title: FOLFOX4 Plus Cetuximab for Patients With Previously Untreated Metastatic Colorectal Cancer According to Tumor RAS and BRAF Mutation Status: Updated Analysis of the CECOG/CORE 1.2.002 Study.
abstract: BACKGROUND
  This updated analysis of the CECOG/CORE 1.2.002 study investigated the association between clinical outcome and RAS and BRAF mutations in metastatic colorectal cancer (mCRC) patients treated with FOLFOX4 plus cetuximab.
  
  
  METHODS
  Available DNA samples from CECOG/CORE 1.2.002 study patients with KRAS exon 2 wild type (wt) (at codons 12 and 13) tumors were screened for mutations at other loci in the KRAS and NRAS (RAS) coding regions by Sanger sequencing, and for BRAF codon 600 mutations by Sanger sequencing and pyrosequencing. Clinical outcome was compared among different mutation subgroups.
  
  
  RESULTS
  Of 152 KRAS wt mCRC patients, 148 were evaluable for RAS and BRAF mutation status. Eleven RAS mutations were detected in 10 patients' tumors (7%). BRAF mutations were detected in 14 patients' tumors (9%). RAS and BRAF tumor mutations were mutually exclusive. Compared with patients with RAS wt/BRAF wt tumors (n = 124; median overall survival, 28.5 months), those with RAS mutations (n = 10; median, 16.3 months; hazard ratio, 0.43; 95% confidence interval, 0.20-0.89; P = .020) or BRAF mutations (n = 14; median, 11.7 months; hazard ratio, 0.23; 95% confidence interval, 0.12-0.41; P < .0001) had worse overall survival, which remained significant (P < .04) when adjusting for differences in baseline characteristics among the mutation subgroups.
  
  
  CONCLUSIONS
  These findings support those from recent studies that RAS and BRAF mutations are associated with poor outcome in patients receiving an epidermal growth factor receptor-targeted monoclonal antibody in combination with oxaliplatin-based chemotherapy. Furthermore, mutation testing should not only include RAS codons 12 and 13 but should also be extended to the entire coding regions.
authors: Department of Surgery, Medical University of Vienna, Vienna, Austria.
authors: Klaus
authors: K
authors: Kaczirek
authors: Institutul Oncologic "Ion Chiricuta" and UMF "Iuliu Hatieganu," Cluj Napoca, Romania.
authors: Tudor E
authors: TE
authors: Ciuleanu
authors: University Hospital Zagreb/Rebro, Zagreb, Croatia.
authors: Damir
authors: D
authors: Vrbanec
authors: Department of Gynecology, Medical University of Vienna, Vienna, Austria.
authors: Erika
authors: E
authors: Marton
authors: Department of Biometrics IST GmbH, Mannheim, Germany.
authors: Diethelm
authors: D
authors: Messinger
authors: Institute of Pathology, Medical University of Graz, Graz, Austria.
authors: Bernadette
authors: B
authors: Liegl-Atzwanger
authors: Clinical Institute of Pathology, Medical University of Vienna, Vienna, Austria.
authors: Fritz
authors: F
authors: Wrba
authors: Central European Cooperative Oncology Group (CECOG).
authors: Regina
authors: R
authors: Knittelfelder
authors: Central European Cooperative Oncology Group (CECOG).
authors: Elisabeth
authors: E
authors: Lindner
authors: Department of Medicine I, Medical University of Vienna, Vienna, Austria.
authors: Christoph C
authors: CC
authors: Zielinski
authors: Department of Gynecology, Medical University of Vienna, Vienna, Austria. Electronic address: berthold.streubel@meduniwien.ac.at.
authors: Berthold
authors: B
authors: Streubel
authors: Department of Medicine I, Medical University of Vienna, Vienna, Austria.
authors: Thomas
authors: T
authors: Brodowicz
mesh_terms: D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D000068818:Cetuximab / Q000008:administration & dosage; D003062:Codon / Q000235:genetics; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality / Q000473:pathology; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D005500:Follow-Up Studies; D020558:GTP Phosphohydrolases / Q000235:genetics*; D006801:Humans; D002955:Leucovorin / Q000008:administration & dosage; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality / Q000556:secondary; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009367:Neoplasm Staging; D009944:Organoplatinum Compounds / Q000008:administration & dosage; D000077150:Oxaliplatin; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras); D012189:Retrospective Studies; D015996:Survival Rate; D018631:ras Proteins / Q000235:genetics*
chemical_list: D003062:Codon; C117307:KRAS protein, human; D008565:Membrane Proteins; D009944:Organoplatinum Compounds; D011518:Proto-Oncogene Proteins; D000077150:Oxaliplatin; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins; D000068818:Cetuximab; D002955:Leucovorin; D005472:Fluorouracil
keywords: BRAF mutation; Cetuximab; FOLFOX4; Metastatic colorectal cancer; RAS mutation