title: Hypoxia-inducible factor-1alpha expression predicts a poor response to primary chemoendocrine therapy and disease-free survival in primary human breast cancer.
abstract: OBJECTIVE
  To investigate the relationship of hypoxia-inducible factor-1alpha (HIF-1alpha) tumor expression in predicting the response to epirubicin and disease-free survival (DFS) in patients with breast cancer enrolled in a single institution trial of primary anthracycline and tamoxifen therapy.
  
  
  METHODS
  The expression of HIF-1alpha was assessed by immunohistochemistry in 187 patients with T(2-4) N(0-1) breast cancer enrolled in a randomized trial comparing four cycles of single agent epirubicin versus epirubicin + tamoxifen as primary systemic treatment. All patients postoperatively received four cycles of the four weekly i.v. CMF regimen (cyclophosphamide, methotrexate, and 5-fluorouracil). Patients with estrogen receptor (ER)-positive primary tumors also underwent 5 years of treatment with adjuvant tamoxifen. Carbonic anhydrase IX (CAIX) was also scored as a marker of HIF activity.
  
  
  RESULTS
  Overall response to therapy progressively decreased with increasing tumor HIF-1alpha (P < 0.05), and HIF-1alpha was an independent predictor of response (P < 0.048). HIF-1alpha expression was also associated with a significantly shorter DFS (P < 0.02) in all patients and in ER-positive but not in ER-negative patients. Furthermore, CAIX positivity conferred a significantly shorter DFS (P = 0.02) compared with CAIX-negative tumors in patients with HIF-1alpha-negative tumors.
  
  
  CONCLUSIONS
  HIF-1alpha expression in patients with breast cancer is a marker of poor therapy response and outcome, especially in ER-positive patients. The combination of two hypoxia markers has greater utility than assessing just one, and patients with hypoxia markers in their tumors may be suitable for administration of drugs that reduce HIF-1alpha expression and increase oxygen delivery to the tumor bed before starting neoadjuvant therapies.
authors.affiliation: Molecular Oncology Laboratories, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom.
authors.forename: Daniele
authors.initials: D
authors.lastname: Generali
authors.forename: Alfredo
authors.initials: A
authors.lastname: Berruti
authors.forename: Maria P
authors.initials: MP
authors.lastname: Brizzi
authors.forename: Leticia
authors.initials: L
authors.lastname: Campo
authors.forename: Simone
authors.initials: S
authors.lastname: Bonardi
authors.forename: Simon
authors.initials: S
authors.lastname: Wigfield
authors.forename: Alessandra
authors.initials: A
authors.lastname: Bersiga
authors.forename: Giovanni
authors.initials: G
authors.lastname: Allevi
authors.forename: Manuela
authors.initials: M
authors.lastname: Milani
authors.forename: Sergio
authors.initials: S
authors.lastname: Aguggini
authors.forename: Valeria
authors.initials: V
authors.lastname: Gandolfi
authors.forename: Luigi
authors.initials: L
authors.lastname: Dogliotti
authors.forename: Alberto
authors.initials: A
authors.lastname: Bottini
authors.forename: Adrian L
authors.initials: AL
authors.lastname: Harris
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Fox
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000096:biosynthesis; D001943:Breast Neoplasms / Q000175:diagnosis / Q000378:metabolism* / Q000628:therapy*; D017024:Chemotherapy, Adjuvant; D018450:Disease Progression; D018572:Disease-Free Survival; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis*; D007150:Immunohistochemistry; D015999:Multivariate Analysis; D011237:Predictive Value of Tests; D011379:Prognosis; D011446:Prospective Studies; D011960:Receptors, Estrogen / Q000096:biosynthesis; D012008:Recurrence; D015996:Survival Rate; D016896:Treatment Outcome
chemical_list: D014408:Biomarkers, Tumor; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D011960:Receptors, Estrogen