Generali Daniele, Fox Stephen B, Berruti Alfredo, Brizzi Maria P, Campo Leticia, Bonardi Simone, Wigfield Simon M, Bruzzi Paolo, Bersiga Alessandra, Allevi Giovanni, Milani Manuela, Aguggini Sergio, Dogliotti Luigi, Bottini Alberto, Harris Adrian L
Weatherall Molecular Oncology Laboratories, Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK.
Endocr Relat Cancer. 2006 Sep;13(3):921-30. doi: 10.1677/erc.1.01216.
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.
本研究的目的是调查碳酸酐酶IX（CAIX）表达在预测接受单机构原发性蒽环类药物和他莫昔芬治疗试验的乳腺癌患者对表柔比星的反应及无病生存期（DFS）中的作用。对183例T2-4 N0-1期乳腺癌患者的CAIX表达进行了评估，这些患者参加了一项随机试验，该试验比较了四个周期的单药表柔比星与表柔比星+他莫昔芬作为主要全身治疗的效果。所有患者术后接受四个周期的静脉注射环磷酰胺、甲氨蝶呤、5-氟尿嘧啶方案，每四周一次。雌激素受体（ER）阳性原发性肿瘤患者接受5年的辅助他莫昔芬治疗。治疗前，p53（P=0.007）、c-erbB2（P<0.01）和Ki67（P=0.02）与CAIX表达直接相关，而bcl2（P<0.000）、ER（P=0.000）和孕激素受体（PgR；P<0.01）与CAIX表达呈负相关。在多变量分析中，只有高p53和低bcl2与CAIX阳性独立相关。CAIX免疫染色与DFS不良结局（P<0.002）和总生存期（P=0.001）显著相关。在多变量分析中，发现CAIX与激素敏感性标志物、bcl2（P=0.01）、ER（P=0.02）、PgR（P=0.02）和淋巴结受累（P=0.04）之间在预测DFS方面存在显著相互作用。目前，ER阳性肿瘤中对他莫昔芬治疗耐药的临床标志物很少。乳腺癌患者的CAIX表达在原发性化疗-内分泌治疗后对ER阳性患者辅助他莫昔芬治疗疗效显示出负性预测作用。计划开展研究调查pH对他莫昔芬摄取的影响以及CA抑制剂治疗的效果。
