title: Somatic profiling of the epidermal growth factor receptor pathway in tumors from patients with advanced colorectal cancer treated with chemotherapy ± cetuximab.
abstract: OBJECTIVE
  To study the somatic molecular profile of the EGF receptor (EGFR) pathway in advanced colorectal cancer, its relationship to prognosis, the site of the primary and metastases, and response to cetuximab.
  
  
  METHODS
  We used Sequenom and Pyrosequencing for high-throughput somatic profiling of the EGFR pathway in 1,976 tumors from patients with advanced colorectal cancer from the COIN trial (oxaliplatin and fluoropyrimidine chemotherapy ± cetuximab). Correlations between mutations, clinicopathologic, response, and survival data were carried out.
  
  
  RESULTS
  Sequenom and Pyrosequencing had 99.0% (9,961/10,063) genotype concordance. We identified 13 different KRAS mutations in 42.3% of advanced colorectal cancers, 2 BRAF mutations in 9.0%, 4 NRAS mutations in 3.6%, and 5 PIK3CA mutations in 12.7%. 4.2% of advanced colorectal cancers had microsatellite instability (MSI). KRAS and PIK3CA exon 9, but not exon 20, mutations cooccurred (P = 8.9 × 10(-4)) as did MSI and BRAF mutations (P = 5.3 × 10(-10)). KRAS mutations were associated with right colon cancers (P = 5.2 × 10(-5)) and BRAF mutations with right (P = 7.2 × 10(-5)) and transverse colon (P = 9.8 × 10(-6)) cancers. KRAS mutations were associated with lung-only metastases (P = 2.3 × 10(-4)), BRAF mutations with peritoneal (P = 9.2 × 10(-4)) and nodal-only (P = 3.7 × 10(-5)) metastases, and MSI (BRAF(WT)) with nodal-only metastases (P = 2.9 × 10(-4)). MSI (BRAF(WT)) was associated with worse survival (HR = 1.89, 95% CI 1.30-2.76, P = 8.5 × 10(-4)). No mutations, subsets of mutations, or MSI status were associated with response to cetuximab.
  
  
  CONCLUSIONS
  Our data support a functional cooperation between KRAS and PIK3CA in colorectal tumorigenesis and link somatic profiles to the sites of metastases. MSI was associated with poor prognosis in advanced disease, and no individual somatic profile was associated with response to cetuximab in COIN.
authors.affiliation: Institute of Cancer and Genetics, School of Medicine, Cardiff University, Cardiff, Wales, United Kingdom.
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Smith
authors.forename: David
authors.initials: D
authors.lastname: Fisher
authors.forename: Bart
authors.initials: B
authors.lastname: Claes
authors.forename: Timothy S
authors.initials: TS
authors.lastname: Maughan
authors.forename: Shelley
authors.initials: S
authors.lastname: Idziaszczyk
authors.forename: Gilian
authors.initials: G
authors.lastname: Peuteman
authors.forename: Rebecca
authors.initials: R
authors.lastname: Harris
authors.forename: Michelle D
authors.initials: MD
authors.lastname: James
authors.forename: Angela
authors.initials: A
authors.lastname: Meade
authors.forename: Bharat
authors.initials: B
authors.lastname: Jasani
authors.forename: Richard A
authors.initials: RA
authors.lastname: Adams
authors.forename: Sarah
authors.initials: S
authors.lastname: Kenny
authors.forename: Richard
authors.initials: R
authors.lastname: Kaplan
authors.forename: Diether
authors.initials: D
authors.lastname: Lambrechts
authors.forename: Jeremy P
authors.initials: JP
authors.lastname: Cheadle
mesh_terms: D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage; D014408:Biomarkers, Tumor / Q000235:genetics; D063646:Carcinogenesis / Q000235:genetics / Q000473:pathology; D000068818:Cetuximab; D058534:Class I Phosphatidylinositol 3-Kinases; D002986:Clinical Trials as Topic; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D066246:ErbB Receptors / Q000235:genetics*; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D053842:Microsatellite Instability; D009154:Mutation; D009362:Neoplasm Metastasis / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D009367:Neoplasm Staging; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics*; D011379:Prognosis; 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: D061067:Antibodies, Monoclonal, Humanized; D014408:Biomarkers, Tumor; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; D066246:ErbB Receptors; D048493:Proto-Oncogene Proteins B-raf; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins; D000068818:Cetuximab