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.
Funding
The results reported herein correspond to the specific aims of the Lundbeck Foundation grant (R167-2013-15861; awarded to D. Cronin-Fenton). The study was additionally supported by funding from the NCI (R01 CA118708, R21 CA185932 and R01 CA166825; awarded to T.L. Lash), the Danish Cancer Society (DP06117; awarded to S. Hamilton-Dutoit, R220-A13165; awarded to Cathrine F. Hjorth and R167-A11045-17-S2; awarded to Deirdre Cronin-Fenton), the Danish Medical Research Council (DOK 1158869; awarded to T.L. Lash), the Karen Elise Jensen Foundation (awarded to Henrik Toft Sørensen), the Program for Clinical Research Infrastructure established by the Lundbeck, the Novo Nordisk Foundations (awarded to Henrik Toft Sørensen) and the Oticon Foundation (18-2137; awarded to Cathrine F. Hjorth).
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