title: Epidermal growth factor receptor (EGFR) and prostaglandin-endoperoxide synthase 2 (PTGS2) are prognostic biomarkers for patients with resected colorectal cancer liver metastases.
abstract: BACKGROUND
  Resection of colorectal cancer liver metastasis (CRCLM) with curative intent has long-term benefit in ~40% of cases. Prognostic biomarkers are needed to improve clinical management and reduce futile surgeries. Expression of epidermal growth factor receptor (EGFR) and prostaglandin-endoperoxide synthase 2 (PTGS2; also known as cyclooxygenase-2) has been associated with carcinogenesis and survival. We investigated the prognostic value of EGFR and PTGS2 expression in patients with resected CRCLM.
  
  
  METHODS
  Formalin-fixed paraffin-embedded CRCLM tissue and corresponding primary tumour specimens from a multi-institutional cohort of patients who underwent liver resection between 1990 and 2010 were incorporated into tissue microarrays (TMAs). TMAs were stained for EGFR and PTGS2 by immunohistochemistry. The hazard rate ratio (HRR) for the association between expression in CRCLM and overall survival was calculated using a 500-fold cross-validation procedure.
  
  
  RESULTS
  EGFR and PTGS2 expression could be evaluated in 323 and 351 patients, respectively. EGFR expression in CRCLM was associated with poor prognosis (HRR 1.54; P<0.01) with a cross-validated HRR of 1.47 (P=0.03). PTGS2 expression was also associated with poor prognosis (HRR 1.60; P<0.01) with a cross-validated HRR of 1.63 (P<0.01). Expression of EGFR and PTGS2 remained prognostic after multivariate analysis with standard clinicopathological variables (cross-validated HRR 1.51; P=0.02 and cross-validated HRR 1.59; P=0.01, respectively). Stratification for the commonly applied systemic therapy regimens demonstrated prognostic value for EGFR and PTGS2 only in the subgroup of patients who were not treated with systemic therapy (HRR 1.78; P<0.01 and HRR 1.64; P=0.04, respectively), with worst prognosis when both EGFR and PTGS2 were highly expressed (HRR 3.08; P<0.01). Expression of PTGS2 in CRCLM was correlated to expression in patient-matched primary tumours (P=0.02, 69.2% concordance).
  
  
  CONCLUSIONS
  EGFR and PTGS2 expressions are prognostic molecular biomarkers with added value to standard clinicopathological variables for patients with resectable CRCLM.
authors.affiliation: 1] Department of Pathology, VU University Medical Center, CCA 1.08, De Boelelaan 1117, 1081HV Amsterdam, The Netherlands [2] Department of Radiology & Nuclear Medicine, VU University Medical Center, CCA 1.08, De Boelelaan 1117, 1081HV Amsterdam, The Netherlands.
authors.forename: J A C M
authors.initials: JA
authors.lastname: Goos
authors.affiliation: Department of Pathology, VU University Medical Center, CCA 1.08, De Boelelaan 1117, 1081HV Amsterdam, The Netherlands.
authors.forename: A C
authors.initials: AC
authors.lastname: Hiemstra
authors.affiliation: Department of Epidemiology and Biostatistics, VU University Medical Center, CCA 1.08, De Boelelaan 1117, 1081HV Amsterdam, The Netherlands.
authors.forename: V M H
authors.initials: VM
authors.lastname: Coupé
authors.affiliation: Department of Pathology, VU University Medical Center, CCA 1.08, De Boelelaan 1117, 1081HV Amsterdam, The Netherlands.
authors.forename: B
authors.initials: B
authors.lastname: Diosdado
authors.affiliation: Department of Pathology, VU University Medical Center, CCA 1.08, De Boelelaan 1117, 1081HV Amsterdam, The Netherlands.
authors.forename: W
authors.initials: W
authors.lastname: Kooijman
authors.affiliation: Department of Pathology, VU University Medical Center, CCA 1.08, De Boelelaan 1117, 1081HV Amsterdam, The Netherlands.
authors.forename: P M
authors.initials: PM
authors.lastname: Delis-Van Diemen
authors.affiliation: Department of Radiology & Nuclear Medicine, VU University Medical Center, CCA 1.08, De Boelelaan 1117, 1081HV Amsterdam, The Netherlands.
authors.forename: C
authors.initials: C
authors.lastname: Karga
authors.affiliation: Department of Pathology, VU University Medical Center, CCA 1.08, De Boelelaan 1117, 1081HV Amsterdam, The Netherlands.
authors.forename: J A M
authors.initials: JA
authors.lastname: Beliën
authors.affiliation: Department of Medical Oncology, VU University Medical Center, CCA 1.08, De Boelelaan 1117, 1081HV Amsterdam, The Netherlands.
authors.forename: C W
authors.initials: CW
authors.lastname: Menke-van der Houven van Oordt
authors.affiliation: Department of Radiology & Nuclear Medicine, VU University Medical Center, CCA 1.08, De Boelelaan 1117, 1081HV Amsterdam, The Netherlands.
authors.forename: A A
authors.initials: AA
authors.lastname: Geldof
authors.affiliation: Department of Pathology, VU University Medical Center, CCA 1.08, De Boelelaan 1117, 1081HV Amsterdam, The Netherlands.
authors.forename: G A
authors.initials: GA
authors.lastname: Meijer
authors.affiliation: Department of Radiology & Nuclear Medicine, VU University Medical Center, CCA 1.08, De Boelelaan 1117, 1081HV Amsterdam, The Netherlands.
authors.forename: O S
authors.initials: OS
authors.lastname: Hoekstra
authors.affiliation: Department of Pathology, VU University Medical Center, CCA 1.08, De Boelelaan 1117, 1081HV Amsterdam, The Netherlands.
authors.forename: R J A
authors.initials: RJ
authors.lastname: Fijneman
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000378:metabolism*; D015179:Colorectal Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology / Q000601:surgery; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D066246:ErbB Receptors / Q000378:metabolism*; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008113:Liver Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000556:secondary / Q000601:surgery; D008297:Male; D008875:Middle Aged; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; C512478:EGFR protein, human; D066246:ErbB Receptors