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¹ Weatherall Molecular Oncology Laboratories, Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK
² Unità di Patologia Mammaria – Breast Cancer Unit, Azienda Istituti Ospitalieri di Cremona, Viale Concordia 1, 26100 Cremona, Italy
³ Anatomia Patologica Azienda Istituti Ospitalieri di Cremona, Viale Concordia 1, 26100 Cremona, Italy
⁴ Oncologia Medica, Dipartimento di Scienze Cliniche e Biologiche, Università di Torino Azienda Ospedaliera San Luigi di Orbassano, Regione Gonzole 10, 10043 Orbassano, Italy
⁵ Istituto Nazionale per la Ricerca sul Cancro, Largo R. Benzi 10, 16132 Genova, Italy

(Requests for offprints should be addressed to A L Harris; Email: aharris.lab{at}cancer.org.uk)

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.

This article has been cited by other articles:

				P. Swietach, S. Wigfield, P. Cobden, C. T. Supuran, A. L. Harris, and R. D. Vaughan-Jones Tumor-associated Carbonic Anhydrase 9 Spatially Coordinates Intracellular pH in Three-dimensional Multicellular Growths J. Biol. Chem., July 18, 2008; 283(29): 20473 - 20483. [Abstract] [Full Text] [PDF]