title: Tumour gene expression predicts response to cetuximab in patients with KRAS wild-type metastatic colorectal cancer.
abstract: BACKGROUND
  Although it is accepted that metastatic colorectal cancers (mCRCs) that carry activating mutations in KRAS are unresponsive to anti-epidermal growth factor receptor (EGFR) monoclonal antibodies, a significant fraction of KRAS wild-type (wt) mCRCs are also unresponsive to anti-EGFR therapy. Genes encoding EGFR ligands amphiregulin (AREG) and epiregulin (EREG) are promising gene expression-based markers but have not been incorporated into a test to dichotomise KRAS wt mCRC patients with respect to sensitivity to anti-EGFR treatment.
  
  
  METHODS
  We used RT-PCR to test 110 candidate gene expression markers in primary tumours from 144 KRAS wt mCRC patients who received monotherapy with the anti-EGFR antibody cetuximab. Results were correlated with multiple clinical endpoints: disease control, objective response, and progression-free survival (PFS).
  
  
  RESULTS
  Expression of many of the tested candidate genes, including EREG and AREG, strongly associate with all clinical endpoints. Using multivariate analysis with two-layer five-fold cross-validation, we constructed a four-gene predictive classifier. Strikingly, patients below the classifier cutpoint had PFS and disease control rates similar to those of patients with KRAS mutant mCRC.
  
  
  CONCLUSIONS
  Gene expression appears to identify KRAS wt mCRC patients who receive little benefit from cetuximab. It will be important to test this model in an independent validation study.
authors.affiliation: Genomic Health, Inc., 301 Penobscot Drive, Redwood City, CA, USA.
authors.forename: J B
authors.initials: JB
authors.lastname: Baker
authors.forename: D
authors.initials: D
authors.lastname: Dutta
authors.forename: D
authors.initials: D
authors.lastname: Watson
authors.forename: T
authors.initials: T
authors.lastname: Maddala
authors.forename: B M
authors.initials: BM
authors.lastname: Munneke
authors.forename: S
authors.initials: S
authors.lastname: Shak
authors.forename: E K
authors.initials: EK
authors.lastname: Rowinsky
authors.forename: L-A
authors.initials: LA
authors.lastname: Xu
authors.forename: C T
authors.initials: CT
authors.lastname: Harbison
authors.forename: E A
authors.initials: EA
authors.lastname: Clark
authors.forename: D J
authors.initials: DJ
authors.lastname: Mauro
authors.forename: S
authors.initials: S
authors.lastname: Khambata-Ford
mesh_terms: D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000627:therapeutic use; D000068818:Cetuximab; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000556:secondary; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D015870:Gene Expression; D006801:Humans; 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; D000970:Antineoplastic Agents; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins; D000068818:Cetuximab