title: Epiregulin gene expression as a biomarker of benefit from cetuximab in the treatment of advanced colorectal cancer.
abstract: BACKGROUND
  Anti-EGFR antibody, cetuximab, improves overall survival (OS) in K-ras wild-type chemotherapy-refractory colorectal cancer. Epidermal growth factor receptor ligand epiregulin (EREG) gene expression may further predict cetuximab benefit.
  
  
  METHODS
  Tumour samples from a phase III clinical trial of cetuximab plus best supportive care (BSC) vs BSC alone (CO.17) were analysed for EREG mRNA gene expression. Predictive effects of high vs low EREG on OS and progression-free survival (PFS) were examined for treatment-biomarker interaction.
  
  
  RESULTS
  Both EREG and K-ras status were ascertained in 385 (193 cetuximab, 192 BSC) tumour samples. Within the high EREG and K-ras wild-type status ('co-biomarker')-positive group (n=139, 36%), median PFS was 5.4 vs 1.9 months (hazard ratio (HR) 0.31; P<0.0001), and median OS was 9.8 vs 5.1 months (HR 0.43; P<0.001) for cetuximab vs BSC, respectively. In the rest (n=246, 64%), PFS (HR 0.82; P=0.12) and OS (HR 0.90; P=0.45) were not significantly different. Test for treatment interaction showed a larger cetuximab effect on OS (HR 0.52; P=0.007) and PFS (HR 0.49; P=0.001) in the co-biomarker-positive group.
  
  
  CONCLUSIONS
  In pre-treated K-ras wild-type status colorectal cancer, patients with high EREG gene expression appear to benefit more from cetuximab therapy compared with low expression. Epiregulin as a selective biomarker requires further evaluation.
authors: The Ottawa Hospital Research Institute, University of Ottawa, 501 Smyth Road, Ottawa, ON K1H 8L6, Canada.
authors: D J
authors: DJ
authors: Jonker
authors: Flinders Medical Centre and Flinders University, Flinders Drive, Bedford Park, Adelaide, SA 5042, Australia.
authors: C S
authors: CS
authors: Karapetis
authors: Research and Development, Bristol-Myers Squibb, 100 Nassau Park Boulevard, Princeton, NJ 08540, USA.
authors: C
authors: C
authors: Harbison
authors: NCIC - Clinical Trials Group, Queens University, Cancer Research Institute, 10 Stuart Street, Kingston, ON K7P 3E3, Canada.
authors: C J
authors: CJ
authors: O'Callaghan
authors: NCIC - Clinical Trials Group, Queens University, Cancer Research Institute, 10 Stuart Street, Kingston, ON K7P 3E3, Canada.
authors: D
authors: D
authors: Tu
authors: National Health and Medical Research Council Clinical Trials Centre, University of Sydney, ABN 15 211 513 464, Camperdown, NSW 1450, Australia.
authors: R J
authors: RJ
authors: Simes
authors: Research and Development, Bristol-Myers Squibb, 100 Nassau Park Boulevard, Princeton, NJ 08540, USA.
authors: D P
authors: DP
authors: Malone
authors: Genetech Inc., 1 Dna Way, South San Francisco, CA 94080, USA.
authors: C
authors: C
authors: Langer
authors: Austin Health and University of Melbourne, 145 Studley Road, Heidelberg, VIC 3084, Australia.
authors: N
authors: N
authors: Tebbutt
authors: The Queen Elizabeth Hospital and University of Adelaide, 28 Woodville Road, Woodville South SA 5011, Australia.
authors: T J
authors: TJ
authors: Price
authors: Cabrini Hospital and Monash University, Isabella Street, Malvern, VIC 3144, Australia.
authors: J
authors: J
authors: Shapiro
authors: Princess Margaret Hospital and University of Toronto, 610 University Avenue, Suite 5-718, Toronto, ON M5G 2M9, Canada.
authors: L L
authors: LL
authors: Siu
authors: Cancercare Manitoba, St Boniface General Hospital, 409 Tache Avenue, Rm L1-102, Winnipeg, MB R2H 2A6, Canada.
authors: R P W
authors: RP
authors: Wong
authors: Sunnybrook Health Sciences Centre, University of Toronto, 2075 Bayview Avenue, Toronto, ON M4N 3M5, Canada.
authors: G
authors: G
authors: Bjarnason
authors: Princess Margaret Hospital and University of Toronto, 610 University Avenue, Suite 5-718, Toronto, ON M5G 2M9, Canada.
authors: M J
authors: MJ
authors: Moore
authors: Peter MacCallum Cancer Centre, Australasian Gastrointestinal Trials Group, University of Melbourne, 1 Street Andrews Place, East Melbourne, VIC 3002, Australia.
authors: J R
authors: JR
authors: Zalcberg
authors: Research and Development, Bristol-Myers Squibb, 100 Nassau Park Boulevard, Princeton, NJ 08540, USA.
authors: S
authors: S
authors: Khambata-Ford
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage*; D014408:Biomarkers, Tumor / Q000235:genetics; D000068818:Cetuximab; D017326:Clinical Trials, Phase III as Topic; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D018572:Disease-Free Survival; D004815:Epidermal Growth Factor / Q000096:biosynthesis* / Q000235:genetics; D066260:Epiregulin; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009367:Neoplasm Staging; D018631:ras Proteins / Q000235:genetics*
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D014408:Biomarkers, Tumor; C587880:EREG protein, human; D066260:Epiregulin; D004815:Epidermal Growth Factor; D018631:ras Proteins; D000068818:Cetuximab