Role of carbonic anhydrase IX expression in prediction of the efficacy and outcome of primary epirubicin/tamoxifen therapy for breast cancer

<jats:p>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 (<jats:italic>P</jats:italic> = 0.007), c-erbB2 (<jats:italic>P</jats:italic> < 0.01), and Ki67 (<jats:italic>P</jats:italic> = 0.02) were directly associated with CAIX expression, while bcl2 (<jats:italic>P</jats:italic> < 0.000) and ER (<jats:italic>P</jats:italic> = 0.000) and progesterone receptor (PgR; <jats:italic>P</jats:italic> < 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 (<jats:italic>P</jats:italic> < 0.002) and overall survival (<jats:italic>P</jats:italic> = 0.001). In multivariate analysis, a significant interaction was found between CAIX and markers of hormone sensitivity, bcl2 (<jats:italic>P</jats:italic> = 0.01), ER (<jats:italic>P</jats:italic> = 0.02), PgR (<jats:italic>P</jats:italic> = 0.02), and lymph node involvement (<jats:italic>P</jats:italic> = 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.</jats:p>