ABTB2 Regulatory Variant as Predictor of Epirubicin-Based Neoadjuvant Chemotherapy in Luminal A Breast Cancer

Abstract

Background: Epirubicin combined with docetaxel is the cornerstone of neoadjuvant chemotherapy (NAC) for breast cancer. The efficacy of NAC for luminal A breast cancer patients is very limited, and single nucleotide polymorphism is one of the most important factors that influences the efficacy. Our study is aimed to explore genetic markers for the efficacy of epirubicin combined with docetaxel for NAC in patients with luminal A breast cancer. Methods: A total of 421 patients with two stages of luminal A breast cancer were enrolled in this study from 2 centers. Among them 231 patients were included in the discovery cohort and 190 patients are in the replication cohort. All patients received epirubicin 75 mg/m2 and docetaxel 75 mg/m2 on day 1, in a 21-day cycle, a cycle for 2–6 cycles. Before treatment, 2 ml of peripheral blood was collected from each patient to isolate genomic DNA. Fourteen functional variants potentially regulating epirubicin/docetaxel response genes were prioritized by CellMiner and bioinformatics approaches. Moreover, biological assays were performed to determine the effect of genetic variations on response to chemotherapy. Results: The patients carrying rs6484711 variant A allele suffered a poor response to epirubicin and docetaxel for NAC (OR = 0.37, 95% CI: 0.18–0.74, P = 0.005) in combined stage. Moreover, expression quantitative trait loci (eQTL) analyses and luciferase reporter assays revealed that rs6484711 A allele significantly increased the expression of ABTB2. Subsequent biological assays illustrated that upregulation of ABTB2 significantly reduced the apoptosis rate of breast cancer cells and enhanced the chemo-resistance to epirubicin. Conclusions: Our study demonstrated rs6484711 polymorphism regulating ABTB2 expression might predict efficacy to epirubicin based NAC in luminal A breast cancer patients. These results provided valuable information about potential role of genetic variations in individualized chemotherapy.