title: Analysis of HER-3, insulin growth factor-1, nuclear factor-kB and epidermal growth factor receptor gene copy number in the prediction of clinical outcome for K-RAS wild-type colorectal cancer patients receiving irinotecan-cetuximab.
abstract: BACKGROUND
  A large proportion of colorectal cancer patients does not benefit from the use of anti-epidermal growth factor receptor (EGFR) treatment although in the absence of a mutation of the K-RAS gene. Preliminary observations suggested that HER-3, insulin-like growth factor-1 (IGF-1), nuclear factor-kB (NF-kB) and EGFR gene copy number (GCN) might identify patients not likely to benefit from anti-EGFR therapy. We tested the interaction between HER-3, IGF-1, NF-kB, EGFR GCN and K-RAS mutational analysis to verify the relative ability of these variables to identify a subgroup of patients more likely to benefit from EGFR-targeted treatment among those harbouring a K-RAS wild-type status.
  
  
  METHODS
  We retrospectively collected tumours from 168 patients with metastatic colorectal cancer treated with irinotecan-cetuximab. K-RAS was assessed with direct sequencing, EGFR amplification was assessed by chromogenic in situ hybridisation (CISH) and HER-3, IGF-1 and NF-kB were assessed by immunohistochemistry.
  
  
  RESULTS
  In patients with K-RAS wild-type tumours, the following molecular factors resulted independently associated with response rate: HER-3 [odds ratio (OR)=4.6, 95% confidence interval (CI) 1.8-13.6, P=0.02], IGF-1 (OR=4.2, 95% CI 2-10.2, P=0.003) and EGFR GCN (OR=4.1, 95% CI 1.9-26.2, P=0.04). These factors also independently correlated with overall survival as follows: HER-3 [hazard ratio (HR)=0.4, 95% CI 0.28-0.85, P=0.008], IGF-1 (HR=0.47, 95% CI 0.24-0.76, P<0.0001) and EGFR GCN (HR=0.59, 95% CI 0.22-0.89, P=0.04).
  
  
  CONCLUSIONS
  We believe that our data may help further composing the molecular mosaic of EGFR-resistant tumours. The role of HER-3, IGF-1 and CISH EGFR GCN should be prospectively validated in clinical trials investigating anti-EGFR treatment strategies in colorectal cancer patients.
authors: Department of Medical Oncology, United Hospitals, and Postgraduate School in Medical Oncology, University of Ancona, Ancona, Italy. marioscartozzi@libero.it
authors: M
authors: M
authors: Scartozzi
authors: R
authors: R
authors: Giampieri
authors: E
authors: E
authors: Maccaroni
authors: A
authors: A
authors: Mandolesi
authors: L
authors: L
authors: Giustini
authors: R
authors: R
authors: Silva
authors: A
authors: A
authors: Zaniboni
authors: T
authors: T
authors: Biscotti
authors: S
authors: S
authors: Biagetti
authors: E
authors: E
authors: Galizia
authors: F
authors: F
authors: Loupakis
authors: A
authors: A
authors: Falcone
authors: I
authors: I
authors: Bearzi
authors: S
authors: S
authors: Cascinu
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives; D000068818:Cetuximab; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D004252:DNA Mutational Analysis; D018572:Disease-Free Survival; D066246:ErbB Receptors / Q000235:genetics* / Q000378:metabolism; D005260:Female; D018628:Gene Dosage; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D000077146:Irinotecan; D053208:Kaplan-Meier Estimate; D008113:Liver Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality / Q000556:secondary; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D016328:NF-kappa B / Q000378:metabolism*; D016016:Proportional Hazards Models; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras); D020893:Receptor, ErbB-3 / Q000378:metabolism*; D012189:Retrospective Studies; D016896:Treatment Outcome; D018631:ras Proteins / Q000235:genetics*
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; C117307:KRAS protein, human; D016328:NF-kappa B; D011518:Proto-Oncogene Proteins; D007334:Insulin-Like Growth Factor I; D000077146:Irinotecan; D066246:ErbB Receptors; D020893:Receptor, ErbB-3; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins; D000068818:Cetuximab; D002166:Camptothecin