title: Controlling angiogenesis in breast cancer: a systematic review of anti-angiogenic trials.
abstract: OBJECTIVE
  Angiogenesis is critical for tumor growth and a promising therapeutic target. This review will summarize and analyze data from clinical trials of anti-angiogenic agents in the treatment of breast cancer (BC).
  
  
  METHODS
  A systematic search of PubMed and conference databases was performed to identify reports of randomized clinical trials investigating specific anti-angiogenic agents in the treatment of BC.
  
  
  CONCLUSIONS
  Phase III trials in advanced BC have demonstrated a reduction in the risk of disease progression (22-52%), improved response rates and net improvements in progression-free survival of 1.2 to 5.5 months, but no significant improvements in overall survival with the addition of bevacizumab to chemotherapy. Results of phase III trials in early breast cancer have been inconsistent. Bevacizumab-containing regimens have also been associated with higher overall adverse event rates compared to chemotherapy alone. Phase III trials of the tyrosine kinase inhibitor sunitinib were negative, while randomized phase II trials of sorafenib and pazopanib have improved some outcomes when combined with chemotherapy or targeted therapy compared to controls. In addition to expected vascular class safety signals, tyrosine kinase inhibitors show "off-target" side effects. Ongoing clinical trials evaluating combinatorial strategies based on biological synergies and translational studies identifying biological predictors of response will be crucial to establish meaningful clinical benefits in selected BC populations.
  
  
  CONCLUSIONS
  Most trials of anti-angiogenic agents in BC have reported improved response rate and progression-free survival but no increase in overall survival compared to chemotherapy alone. Optimizing the therapeutic indices of these agents is a focus of ongoing research and will be critical to their future development.
authors.affiliation: Cross Cancer Institute, 11560 University Avenue, Edmonton, Alberta, Canada. john.mackey@trioncology.org
authors.forename: John R
authors.initials: JR
authors.lastname: Mackey
authors.forename: Robert S
authors.initials: RS
authors.lastname: Kerbel
authors.forename: Karen A
authors.initials: KA
authors.lastname: Gelmon
authors.forename: Deanna M
authors.initials: DM
authors.lastname: McLeod
authors.forename: Stephen K
authors.initials: SK
authors.lastname: Chia
authors.forename: Daniel
authors.initials: D
authors.lastname: Rayson
authors.forename: Sunil
authors.initials: S
authors.lastname: Verma
authors.forename: Loretta L
authors.initials: LL
authors.lastname: Collins
authors.forename: Alexander H G
authors.initials: AH
authors.lastname: Paterson
authors.forename: André
authors.initials: A
authors.lastname: Robidoux
authors.forename: Kathleen I
authors.initials: KI
authors.lastname: Pritchard
mesh_terms: D020533:Angiogenesis Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D005260:Female; D006801:Humans; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000627:therapeutic use; D016032:Randomized Controlled Trials as Topic; D016896:Treatment Outcome
chemical_list: D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors