title: Pharmacogenomic and pharmacoproteomic studies of cetuximab in metastatic colorectal cancer: biomarker analysis of a phase I dose-escalation study.
abstract: OBJECTIVE
  This study assessed biomarkers for cetuximab efficacy in tissue samples collected during a phase I dose-escalation study exploring every second week administration of cetuximab as first-line therapy in patients with metastatic colorectal cancer (mCRC).
  
  
  METHODS
  Sixty-two patients received cetuximab monotherapy for 6 weeks, followed by cetuximab plus infusional fluorouracil, leucovorin, and irinotecan until disease progression. Patients in the control arm received cetuximab as a 400 mg/m(2) initial dose then 250 mg/m(2) per week; patients in the dose-escalation arms received 400 to 700 mg/m(2) every second week. Tumor and skin biopsies were taken for immunohistochemical and microarray expression analyses (tumor only) at baseline and week 4. Plasma was collected for proteomic analysis at baseline and week 4. KRAS tumor mutation status was assessed.
  
  
  RESULTS
  In subsets of paired skin samples from 35 patients, cetuximab treatment was associated with substantial downregulation of phospho(p)-EGFR, p-MAPK and proliferation and substantial upregulation of p27(Kip1) and p-STAT3 levels. No marked difference in these effects was noted for different schedules of administration and dose levels. In the cetuximab monotherapy phase, responses were seen only in patients whose tumors were wild-type for KRAS (eight of 29 v zero of 19 for KRAS mutant tumors; P = .015). Progression-free survival was longer for patients with KRAS wild-type compared with KRAS mutant tumors (log-rank P = .048). Genomics/proteomics analyses (42 and 45 patients, respectively) identified candidate biomarkers associated with response.
  
  
  CONCLUSIONS
  Biomarker analysis supported the functional equivalence of weekly and every second week administration of cetuximab and provided further confirmation that patients with KRAS wild-type mCRC were those most likely to benefit from cetuximab treatment.
authors.affiliation: Medical Oncology Department, Vall d'Hebron University Hospital, P. Vall d'Hebron, 119-129, 08035 Barcelona, Spain. jtabernero@vhebron.net
authors.forename: Josep
authors.initials: J
authors.lastname: Tabernero
authors.forename: Andres
authors.initials: A
authors.lastname: Cervantes
authors.forename: Fernando
authors.initials: F
authors.lastname: Rivera
authors.forename: Erika
authors.initials: E
authors.lastname: Martinelli
authors.forename: Federico
authors.initials: F
authors.lastname: Rojo
authors.forename: Anja
authors.initials: A
authors.lastname: von Heydebreck
authors.forename: Teresa
authors.initials: T
authors.lastname: Macarulla
authors.forename: Edith
authors.initials: E
authors.lastname: Rodriguez-Braun
authors.forename: Maria
authors.initials: M
authors.lastname: Eugenia Vega-Villegas
authors.forename: Stefanie
authors.initials: S
authors.lastname: Senger
authors.forename: Francisco Javier
authors.initials: FJ
authors.lastname: Ramos
authors.forename: Susana
authors.initials: S
authors.lastname: Roselló
authors.forename: Ilhan
authors.initials: I
authors.lastname: Celik
authors.forename: Christopher
authors.initials: C
authors.lastname: Stroh
authors.forename: José
authors.initials: J
authors.lastname: Baselga
authors.forename: Fortunato
authors.initials: F
authors.lastname: Ciardiello
mesh_terms: D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000032:analysis*; D000068818:Cetuximab; D015179:Colorectal Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D050760:Cyclin-Dependent Kinase Inhibitor p27; D066246:ErbB Receptors / Q000032:analysis / Q000037:antagonists & inhibitors*; D006801:Humans; D007150:Immunohistochemistry; D047908:Intracellular Signaling Peptides and Proteins / Q000032:analysis; D009154:Mutation; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000097:blood*; D020411:Oligonucleotide Array Sequence Analysis; D010597:Pharmacogenetics; D040901:Proteomics / Q000379:methods*; D011518:Proto-Oncogene Proteins / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins / Q000235:genetics
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D014408:Biomarkers, Tumor; C436291:CDKN1B protein, human; D047908:Intracellular Signaling Peptides and Proteins; C117307:KRAS protein, human; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D066246:ErbB Receptors; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins; D000068818:Cetuximab