title: Role of carbonic anhydrase IX expression in prediction of the efficacy and outcome of primary epirubicin/tamoxifen therapy for breast cancer.
abstract: The purpose of this study is to investigate the role of carbonic anhydrase IX (CAIX) expression in predicting the response to epirubicin and disease-free survival (DFS) in breast cancer patients enrolled in a single institution trial of primary anthracycline and tamoxifen therapy. CAIX expression was assessed in 183 patients with T2-4 N0-1 breast cancer enrolled in a randomized trial comparing four cycles of single agent epirubicin versus epirubicin+tamoxifen as primary systemic treatment. All patients received postoperatively four cycles of the four weekly i.v. cyclophosphamide, methotrexate, 5-fluorouracil regimen. Patients with estrogen receptor (ER)-positive primary tumors received 5 years of adjuvant tamoxifen. Pretreatment, p53 (P=0.007), c-erbB2 (P<0.01), and Ki67 (P=0.02) were directly associated with CAIX expression, while bcl2 (P<0.000) and ER (P=0.000) and progesterone receptor (PgR; P<0.01) were inversely correlated. In multivariate analysis, only high p53 and low bcl2 were independently associated with CAIX positivity. CAIX immunostaining was significantly associated with poor outcome for DFS (P<0.002) and overall survival (P=0.001). In multivariate analysis, a significant interaction was found between CAIX and markers of hormone sensitivity, bcl2 (P=0.01), ER (P=0.02), PgR (P=0.02), and lymph node involvement (P=0.04), in predicting DFS. Presently, there are few clinical markers of resistance to tamoxifen treatment in ER-positive tumors. CAIX expression in breast cancer patients shows a negative predictive role of treatment efficacy in ER-positive patients on the adjuvant tamoxifen after primary chemo-endocrine therapy. Studies investigating the effects of pH on tamoxifen uptake and the effects of therapy with CA inhibitors are planned.
authors.affiliation: Weatherall Molecular Oncology Laboratories, Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK.
authors.forename: Daniele
authors.initials: D
authors.lastname: Generali
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Fox
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 M
authors.initials: SM
authors.lastname: Wigfield
authors.forename: Paolo
authors.initials: P
authors.lastname: Bruzzi
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: 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
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000627:therapeutic use; D000951:Antigens, Neoplasm / Q000235:genetics* / Q000378:metabolism; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001706:Biopsy; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics / Q000401:mortality / Q000473:pathology; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases / Q000235:genetics* / Q000378:metabolism; D018572:Disease-Free Survival; D015251:Epirubicin / Q000627:therapeutic use*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D017698:Postmenopause; D017697:Premenopause; D011960:Receptors, Estrogen / Q000378:metabolism; D016019:Survival Analysis; D013629:Tamoxifen / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D000903:Antibiotics, Antineoplastic; D000951:Antigens, Neoplasm; D018931:Antineoplastic Agents, Hormonal; D011960:Receptors, Estrogen; D013629:Tamoxifen; D015251:Epirubicin; C089226:CA9 protein, human; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases