title: Predicting response to vascular endothelial growth factor inhibitor and chemotherapy in metastatic colorectal cancer.
abstract: BACKGROUND
  Bevacizumab improves progression free survival (PFS) and overall survival (OS) in metastatic colorectal cancer patients however currently there are no biomarkers that predict response to this treatment. The aim of this study was to assess if differential protein expression can differentiate patients who respond to chemotherapy and bevacizumab, and to assess if select proteins correlate with patient survival.
  
  
  METHODS
  Pre-treatment serum from patients with metastatic colorectal cancer (mCRC) treated with chemotherapy and bevacizumab were divided into responders and nonresponders based on their progression free survival (PFS). Serum samples underwent immunoaffinity depletion and protein expression was analysed using two-dimensional difference gel electrophoresis (2D-DIGE), followed by LC-MS/MS for protein identification. Validation on selected proteins was performed on serum and tissue samples from a larger cohort of patients using ELISA and immunohistochemistry, respectively (n = 68 and n = 95, respectively).
  
  
  RESULTS
  68 proteins were identified following LC-MS/MS analysis to be differentially expressed between the groups. Three proteins (apolipoprotein E (APOE), angiotensinogen (AGT) and vitamin D binding protein (DBP)) were selected for validation studies. Increasing APOE expression in the stroma was associated with shorter progression free survival (PFS) (p = 0.0001) and overall survival (OS) (p = 0.01), DBP expression (stroma) was associated with shorter OS (p = 0.037). Increasing APOE expression in the epithelium was associated with a longer PFS and OS, and AGT epithelial expression was associated with a longer PFS (all p < .05). Increasing serum AGT concentration was associated with shorter OS (p = 0.009).
  
  
  CONCLUSIONS
  APOE, DBP and AGT identified were associated with survival outcomes in mCRC patients treated with chemotherapy and bevacizumab.
authors.forename: Petra
authors.initials: P
authors.lastname: Martin
authors.forename: Sinead
authors.initials: S
authors.lastname: Noonan
authors.forename: Michael P
authors.initials: MP
authors.lastname: Mullen
authors.forename: Caitriona
authors.initials: C
authors.lastname: Scaife
authors.forename: Miriam
authors.initials: M
authors.lastname: Tosetto
authors.forename: Blathnaid
authors.initials: B
authors.lastname: Nolan
authors.forename: Kieran
authors.initials: K
authors.lastname: Wynne
authors.forename: John
authors.initials: J
authors.lastname: Hyland
authors.forename: Kieran
authors.initials: K
authors.lastname: Sheahan
authors.forename: Giuliano
authors.initials: G
authors.lastname: Elia
authors.forename: Diarmuid
authors.initials: D
authors.lastname: O'Donoghue
authors.forename: David
authors.initials: D
authors.lastname: Fennelly
authors.affiliation: Department of Surgery, Trinity Centre for Health Sciences, Institute of Molecular Medicine, St, James's Hospital, Dublin 8, Ireland. osullij4@tcd.ie.
authors.forename: Jacintha
authors.initials: J
authors.lastname: O'Sullivan
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000808:Angiotensinogen / Q000097:blood*; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage*; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D001057:Apolipoproteins E / Q000097:blood*; D000068258:Bevacizumab; D014408:Biomarkers, Tumor / Q000097:blood; D015179:Colorectal Neoplasms / Q000097:blood / Q000188:drug therapy*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D040901:Proteomics; D016019:Survival Analysis; D016896:Treatment Outcome; D014809:Vitamin D-Binding Protein / Q000097:blood*
chemical_list: C534931:AGT protein, human; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D001057:Apolipoproteins E; D014408:Biomarkers, Tumor; D014809:Vitamin D-Binding Protein; D000808:Angiotensinogen; D000068258:Bevacizumab