title: Comprehensive pharmacogenetic profiling of the epidermal growth factor receptor pathway for biomarkers of response to, and toxicity from, cetuximab.
abstract: Somatic mutations in the epidermal growth factor receptor (EGFR) intracellular signalling pathways predict non-response to cetuximab in the treatment of advanced colorectal cancer (aCRC). We hypothesised that common germline variants within these pathways may also play similar roles.
  
  
  
  We analysed 54 potentially functional, common, inherited EGFR pathway variants in 815 patients with aCRC treated with oxaliplatin-fluoropyrimidine chemotherapy plus cetuximab. Primary endpoints were response and skin rash (SR). We had >85% power to detect ORs=1.6 for variants with minor allele frequencies >20%.
  
  
  
  We identified five potential biomarkers for response and four for SR, although none remained significant after correction for multiple testing. Our initial data supported a role for Ser313Pro inPIK3R2in modulating response to cetuximab-in patients withKRASwild-type CRCs, 36.4% with one allele encoding proline responded, as compared with 71.2% homozygous for allele encoding serine (OR 0.23, 95% CI 0.09 to 0.56, p=0.0014), and this association was predictive for cetuximab (pinteraction=0.017); however, independent replication failed to validate this association. No previously proposed predictive biomarkers were validated.
  
  
  
  Our study highlights the need to validate potential pharmacogenetic biomarkers. We did not find strong evidence for common germline biomarkers of cetuximab response and toxicity.
authors.affiliation: Division of Cancer and Genetics, School of Medicine, Cardiff University, Heath Park, Cardiff, UK.
authors.forename: Ayman
authors.initials: A
authors.lastname: Madi
authors.affiliation: MRC Clinical Trials Unit, London, UK.
authors.forename: David
authors.initials: D
authors.lastname: Fisher
authors.affiliation: Division of Cancer and Genetics, School of Medicine, Cardiff University, Heath Park, Cardiff, UK.
authors.forename: Timothy S
authors.initials: TS
authors.lastname: Maughan
authors.affiliation: Division of Cancer and Genetics, School of Medicine, Cardiff University, Heath Park, Cardiff, UK.
authors.forename: James P
authors.initials: JP
authors.lastname: Colley
authors.affiliation: MRC Clinical Trials Unit, London, UK.
authors.forename: Angela M
authors.initials: AM
authors.lastname: Meade
authors.affiliation: Laboratory of Molecular Digestive Oncology, Department of Oncology, Katholieke Universiteit Leuven, Leuven, Belgium.
authors.forename: Sabine
authors.initials: S
authors.lastname: Tejpar
authors.affiliation: Laboratory of Molecular Digestive Oncology, Department of Oncology, Katholieke Universiteit Leuven, Leuven, Belgium.
authors.forename: Ben
authors.initials: B
authors.lastname: Van den Bosch
authors.affiliation: Division of Cancer and Genetics, School of Medicine, Cardiff University, Heath Park, Cardiff, UK.
authors.forename: Julie
authors.initials: J
authors.lastname: Maynard
authors.affiliation: Division of Cancer and Genetics, School of Medicine, Cardiff University, Heath Park, Cardiff, UK.
authors.forename: Vikki
authors.initials: V
authors.lastname: Humphreys
authors.affiliation: Imperial College Healthcare NHS Trust, Hammersmith Hospital, London, UK.
authors.forename: Harpreet
authors.initials: H
authors.lastname: Wasan
authors.affiliation: Division of Cancer and Genetics, School of Medicine, Cardiff University, Heath Park, Cardiff, UK.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Adams
authors.affiliation: Division of Cancer and Genetics, School of Medicine, Cardiff University, Heath Park, Cardiff, UK.
authors.forename: Shelley
authors.initials: S
authors.lastname: Idziaszczyk
authors.affiliation: Division of Cancer and Genetics, School of Medicine, Cardiff University, Heath Park, Cardiff, UK.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Harris
authors.affiliation: MRC Clinical Trials Unit, London, UK.
authors.forename: Richard S
authors.initials: RS
authors.lastname: Kaplan
authors.affiliation: Division of Cancer and Genetics, School of Medicine, Cardiff University, Heath Park, Cardiff, UK.
authors.forename: Jeremy P
authors.initials: JP
authors.lastname: Cheadle
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D054316:Biomarkers, Pharmacological; D000068818:Cetuximab / Q000627:therapeutic use*; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D066246:ErbB Receptors / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D018095:Germ-Line Mutation; D006801:Humans; D008297:Male; D008875:Middle Aged; D009944:Organoplatinum Compounds / Q000627:therapeutic use*; D000077150:Oxaliplatin; D000071184:Pharmacogenomic Variants / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D054316:Biomarkers, Pharmacological; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; C512478:EGFR protein, human; D066246:ErbB Receptors; D000068818:Cetuximab
keywords: Pharmacogenetics; biomarkers.; cetuximab; colorectal cancer