title: Fluorouracil, leucovorin, and irinotecan plus cetuximab treatment and RAS mutations in colorectal cancer.
abstract: OBJECTIVE
  The phase III CRYSTAL study demonstrated that addition of cetuximab to fluorouracil, leucovorin, and irinotecan (FOLFIRI) significantly improved overall survival, progression-free survival, and objective response in the first-line treatment of patients with KRAS codon 12/13 (exon 2) wild-type metastatic colorectal cancer (mCRC). Outcome was reassessed in subgroups defined by extended RAS mutation testing.
  
  
  METHODS
  Existing DNA samples from KRAS exon 2 wild-type tumors from CRYSTAL study patients were reanalyzed for other RAS mutations in four additional KRAS codons (exons 3 and 4) and six NRAS codons (exons 2, 3, and 4) using beads, emulsion, amplification, and magnetics technology. No tissue microdissection was performed. A ≥ 5% mutant allele cutoff was used to call mutations.
  
  
  RESULTS
  Mutation status was evaluable in 430 (64.6%) of 666 patients with KRAS exon 2 wild-type tumors. Other RAS mutations were detected in 63 (14.7%) of 430 patients. In those with RAS wild-type tumors, a significant benefit across all efficacy end points was associated with the addition of cetuximab to FOLFIRI. In patients with other RAS tumor mutations, no difference in efficacy outcomes between treatment groups was seen. The safety profile in RAS subgroups was similar and in line with expectations.
  
