title: Clinical usefulness of EGFR gene copy number as a predictive marker in colorectal cancer patients treated with cetuximab: a fluorescent in situ hybridization study.
abstract: OBJECTIVE
  To evaluate the usefulness and the pitfalls inherent to the assessment of the epidermal growth factor receptor (EGFR) gene copy number (GCN) by fluorescence in situ hybridization (FISH) for outcome prediction to cetuximab in metastatic colorectal cancer. The value of testing KRAS mutation status, in addition to EGFR GCN, was also explored.
  
  
  METHODS
  FISH analysis of 87 metastatic colorectal cancer patients treated with cetuximab was done, recording individual GCN per cell and using different samples per tumor. Performances of published cutoff points and different summaries of EGFR GCN distribution were assessed for response prediction.
  
  
  RESULTS
  In our data set, two published cutoff points performed less well than in their training set, yielding positive predictive values and negative predictive values between 40.0% and 48.3% and between 81.0% and 86.5%, respectively. Among summaries of GCN distribution explored, mean and right-tailed distribution of GCN yielded the highest performances. A mean EGFR GCN > or = 2.83 provided an area under the curve of 0.71. Important heterogeneity of repeated measures of mean EGFR GCN was observed within tumors (intraclass correlation, 0.61; within-class SD, 0.40), leading to potential misclassifications of FISH status in 7 of 18 (38.8%) patients if a cutoff point were used. In multivariable analysis, EGFR GCN testing provided significant information independent of the KRAS status to predict response (P = 0.016) and overall survival (P = 0.005).
  
  
  CONCLUSIONS
  We confirm the association between increased EGFR GCN and outcome after cetuximab. However, because of reproducibility concerns, any decision making based on published cutoff points is not warranted.
authors.affiliation: Digestive Oncology Unit, University Hospital Gasthuisberg, Leuven, Belgium.
authors.forename: Nicola
authors.initials: N
authors.lastname: Personeni
authors.forename: Steffen
authors.initials: S
authors.lastname: Fieuws
authors.forename: Hubert
authors.initials: H
authors.lastname: Piessevaux
authors.forename: Gert
authors.initials: G
authors.lastname: De Hertogh
authors.forename: Jef
authors.initials: J
authors.lastname: De Schutter
authors.forename: Bart
authors.initials: B
authors.lastname: Biesmans
authors.forename: Wendy
authors.initials: W
authors.lastname: De Roock
authors.forename: An
authors.initials: A
authors.lastname: Capoen
authors.forename: Maria
authors.initials: M
authors.lastname: Debiec-Rychter
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Van Laethem
authors.forename: Marc
authors.initials: M
authors.lastname: Peeters
authors.forename: Yves
authors.initials: Y
authors.lastname: Humblet
authors.forename: Eric
authors.initials: E
authors.lastname: Van Cutsem
authors.forename: Sabine
authors.initials: S
authors.lastname: Tejpar
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000068818:Cetuximab; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D018572:Disease-Free Survival; D005260:Female; D018628:Gene Dosage; D018773:Genes, erbB-1; D005819:Genetic Markers; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D008875:Middle Aged; D011379:Prognosis
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D005819:Genetic Markers; D000068818:Cetuximab