
authors.initials: R
authors.lastname: Williams
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Wiezorek
mesh_terms: D000483:Alleles; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000235:genetics; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives; D003062:Codon / Q000235:genetics; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005472:Fluorouracil / Q000008:administration & dosage; D005787:Gene Frequency; D006801:Humans; D000077146:Irinotecan; D002955:Leucovorin / Q000008:administration & dosage; D009154:Mutation; D009362:Neoplasm Metastasis; D009944:Organoplatinum Compounds / Q000008:administration & dosage; D017063:Outcome Assessment, Health Care; D000077150:Oxaliplatin; D000077544:Panitumumab; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras); D016032:Randomized Controlled Trials as Topic; D012189:Retrospective Studies; D016019:Survival Analysis; D018631:ras Proteins / Q000235:genetics*
chemical_list: D000911:Antibodies, Monoclonal; D014408:Biomarkers, Tumor; D003062:Codon; C117307:KRAS protein, human; D009944:Organoplatinum Compounds; D011518:Proto-Oncogene Proteins; D000077150:Oxaliplatin; D000077544:Panitumumab; D000077146:Irinotecan; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins; D002955:Leucovorin; D005472:Fluorouracil; D002166:Camptothecin