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


METHODS
Genomic 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.


RESULTS
In 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).


CONCLUSIONS
This 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.
Department of Pharmacology, Faculty of Science, Mahidol University, Bangkok, Thailand.
Insee
I
Sensorn
Division of Pharmacogenomics and Personalized Medicine, Department of Pathology, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.
Chonlaphat
C
Sukasem
Division of Medical Oncology, Department of Medicine, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.
Ekaphop
E
Sirachainan
Division of Pharmacogenomics and Personalized Medicine, Department of Pathology, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.
Montri
M
Chamnanphon
Division of Virology, Department of Pathology, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.
Ekawat
E
Pasomsub
Research Center, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.
Narumol
N
Trachu
Department of Pharmacology, Faculty of Science, Mahidol University, Bangkok, Thailand.
Porntip
P
Supavilai
Department of Pharmacology, Faculty of Science, Mahidol University, Bangkok, Thailand.
Darawan
D
Pinthong
Division of Anatomical Pathology, Department of Pathology, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.
Sansanee
S
Wongwaisayawan
ABCB1; ABCC2; breast cancer; distant metastasis; pharmacogenetics; tamoxifen