ABCB1 and ABCC2 and the risk of distant metastasis in Thai breast cancer patients treated with tamoxifen

Abstract

BackgroundGenetic polymorphisms of drug-metabolizing enzymes and transporters have been extensively studied with regard to tamoxifen treatment outcomes. However, the results are inconclusive. Analysis of organ-specific metastasis may reveal the association of these pharmacogenetic factors. The aim of this study is to investigate the impact of CYP3A5, CYP2D6, ABCB1, and ABCC2 polymorphisms on the risk of all distant and organ-specific metastases in Thai patients who received tamoxifen adjuvant therapy.MethodsGenomic DNA was extracted from blood samples of 73 patients with breast cancer who received tamoxifen adjuvant therapy. CYP3A5 (6986A>G), CYP2D6 (100C>T), ABCB1 (3435C>T), and ABCC2 (−24C>T) were genotyped using allelic discrimination real-time polymerase chain reaction assays. The impacts of prognostic clinical factors and genetic variants on disease-free survival were analyzed using the Kaplan–Meier method and Cox regression analysis.ResultsIn the univariate analysis, primary tumor size >5 cm was significantly associated with increased risk of distant metastasis (P=0.004; hazard ratio [HR] =3.05; 95% confidence interval [CI], 1.44–6.47). In the multivariate analysis, tumor size >5 cm remained predictive of distant metastasis (P<0.001; HR=5.49; 95% CI, 2.30–13.10). ABCC2 −24CC were shown to be associated with increased risk of distant metastasis (P=0.040; adjusted HR=2.34; 95% CI, 1.04–5.27). The combined genotype of ABCC2 −24CC − ABCB1 3435 CT+TT was associated with increased risk of distant and bone metastasis (P=0.020; adjusted HR=2.46; 95% CI, 1.15–5.26 and P=0.040; adjusted HR=3.70; 95% CI, 1.06–12.89, respectively).ConclusionThis study indicates that polymorphisms of ABCC2 and ABCB1 are independently associated with bone metastasis. Further prospective studies with larger sample sizes are needed to verify this finding.

Comparative Analysis of Patient-Matched PDOs Revealed a Reduction in OLFM4-Associated Clusters in Metastatic Lesions in Colorectal Cancer

“…Two ABC transporters, ABCC2 and ABCB1, exhibited the most significant differences (fold change = 2.73, p = 0.0006 and fold change = 2.58, p = 0.0003, respectively). These proteins are involved in the transport of tamoxifen ( Iusuf et al., 2011 ), and polymorphisms in their genes are associated with the risk of metastasis and recurrence in hormone receptor-positive breast cancer ( Kiyotani et al., 2010 ; Sensorn et al., 2013 , 2016 ), suggesting their roles in the metastasis process. Furthermore, overexpression of these genes confers cancer cell resistance to various chemotherapeutic agents ( Taniguchi et al., 1996 ; Xie et al., 2010 ).…”

CYP2D6 Genotype Predicts Plasma Concentrations of Tamoxifen Metabolites in Ethiopian Breast Cancer Patients

“…Moreover, several other studies also substantiated the impact of ABCB1 in relation to clinical outcome of tamoxifen. ABCB1 polymorphism was associated with risk of recurrence or disease free survival (DFS), in breast cancer patients on tamoxifen treatment [16,42,43].…”

The Underrated Risks of Tamoxifen Drug Interactions

“…Another study of 73 breast cancer patients also found reduced tamoxifen efficacy associated with a wild-type allele ABCC2 as compared to variant alleles with reduced ABCC2 activity [ 41 ]. Further, they found that the combination of higher ABCC2 activity (ABCC2 CC) with higher ABCB1 activity (ABCB1 CT + TT) was associated with reduced disease-free survival compared to any other combination of genotypes for ABCC2 and ABCB1.…”