title: Carbonic anhydrase IX is a predictive marker of doxorubicin resistance in early-stage breast cancer independent of HER2 and TOP2A amplification.
abstract: BACKGROUND
  In early-stage breast cancer, adjuvant chemotherapy is associated with significant systemic toxicity with only a modest survival benefit. Therefore, there is considerable interest in identifying predictive markers of response to therapy. Doxorubicin, one of the most common drugs used to treat breast cancer, is an anthracycline chemotherapeutic agent, a class of drugs known to be affected by hypoxia. Accordingly, we examined whether expression of the endogenous hypoxia marker carbonic anhydrase IX (CA IX) is predictive of outcome in early-stage breast cancer patients treated with doxorubicin.
  
  
  METHODS
  We obtained 209 early-stage pre-treatment surgically-resected breast tumours from patients, who received doxorubicin in their chemotherapeutic regimen and had >10 years of follow-up. Immunohistochemistry was used to detect CA IX, and we used fluorescence in situ hybridisation to detect both human epidermal growth factor receptor (HER2) and DNA topoisomerase II-alpha (TOP2A) gene amplification.
  
  
  RESULTS
  Carbonic anhydrase IX intensity was significantly correlated with progression-free survival (PFS) and overall survival (OS) in patients receiving 300 mg m(-2) of doxorubicin (HR=1.82 and 3.77; P=0.0014 and 0.010, respectively). There was a significant, inverse correlation between CA IX score and oestrogen receptor expression, but no significant correlations were seen with either HER2 or TOP2A ratio.
  
  
  CONCLUSIONS
  We demonstrate that CA IX expression is correlated with worse PFS and OS for breast cancer patients treated with doxorubicin, independent of HER2 or TOP2A gene amplification. This study provides evidence that using CA IX to detect hypoxia in surgically-resected breast tumours may be of clinical use in choosing an appropriate chemotherapy regimen.
authors.affiliation: Department of Pathology, Duke University Medical Center, Research Drive, Box 3455 DUMC, Durham, NC, USA.
authors.forename: A S
authors.initials: AS
authors.lastname: Betof
authors.forename: Z N
authors.initials: ZN
authors.lastname: Rabbani
authors.forename: M E
authors.initials: ME
authors.lastname: Hardee
authors.forename: S J
authors.initials: SJ
authors.lastname: Kim
authors.forename: G
authors.initials: G
authors.lastname: Broadwater
authors.forename: R C
authors.initials: RC
authors.lastname: Bentley
authors.forename: S A
authors.initials: SA
authors.lastname: Snyder
authors.forename: Z
authors.initials: Z
authors.lastname: Vujaskovic
authors.forename: E
authors.initials: E
authors.lastname: Oosterwijk
authors.forename: L N
authors.initials: LN
authors.lastname: Harris
authors.forename: J K
authors.initials: JK
authors.lastname: Horton
authors.forename: M W
authors.initials: MW
authors.lastname: Dewhirst
authors.forename: K L
authors.initials: KL
authors.lastname: Blackwell
mesh_terms: D000328:Adult; D000368:Aged; D000903:Antibiotics, Antineoplastic / Q000627:therapeutic use*; D000951:Antigens, Neoplasm / Q000235:genetics / Q000378:metabolism*; D014408:Biomarkers, Tumor; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000601:surgery; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases / Q000378:metabolism*; D015687:Cell Hypoxia; D017024:Chemotherapy, Adjuvant; D004250:DNA Topoisomerases, Type II / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D018572:Disease-Free Survival; D004317:Doxorubicin / Q000627:therapeutic use*; D019008:Drug Resistance, Neoplasm; D005260:Female; D005784:Gene Amplification; D018734:Genes, erbB-2; D006801:Humans; D008875:Middle Aged; D000075223:Poly-ADP-Ribose Binding Proteins
chemical_list: D000903:Antibiotics, Antineoplastic; D000951:Antigens, Neoplasm; D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; D000075223:Poly-ADP-Ribose Binding Proteins; D004317:Doxorubicin; C089226:CA9 protein, human; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases; D004250:DNA Topoisomerases, Type II; C000618811:TOP2A protein, human