Multi-drug Resistance Protein 2 (MRP2) Expression, Adjuvant Tamoxifen Therapy, and Risk of Breast Cancer Recurrence: a Danish Population-Based Nested Case-Control Study

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 (ORadj = 0.96, 95% CI 0.70, 1.33). Further, no prognostic utility was found in the ER-/TAM - group (ORadj = 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.