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

• Authors: Cathrine F. Hjorth, Aarhus University; Anja S. Nielsen, Aarhus University; Henrik T. Sørensen, Aarhus University; Timothy Lash, Emory University; Per Damkier, University of Southern Denmark; Stephen Hamilton-Dutoit, Aarhus University; Deidre Cronin-Fenton, Aarhus University
• Journal Title: Acta Oncol
• Volume: Volume 58, Number 2
• Publisher: Taylor & Francis | 2019-02, Pages 168-174
• Type of Work: Article | Post-print: After Peer Review
• Publisher DOI: http://doi.org/10.1080/0284186X.2018.1537508
• Subjects: Health Sciences, Oncology
• Keywords: Adult; Aged; Antineoplastic Agents, Hormonal; Breast Neoplasms; Case-Control Studies; Chemotherapy, Adjuvant; Denmark; Female; Humans; Immunohistochemistry; Middle Aged; Multidrug Resistance-Associated Proteins; Neoplasm Recurrence, Local; Prognosis; Risk Factors; Tamoxifen; Treatment Outcome

Abstract

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.