title: Biomarkers of anti-angiogenic therapy in metastatic colorectal cancer (mCRC): original data and review of the literature.
abstract: BACKGROUND
  Tumour angiogenesis via vascular endothelial growth factor (VEGF) is essential for promoting tumour progression and is overexpressed in colorectal cancer. The humanised monoclonal anti-VEGF antibody bevacizumab (Avastin®, Genentech Inc., South San Francisco, CA) has shown activity in metastatic colorectal cancer (mCRC) combined with conventional chemotherapy. The search for biomarkers to predict response to anti-angiogenic therapy in mCRC is of great interest. We investigated several potential predictive anti-angiogenic markers including circulating endothelial progenitor cells (EPC) in patients with mCRC receiving bevacizumab containing treatment within a randomised multicenter phase 2 study of the German AIO GI tumour study group.
  
  
  METHODS
  We collected sequential blood samples and tumour tissues from patients participating in a clinical trial for patients with mCRC. We performed flow cytometry of mononuclear cells isolated from peripheral blood to assess CD 133 + or CD 34 + /KDR + EPC before the first bevacizumab containing chemotherapy and after 21 days. Circulating VEGF blood levels before a bevacizumab containing chemotherapy regimen and after 21 days and VEGF expression in tumour tissue were examined.
  
  
  RESULTS
  Patients with mCRC and a partial remission after six months of immuno-chemotherapy containing bevacizumab showed a reduction of CD 34 negative KDR positive cells as early as 3 weeks after start of therapy. In contrast, no remarkable change in the number of CD 34 /KDR positive or CD 34 /CD133 positive cells was seen. Furthermore, there was no correlation between treatment response and VEGF expression within the tumour tissue. The mAb bevacizumab reduced serum-VEGF levels in patients independent of their treatment response to bevacizumab.
  
  
  CONCLUSIONS
  We examined circulating endothelial progenitor cells (EPC), serum-VEGF levels and the tumour tissue VEGF expression of patients with mCRC under a bevacizumab containing chemotherapy. The patients with a partial remission after six months of immuno-chemotherapy showed a reduction of CD 34 negative KDR positive cells as early as 3 weeks after start of therapy. Neither serum nor tissue markers were of significant predictive value in our pilot study. Furthermore, we review the current data on biomarkers for anti-angiogenic therapy of mCRC.
authors.affiliation: Department of Medicine, Knappschaftskrankenhaus, Ruhr University, Bochum, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Pohl
authors.forename: N
authors.initials: N
authors.lastname: Werner
authors.forename: J
authors.initials: J
authors.lastname: Munding
authors.forename: A
authors.initials: A
authors.lastname: Tannapfel
authors.forename: U
authors.initials: U
authors.lastname: Graeven
authors.forename: G
authors.initials: G
authors.lastname: Nickenig
authors.forename: W
authors.initials: W
authors.lastname: Schmiegel
authors.forename: A
authors.initials: A
authors.lastname: Reinacher-Schick
mesh_terms: D000071916:AC133 Antigen; D000368:Aged; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage*; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage*; D015703:Antigens, CD / Q000097:blood; D018952:Antigens, CD34 / Q000097:blood; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D000068258:Bevacizumab; D015415:Biomarkers / Q000097:blood*; D002452:Cell Count; D015179:Colorectal Neoplasms / Q000098:blood supply* / Q000188:drug therapy* / Q000473:pathology; D018450:Disease Progression; D042783:Endothelial Cells / Q000187:drug effects* / Q000473:pathology; D004730:Endothelium, Vascular / Q000187:drug effects; D005260:Female; D005434:Flow Cytometry; D006023:Glycoproteins / Q000097:blood; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D010455:Peptides / Q000097:blood; D010865:Pilot Projects; D013234:Stem Cells / Q000187:drug effects; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000097:blood / Q000187:drug effects
chemical_list: D000071916:AC133 Antigen; D020533:Angiogenesis Inhibitors; D061067:Antibodies, Monoclonal, Humanized; D015703:Antigens, CD; D018952:Antigens, CD34; D015415:Biomarkers; D006023:Glycoproteins; C000606023:PROM1 protein, human; D010455:Peptides; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D000068258:Bevacizumab; D040301:Vascular Endothelial Growth Factor Receptor-2