  
  CONCLUSIONS
  In the first-line treatment of mCRC, patients with RAS wild-type tumors derived a significant benefit from the addition of cetuximab to FOLFIRI; patients with RAS tumor mutations did not. Molecular testing of tumors for all activating RAS mutations is essential before considering anti-epidermal growth factor receptor therapy, thereby allowing the further tailoring of cetuximab administration to maximize patient benefit.
authors.affiliation: Eric Van Cutsem and Sabine Tejpar, University Hospitals Leuven and Katholieke Universiteit Leuven, Leuven, Belgium; Heinz-Josef Lenz, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA; Claus-Henning Köhne, Klinikum Oldenburg, Oldenburg; Volker Heinemann, University Hospital Grosshadern, Munich; Ivan Melezínek, Frank Beier, and Christopher Stroh, Merck KGaA, Darmstadt, Germany; Philippe Rougier, Paris Descartes University, Hôpital Européen Georges Pompidou, Paris, France; J. Han van Krieken, Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands; and Fortunato Ciardiello, Second University of Naples, Naples, Italy. eric.vancutsem@uzleuven.be.
authors.forename: Eric
authors.initials: E
authors.lastname: Van Cutsem
authors.affiliation: Eric Van Cutsem and Sabine Tejpar, University Hospitals Leuven and Katholieke Universiteit Leuven, Leuven, Belgium; Heinz-Josef Lenz, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA; Claus-Henning Köhne, Klinikum Oldenburg, Oldenburg; Volker Heinemann, University Hospital Grosshadern, Munich; Ivan Melezínek, Frank Beier, and Christopher Stroh, Merck KGaA, Darmstadt, Germany; Philippe Rougier, Paris Descartes University, Hôpital Européen Georges Pompidou, Paris, France; J. Han van Krieken, Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands; and Fortunato Ciardiello, Second University of Naples, Naples, Italy.
authors.forename: Heinz-Josef
authors.initials: HJ
authors.lastname: Lenz
authors.affiliation: Eric Van Cutsem and Sabine Tejpar, University Hospitals Leuven and Katholieke Universiteit Leuven, Leuven, Belgium; Heinz-Josef Lenz, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA; Claus-Henning Köhne, Klinikum Oldenburg, Oldenburg; Volker Heinemann, University Hospital Grosshadern, Munich; Ivan Melezínek, Frank Beier, and Christopher Stroh, Merck KGaA, Darmstadt, Germany; Philippe Rougier, Paris Descartes University, Hôpital Européen Georges Pompidou, Paris, France; J. Han van Krieken, Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands; and Fortunato Ciardiello, Second University of Naples, Naples, Italy.
authors.forename: Claus-Henning
authors.initials: CH
authors.lastname: Köhne
authors.affiliation: Eric Van Cutsem and Sabine Tejpar, University Hospitals Leuven and Katholieke Universiteit Leuven, Leuven, Belgium; Heinz-Josef Lenz, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA; Claus-Henning Köhne, Klinikum Oldenburg, Oldenburg; Volker Heinemann, University Hospital Grosshadern, Munich; Ivan Melezínek, Frank Beier, and Christopher Stroh, Merck KGaA, Darmstadt, Germany; Philippe Rougier, Paris Descartes University, Hôpital Européen Georges Pompidou, Paris, France; J. Han van Krieken, Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands; and Fortunato Ciardiello, Second University of Naples, Naples, Italy.
authors.forename: Volker
authors.initials: V
authors.lastname: Heinemann
authors.affiliation: Eric Van Cutsem and Sabine Tejpar, University Hospitals Leuven and Katholieke Universiteit Leuven, Leuven, Belgium; Heinz-Josef Lenz, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA; Claus-Henning Köhne, Klinikum Oldenburg, Oldenburg; Volker Heinemann, University Hospital Grosshadern, Munich; Ivan Melezínek, Frank Beier, and Christopher Stroh, Merck KGaA, Darmstadt, Germany; Philippe Rougier, Paris Descartes University, Hôpital Européen Georges Pompidou, Paris, France; J. Han van Krieken, Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands; and Fortunato Ciardiello, Second University of Naples, Naples, Italy.
authors.forename: Sabine
authors.initials: S
authors.lastname: Tejpar
authors.affiliation: Eric Van Cutsem and Sabine Tejpar, University Hospitals Leuven and Katholieke Universiteit Leuven, Leuven, Belgium; Heinz-Josef Lenz, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA; Claus-Henning Köhne, Klinikum Oldenburg, Oldenburg; Volker Heinemann, University Hospital Grosshadern, Munich; Ivan Melezínek, Frank Beier, and Christopher Stroh, Merck KGaA, Darmstadt, Germany; Philippe Rougier, Paris Descartes University, Hôpital Européen Georges Pompidou, Paris, France; J. Han van Krieken, Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands; and Fortunato Ciardiello, Second University of Naples, Naples, Italy.
authors.forename: Ivan
authors.initials: I
authors.lastname: Melezínek
authors.affiliation: Eric Van Cutsem and Sabine Tejpar, University Hospitals Leuven and Katholieke Universiteit Leuven, Leuven, Belgium; Heinz-Josef Lenz, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA; Claus-Henning Köhne, Klinikum Oldenburg, Oldenburg; Volker Heinemann, University Hospital Grosshadern, Munich; Ivan Melezínek, Frank Beier, and Christopher Stroh, Merck KGaA, Darmstadt, Germany; Philippe Rougier, Paris Descartes University, Hôpital Européen Georges Pompidou, Paris, France; J. Han van Krieken, Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands; and Fortunato Ciardiello, Second University of Naples, Naples, Italy.
authors.forename: Frank
authors.initials: F
authors.lastname: Beier
authors.affiliation: Eric Van Cutsem and Sabine Tejpar, University Hospitals Leuven and Katholieke Universiteit Leuven, Leuven, Belgium; Heinz-Josef Lenz, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA; Claus-Henning Köhne, Klinikum Oldenburg, Oldenburg; Volker Heinemann, University Hospital Grosshadern, Munich; Ivan Melezínek, Frank Beier, and Christopher Stroh, Merck KGaA, Darmstadt, Germany; Philippe Rougier, Paris Descartes University, Hôpital Européen Georges Pompidou, Paris, France; J. Han van Krieken, Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands; and Fortunato Ciardiello, Second University of Naples, Naples, Italy.
authors.forename: Christopher
authors.initials: C
authors.lastname: Stroh
authors.affiliation: Eric Van Cutsem and Sabine Tejpar, University Hospitals Leuven and Katholieke Universiteit Leuven, Leuven, Belgium; Heinz-Josef Lenz, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA; Claus-Henning Köhne, Klinikum Oldenburg, Oldenburg; Volker Heinemann, University Hospital Grosshadern, Munich; Ivan Melezínek, Frank Beier, and Christopher Stroh, Merck KGaA, Darmstadt, Germany; Philippe Rougier, Paris Descartes University, Hôpital Européen Georges Pompidou, Paris, France; J. Han van Krieken, Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands; and Fortunato Ciardiello, Second University of Naples, Naples, Italy.
authors.forename: Philippe
authors.initials: P
authors.lastname: Rougier
authors.affiliation: Eric Van Cutsem and Sabine Tejpar, University Hospitals Leuven and Katholieke Universiteit Leuven, Leuven, Belgium; Heinz-Josef Lenz, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA; Claus-Henning Köhne, Klinikum Oldenburg, Oldenburg; Volker Heinemann, University Hospital Grosshadern, Munich; Ivan Melezínek, Frank Beier, and Christopher Stroh, Merck KGaA, Darmstadt, Germany; Philippe Rougier, Paris Descartes University, Hôpital Européen Georges Pompidou, Paris, France; J. Han van Krieken, Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands; and Fortunato Ciardiello, Second University of Naples, Naples, Italy.
authors.forename: J Han
authors.initials: JH
authors.lastname: van Krieken
authors.affiliation: Eric Van Cutsem and Sabine Tejpar, University Hospitals Leuven and Katholieke Universiteit Leuven, Leuven, Belgium; Heinz-Josef Lenz, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA; Claus-Henning Köhne, Klinikum Oldenburg, Oldenburg; Volker Heinemann, University Hospital Grosshadern, Munich; Ivan Melezínek, Frank Beier, and Christopher Stroh, Merck KGaA, Darmstadt, Germany; Philippe Rougier, Paris Descartes University, Hôpital Européen Georges Pompidou, Paris, France; J. Han van Krieken, Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands; and Fortunato Ciardiello, Second University of Naples, Naples, Italy.
authors.forename: Fortunato
authors.initials: F
authors.lastname: Ciardiello
mesh_terms: D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000378:metabolism; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives; D000068818:Cetuximab; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D018572:Disease-Free Survival; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D020558:GTP Phosphohydrolases / Q000235:genetics; D005820:Genetic Testing; D006801:Humans; D053208:Kaplan-Meier Estimate; D002955:Leucovorin / Q000008:administration & dosage; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D008875:Middle Aged; D058990:Molecular Targeted Therapy / Q000379:methods; D009154:Mutation; D011518:Proto-Oncogene Proteins / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D016896:Treatment Outcome; D018631:ras Proteins / Q000235:genetics*
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D014408:Biomarkers, Tumor; C117307:KRAS protein, human; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; C512478:EGFR protein, human; D066246:ErbB Receptors; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins; D000068818:Cetuximab; D002955:Leucovorin; D005472:Fluorouracil; D002166:Camptothecin