Multi-drug resistance protein 2 (MRP2) expression, adjuvant tamoxifen therapy, and risk of breast cancer recurrence: a Danish population-based nested case-control study

<b>Background:</b> Adjuvant tamoxifen therapy approximately halves the risk of recurrence in estrogen receptor-positive (ER+) breast cancer patients, but many women respond insufficiently to therapy. Expression of multi-drug resistance protein 2 (MRP2) in breast cancer may potentiate tamoxifen resistance. Thus, we investigated the expression of MRP2 in breast cancer as a predictor of tamoxifen therapy effectiveness. <b>Material and methods:</b> We conducted a case-control study nested in the Danish Breast Cancer Group clinical database. The study included women aged 35–69 years diagnosed with stage l–lll breast cancer during 1985–2001, in Jutland, Denmark. We identified 541 recurrent breast cancers (cases) among women with estrogen receptor positive (ER+) disease treated with tamoxifen for at least 1 year (ER+/TAM+) and 300 cases among women with estrogen receptor-negative (ER−) disease, never treated with tamoxifen (ER−/TAM−). We matched one recurrence-free control to each recurrent case. We retrieved paraffin-embedded primary tumor tissue for all patients, and all available recurrent tumor tissue from pathology archives. MRP2 expression was evaluated using immunohistochemistry. We computed odds ratios (ORs) and 95% confidence intervals (95% CIs) associating MRP2 expression (positive vs. none) with breast cancer recurrence in conditional logistic regression models. We compared MRP2 expression in paired primary- and recurrent tumors. <b>Results:</b> MRP2 expression was more prevalent in the ER+/TAM + group, than in the ER−/TAM − group. No predictive utility of MRP2 for breast cancer recurrence was found in the ER+/TAM + group (OR_adj = 0.96, 95% CI 0.70, 1.33). Further, no prognostic utility was found in the ER−/TAM − group (OR_adj = 0.81, 95% CI 0.53, 1.23). MRP2 expression was not increased in recurrent versus primary tumors. <b>Conclusions:</b> MRP2 expression is neither a predictive marker of tamoxifen effectiveness nor a prognostic marker in breast cancer.

**背景：** 辅助他莫昔芬治疗可使雌激素受体阳性（estrogen receptor-positive, ER+）乳腺癌患者的复发风险降低约一半，但众多患者对该治疗应答不佳。多药耐药蛋白2（multi-drug resistance protein 2, MRP2）在乳腺癌组织中的表达可能增强他莫昔芬耐药性，因此本研究探讨MRP2在乳腺癌中的表达作为他莫昔芬治疗疗效预测标志物的价值。**材料与方法：** 本研究为嵌套于丹麦乳腺癌小组临床数据库的病例对照研究。研究对象为1985年至2001年间在丹麦日德兰半岛确诊为I~III期乳腺癌的35~69岁女性。我们在接受至少1年他莫昔芬治疗的雌激素受体阳性（ER+）患者中纳入541例复发性乳腺癌病例（ER+/TAM+组），在从未接受他莫昔芬治疗的雌激素受体阴性（estrogen receptor-negative, ER-）患者中纳入300例复发性乳腺癌病例（ER-/TAM-组）。每例复发病例匹配1例无复发对照。收集所有患者的石蜡包埋原发肿瘤组织，以及病理档案中可获取的全部复发性肿瘤组织。采用免疫组织化学法检测MRP2的表达水平。通过条件logistic回归模型计算MRP2表达（阳性vs. 阴性）与乳腺癌复发的比值比（odds ratios, OR）及95%置信区间（95% confidence intervals, 95% CI）。对比配对的原发肿瘤与复发性肿瘤中的MRP2表达情况。**结果：** MRP2表达在ER+/TAM+组中的检出率高于ER-/TAM-组。在ER+/TAM+组中，未发现MRP2对乳腺癌复发具有预测价值（校正比值比OR_adj=0.96，95%CI 0.70~1.33）。此外，在ER-/TAM-组中亦未发现MRP2具备预后价值（OR_adj=0.81，95%CI 0.53~1.23）。与原发肿瘤相比，复发性肿瘤中的MRP2表达水平未出现升高。**结论：** MRP2表达既不能作为乳腺癌患者他莫昔芬治疗疗效的预测标志物，也不能作为乳腺癌的预后标志物。