title: Proteins of the VEGFR and EGFR pathway as predictive markers for adjuvant treatment in patients with stage II/III colorectal cancer: results of the FOGT-4 trial.
abstract: BACKGROUND
  Unlike metastatic colorectal cancer (CRC) there are to date few reports concerning the predictive value of molecular biomarkers on the clinical outcome in stage II/III CRC patients receiving adjuvant chemotherapy. Aim of this study was to assess the predictive value of proteins related with the EGFR- and VEGFR- signalling cascades in these patients.
  
  
  METHODS
  The patients' data examined in this study were from the collective of the 5-FU/FA versus 5-FU/FA/irinotecan phase III FOGT-4 trial. Tumor tissues were stained by immunohistochemistry for VEGF-C, VEGF-D, VEGFR-3, Hif-1 α, PTEN, AREG and EREG expression and evaluated by two independent, blinded investigators.
  
  
  RESULTS
  Patients with negative AREG and EREG expression on their tumor had a significant longer DFS in comparison to AREG/EREG positive ones (p< 0.05). The benefit on DFS in AREG-/EREG- patients was even stronger in the group that received 5-FU/FA/irinotecan as adjuvant treatment (p=0.002). Patients with strong expression of PTEN profited more in terms of OS under adjuvant treatment containing irinotecan (p< 0.05). Regarding markers of the VEGFR- pathway we found no correlation of VEGF-C- and VEGFR-3 expression with clinical outcome. Patients with negative VEGF-D expression had a trend to live longer when treated with 5-FU/FA (p=0.106). Patients who were negative for Hif-1 α, were disease-free in more than 50% at the end of the study and showed significant longer DFS-rates than those positive for Hif-1 α (p=0.007). This benefit was even stronger at the group treated with 5-FU/FA/irinotecan (p=0.026). Finally, AREG-/EREG-/PTEN+ patients showed a trend to live longer under combined treatment combination.
  
  
  CONCLUSIONS
  The addition of irinotecan to adjuvant treatment with 5-FU/FA does not provide OS or DFS benefit in patients with stage II/III CRC. Nevertheless, AREG/EREG negative, PTEN positive and Hif-1 α negative patients might profit significantly in terms of DFS from a treatment containing fluoropyrimidines and irinotecan. Our results suggest a predictive value of these biomarkers concerning adjuvant chemotherapy with 5-FU/FA +/- irinotecan in stage II/III colorectal cancer.
authors.forename: Thomas
authors.initials: T
authors.lastname: Thomaidis
authors.forename: Annett
authors.initials: A
authors.lastname: Maderer
authors.forename: Andrea
authors.initials: A
authors.lastname: Formentini
authors.forename: Susanne
authors.initials: S
authors.lastname: Bauer
authors.forename: Mario
authors.initials: M
authors.lastname: Trautmann
authors.forename: Michael
authors.initials: M
authors.lastname: Schwarz
authors.forename: Wiebke
authors.initials: W
authors.lastname: Neumann
authors.forename: Jens Martin
authors.initials: JM
authors.lastname: Kittner
authors.forename: Arno
authors.initials: A
authors.lastname: Schad
authors.forename: Karl-Heinrich
authors.initials: KH
authors.lastname: Link
authors.forename: Johannes Wilhelm
authors.initials: JW
authors.lastname: Rey
authors.forename: Arndt
authors.initials: A
authors.lastname: Weinmann
authors.forename: Arthur
authors.initials: A
authors.lastname: Hoffman
authors.forename: Peter Robert
authors.initials: PR
authors.lastname: Galle
authors.forename: Marko
authors.initials: M
authors.lastname: Kornmann
authors.forename: Markus
authors.initials: M
authors.lastname: Moehler
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives; D017024:Chemotherapy, Adjuvant; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D066246:ErbB Receptors / Q000378:metabolism*; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D000077146:Irinotecan; D009367:Neoplasm Staging; D040262:Receptors, Vascular Endothelial Growth Factor / Q000378:metabolism*; D015398:Signal Transduction; D016896:Treatment Outcome
chemical_list: D000077146:Irinotecan; D066246:ErbB Receptors; D040262:Receptors, Vascular Endothelial Growth Factor; D005472:Fluorouracil; D002166:Camptothecin