title: CA IX is an independent prognostic marker in premenopausal breast cancer patients with one to three positive lymph nodes and a putative marker of radiation resistance.
abstract: OBJECTIVE
  Hypoxia in breast cancer is associated with poor prognosis and down-regulation of the estrogen receptor. Carbonic anhydrase IX (CA IX) is a hypoxia-inducible gene that has been associated with poor outcome in many epithelial cancers. Previous studies of CA IX in breast cancer have been carried out on mixed cohorts of premenopausal and postmenopausal patients with locally advanced disease and varying treatment regimens. We examined the potential prognostic and predictive role of CA IX in premenopausal breast cancer patients.
  
  
  METHODS
  Using tissue microarrays, we analyzed CA IX expression in 400 stage II breast cancers from premenopausal women. The patients had previously participated in a randomized control trial comparing 2 years of tamoxifen to no systemic adjuvant treatment. Median follow-up was 13.9 years.
  
  
  RESULTS
  CA IX expression correlated positively with tumor size, grade, hypoxia-inducible factor 1alpha, Ki-67, cyclin E, and cyclin A2 expression. CA IX expression correlated negatively with cyclin D1, estrogen receptor, and progesterone receptor. CA IX expression was associated with a reduced relapse-free survival (P=0.032), overall survival (P=0.022), and breast cancer-specific survival (P=0.005). Multivariate analysis revealed that CA IX was an independent prognostic marker in untreated patients with one to three positive lymph nodes (hazard ratio, 3.2; 95% confidence interval, 1.15-9.13; P=0.027).
  
  
  CONCLUSIONS
  CA IX is marker of poor prognosis in premenopausal breast cancer patients and it is an independent predictor of survival in patients with one to three positive lymph nodes. As all these patients received locoregional radiation therapy, CA IX may be associated with resistance to radiotherapy.
authors.affiliation: UCD School of Biomolecular and Biomedical Science, UCD Conway Institute, University College, Dublin, and Department of Pathology and Laboratory Medicine, St. Vincent's University Hospital, Ireland.
authors.forename: Donal J
authors.initials: DJ
authors.lastname: Brennan
authors.forename: Karin
authors.initials: K
authors.lastname: Jirstrom
authors.forename: Asa
authors.initials: A
authors.lastname: Kronblad
authors.forename: Robert C
authors.initials: RC
authors.lastname: Millikan
authors.forename: Goran
authors.initials: G
authors.lastname: Landberg
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Duffy
authors.forename: Lisa
authors.initials: L
authors.lastname: Rydén
authors.forename: William M
authors.initials: WM
authors.lastname: Gallagher
authors.forename: Sallyann L
authors.initials: SL
authors.lastname: O'Brien
mesh_terms: D000328:Adult; D000951:Antigens, Neoplasm / Q000096:biosynthesis*; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000032:analysis*; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases / Q000096:biosynthesis*; D017024:Chemotherapy, Adjuvant; D019925:Cyclin A / Q000096:biosynthesis; D056751:Cyclin A2; D019938:Cyclin D1 / Q000096:biosynthesis; D019927:Cyclin E / Q000096:biosynthesis; D005260:Female; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis; D007150:Immunohistochemistry; D019394:Ki-67 Antigen / Q000096:biosynthesis; D008207:Lymphatic Metastasis / Q000532:radiotherapy*; D015412:Mastectomy, Segmental; D008875:Middle Aged; D017697:Premenopause; D011379:Prognosis; D011836:Radiation Tolerance; D011878:Radiotherapy; D011960:Receptors, Estrogen / Q000096:biosynthesis; D011980:Receptors, Progesterone / Q000096:biosynthesis; D016019:Survival Analysis; D013629:Tamoxifen / Q000627:therapeutic use
chemical_list: D000951:Antigens, Neoplasm; D018931:Antineoplastic Agents, Hormonal; D014408:Biomarkers, Tumor; C503721:CCNA2 protein, human; D019925:Cyclin A; D056751:Cyclin A2; D019927:Cyclin E; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D019394:Ki-67 Antigen; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D013629:Tamoxifen; D019938:Cyclin D1; C089226:CA9 protein, human; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases