多药耐药相关蛋白 2（MRP2）表达、辅助他莫昔芬治疗与乳腺癌复发风险：一项丹麦基于人群的巢式病例对照研究。
Multi-drug resistance protein 2 (MRP2) expression, adjuvant tamoxifen therapy, and risk of breast cancer recurrence: a Danish population-based nested case-control study.
机构信息
a Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark.
b Department of Pathology, Aarhus University Hospital, Aarhus, Denmark.
出版信息
Acta Oncol. 2019 Feb;58(2):168-174. doi: 10.1080/0284186X.2018.1537508. Epub 2018 Nov 20.
BACKGROUND
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.
MATERIAL AND METHODS
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.
RESULTS
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 = 0.96, 95% CI 0.70, 1.33). Further, no prognostic utility was found in the ER-/TAM - group (OR = 0.81, 95% CI 0.53, 1.23). MRP2 expression was not increased in recurrent versus primary tumors.
CONCLUSIONS
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（ER+）乳腺癌患者的复发风险降低约一半，但许多女性对治疗的反应不足。多药耐药蛋白 2（MRP2）在乳腺癌中的表达可能增强他莫昔芬耐药性。因此，我们研究了乳腺癌中 MRP2 的表达作为他莫昔芬治疗效果的预测因子。
材料和方法
我们进行了一项嵌套在丹麦乳腺癌组临床数据库中的病例对照研究。该研究纳入了 1985-2001 年在丹麦日德兰地区诊断为 I-III 期乳腺癌且年龄在 35-69 岁的女性。我们确定了 541 例接受至少 1 年他莫昔芬治疗的 ER+疾病（ER+/TAM+）女性中出现的复发性乳腺癌（病例），以及 300 例 ER-疾病（ER-/TAM-）、从未接受他莫昔芬治疗的女性中的复发性乳腺癌。我们为每个复发性病例匹配了 1 例无复发的对照。我们从所有患者的石蜡包埋原发性肿瘤组织和病理档案中所有可用的复发性肿瘤组织中提取了样本。使用免疫组织化学评估 MRP2 表达。我们在条件逻辑回归模型中计算了与 MRP2 表达（阳性与阴性）相关的比值比（OR）和 95%置信区间（95%CI），以关联乳腺癌复发。我们比较了配对的原发性和复发性肿瘤中的 MRP2 表达。
结果
MRP2 表达在 ER+/TAM+组中比在 ER-/TAM-组中更为普遍。在 ER+/TAM+组中，MRP2 表达对乳腺癌复发没有预测作用（OR=0.96，95%CI 0.70，1.33）。此外，在 ER-/TAM-组中，MRP2 表达也没有预后作用（OR=0.81，95%CI 0.53，1.23）。MRP2 表达在复发性肿瘤与原发性肿瘤之间没有增加。
结论
MRP2 表达既不是他莫昔芬疗效的预测标志物，也不是乳腺癌的预后标志物。
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