title: Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer.
abstract: BACKGROUND
  Patients with metastatic colorectal cancer that harbors KRAS mutations in exon 2 do not benefit from anti-epidermal growth factor receptor (EGFR) therapy. Other activating RAS mutations may also be negative predictive biomarkers for anti-EGFR therapy.
  
  
  METHODS
  In this prospective-retrospective analysis, we assessed the efficacy and safety of panitumumab plus oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) as compared with FOLFOX4 alone, according to RAS (KRAS or NRAS) or BRAF mutation status. A total of 639 patients who had metastatic colorectal cancer without KRAS mutations in exon 2 had results for at least one of the following: KRAS exon 3 or 4; NRAS exon 2, 3, or 4; or BRAF exon 15. The overall rate of ascertainment of RAS status was 90%.
  
  
  RESULTS
  Among 512 patients without RAS mutations, progression-free survival was 10.1 months with panitumumab-FOLFOX4 versus 7.9 months with FOLFOX4 alone (hazard ratio for progression or death with combination therapy, 0.72; 95% confidence interval [CI], 0.58 to 0.90; P=0.004). Overall survival was 26.0 months in the panitumumab-FOLFOX4 group versus 20.2 months in the FOLFOX4-alone group (hazard ratio for death, 0.78; 95% CI, 0.62 to 0.99; P=0.04). A total of 108 patients (17%) with nonmutated KRAS exon 2 had other RAS mutations. These mutations were associated with inferior progression-free survival and overall survival with panitumumab-FOLFOX4 treatment, which was consistent with the findings in patients with KRAS mutations in exon 2. BRAF mutations were a negative prognostic factor. No new safety signals were identified.
  
  
  CONCLUSIONS
  Additional RAS mutations predicted a lack of response in patients who received panitumumab-FOLFOX4. In patients who had metastatic colorectal cancer without RAS mutations, improvements in overall survival were observed with panitumumab-FOLFOX4 therapy. (Funded by Amgen and others; PRIME ClinicalTrials.gov number, NCT00364013.).
authors.affiliation: Institut de Cancérologie de l'Ouest (ICO) René Gauducheau, Nantes, France. jean-yves.douillard@ico.unicancer.fr
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Douillard
authors.forename: Kelly S
authors.initials: KS
authors.lastname: Oliner
authors.forename: Salvatore
authors.initials: S
authors.lastname: Siena
authors.forename: Josep
authors.initials: J
authors.lastname: Tabernero
authors.forename: Ronald
authors.initials: R
authors.lastname: Burkes
authors.forename: Mario
authors.initials: M
authors.lastname: Barugel
authors.forename: Yves
authors.initials: Y
authors.lastname: Humblet
authors.forename: Gyorgy
authors.initials: G
authors.lastname: Bodoky
authors.forename: David
authors.initials: D
authors.lastname: Cunningham
authors.forename: Jacek
authors.initials: J
authors.lastname: Jassem
authors.forename: Fernando
authors.initials: F
authors.lastname: Rivera
authors.forename: Ilona
authors.initials: I
authors.lastname: Kocákova
authors.forename: Paul
authors.initials: P
authors.lastname: Ruff
authors.forename: Maria
authors.initials: M
authors.lastname: Błasińska-Morawiec
authors.forename: Martin
authors.initials: M
authors.lastname: Šmakal
authors.forename: Jean Luc
authors.initials: JL
authors.lastname: Canon
authors.forename: Mark
authors.initials: M
authors.lastname: Rother
authors.forename: Richard
authors.initials: R
authors.lastname: Williams
authors.forename: Alan
authors.initials: A
authors.lastname: Rong
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Wiezorek
authors.forename: Roger
authors.initials: R
authors.lastname: Sidhu
authors.forename: Scott D
authors.initials: SD
authors.lastname: Patterson
mesh_terms: D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D018572:Disease-Free Survival; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D005472:Fluorouracil / Q000627:therapeutic use; D020558:GTP Phosphohydrolases / Q000235:genetics; D011905:Genes, ras; D006801:Humans; D002955:Leucovorin / Q000627:therapeutic use; D008565:Membrane Proteins / Q000235:genetics; D009154:Mutation; D009362:Neoplasm Metastasis; D009944:Organoplatinum Compounds / Q000627:therapeutic use; D000077544:Panitumumab; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins / Q000235:genetics*
chemical_list: D000911:Antibodies, Monoclonal; C117307:KRAS protein, human; D008565:Membrane Proteins; D009944:Organoplatinum Compounds; D011518:Proto-Oncogene Proteins; D000077544:Panitumumab; D066246:ErbB Receptors; 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; D002955:Leucovorin; D005472:Fluorouracil