[Show abstract][Hide abstract] ABSTRACT: Tamoxifen is the standard-of-care treatment for estrogen receptor-positive premenopausal breast cancer. We examined tamoxifen metabolism via blood metabolite concentrations and germline variations of CYP3A5, CYP2C9, CYP2C19 and CYP2D6 in 587 premenopausal patients (Asians, Middle Eastern Arabs, Caucasian-UK; median age 39 years) and clinical outcome in 306 patients. N-desmethyltamoxifen (DM-Tam)/(Z)-endoxifen and CYP2D6 phenotype significantly correlated across ethnicities (R(2): 53%, P<10(-77)). CYP2C19 and CYP2C9 correlated with norendoxifen and (Z)-4-hydroxytamoxifen concentrations, respectively (P<0.001). DM-Tam was influenced by body mass index (P<0.001). Improved distant relapse-free survival (DRFS) was associated with decreasing DM-Tam/(Z)-endoxifen (P=0.036) and increasing CYP2D6 activity score (hazard ratio (HR)=0.62; 95% confidence interval (CI), 0.43-0.91; P=0.013). Low (<14 nM) compared with high (>35 nM) endoxifen concentrations were associated with shorter DRFS (univariate P=0.03; multivariate HR=1.94; 95% CI, 1.04-4.14; P=0.064). Our data indicate that endoxifen formation in premenopausal women depends on CYP2D6 irrespective of ethnicity. Low endoxifen concentration/formation and decreased CYP2D6 activity predict shorter DRFS.The Pharmacogenomics Journal advance online publication, 5 August 2014; doi:10.1038/tpj.2014.34.
The Pharmacogenomics Journal 08/2014; · 5.51 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Genome-wide association studies (GWAS) have identified various genetic susceptibility loci for breast cancer based mainly on European-ancestry populations. Differing linkage disequilibrium patterns exist between European and Asian populations, and thus GWAS-identified single nucleotide polymorphisms (SNPs) in one population may not be of significance in another population. In order to explore the role of breast cancer susceptibility variants in a Chinese population of Southern Chinese descent, we analyzed 22 SNPs for 1,191 breast cancer cases and 1,534 female controls. Associations between the SNPs and clinicopathological features were also investigated. In addition, we evaluated the combined effects of associated SNPs by constructing risk models. Eight SNPs were associated with an elevated breast cancer risk. Rs2046210/6q25.1 increased breast cancer risk via an additive model [per-allele odds ratio (OR) = 1.43, 95 % confidence interval (CI) = 1.26-1.62], and was associated with estrogen receptor (ER)-positive (per-allele OR = 1.39, 95 % CI = 1.20-1.61) and ER-negative (per-allele OR = 1.55, 95 % CI = 1.28-1.89) disease. Rs2046210 was also associated with stage 1, stage 2, and stage 3 disease, with per-allele ORs of 1.38 (1.14-1.68), 1.48 (1.25-1.74), and 1.58 (1.28-1.94), respectively. Four SNPs mapped to 10q26.13/FGFR2 were associated with increased breast cancer risk via an additive model with per-allelic risks (95 % CI) of 1.26 (1.12-1.43) at rs1219648, 1.22 (1.07-1.38) at rs2981582, 1.21 (1.07-1.36) at rs2981579, and 1.18 (1.04-1.35) at rs11200014. Variants of rs7696175/TLR1, TLR6, rs13281615/8q24, and rs16886165/MAP3K1 were also associated with increased breast cancer risk, with per-allele ORs (95 % CI) of 1.16 (1.00-1.34), 1.15 (1.02-1.29), and 1.15 (1.01-1.29), respectively. Five SNPs associated with breast cancer risk predominantly among ER-positive tumors (rs2981582/FGFR2, rs4415084/MRPS30, rs1219648/FGFR2, rs2981579/FGFR2, and rs11200014/FGFR2). Among our Chinese population, the risk of developing breast cancer increased by 90 % for those with a combination of 6 or more risk alleles, compared to patients with ≤3 risk alleles.
Breast Cancer Research and Treatment 09/2012; 136(1):209-20. · 4.47 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background:In Asia, large-scale studies on anti-HER2 treatment in HER2-positive breast cancer patients with brain metastases are limited. We studied the treatment patterns of these patients in Asia to evaluate the impact of anti-HER2 treatment on the time to occurrence of brain metastases (TTBM) and survival after brain metastasis (BM).Methods:A retrospective study of HER2-positive breast cancer patients diagnosed with BM between January 2006 and December 2008 in six Asian countries was conducted. Demographics, tumour characteristics, treatment details, and events dates were collected from medical records.Results:Data from 280 patients were analysed. Before BM, 63% received anti-HER2 treatment. These patients had significantly longer TTBM than those without anti-HER2 treatment (median 33 vs 19 months; P<0.002). After BM, 93% received radiotherapy, 57% received chemotherapy, and 41% received anti-HER2 treatment (trastuzumab and/or lapatinib). Use of both anti-HER2 agents, primarily sequentially, after BM demonstrated the longest survival after BM and was associated with a significant survival benefit over no anti-HER2 treatment (median 26 vs 6 months; hazard ratio 0.37; 95% CI 0.19-0.72).Conclusion:Anti-HER2 treatment before BM was associated with longer TTBM. Anti-HER2 treatment after BM was associated with a survival benefit, especially when both trastuzumab and lapatinib were utilised.
British Journal of Cancer 08/2012; 107(7):1075-82. · 5.08 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Tamoxifen (TAM) is a prodrug with a complex metabolic pathway involving several metabolic enzymes. Although TAM is mainly metabolised by cytochrome P450 (CYP) 2D6 and CYP3A4/5 enzymes, other CYP enzymes such as CYP1A2, CYP2B6, CYP2C9, and CYP2C19, also catalysed the metabolism of TAM to N-desmethyltamoxifen (NDM), 4-hydroxytamoxifen (4OHT) and endoxifen (END) with 4OHT and END being the active metabolites of TAM. The aim of this study was to investigate the impact of CYP2C19 polymorphisms on the plasma concentrations and metabolic ratios of TAM and its three metabolites, NDM, 4OHT and END. The exons and intron-boundaries of CYP2C19 gene as well as the upstream and downstream regions (about 14 kilobases) were sequenced in 240 Asian healthy subjects (Chinese, Malay, Indians, N=80 each) to identify the polymorphisms present in Asian population. Linkage disequilibrium between identified polymorphisms was examined via Haploview (version 4.0) and tag-SNPs were identified via TAGGER. These tag-SNPs were subsequently genotyped in 164 Asian breast cancer patients using direct sequencing. Plasma levels of TAM and its metabolites were determined at steady state using HPLC with fluorescence detection. Genotypic-phenotypic associations were performed using non-parametric Kruskal-Wallis test and Mann-Whitney U-test. A moderate linkage pattern was observed across the CYP2C19 polymorphisms in the three Asian healthy populations. A total of 13 tag-SNPs and one reported functional SNP were analyzed in Asian breast cancer patients. Patients carrying the AC and CC genotypes of the exonic polymorphism 1251A>C (rs17886522) was associated with 2.3-fold reduction in the median (range) MREND-NDM compared to patients with the reference genotype [AA vs AC+CC: 5.14 (0.92 – 27.81) vs 2.25 (1.26 – 10.72), P = 0.026]. In contrast, median (range) MREND-4-OHT was found to be 1.3-fold higher in patients carrying one or two copies of the -3219T>G variant allele compared to patients carrying the two copies of wild-type allele [TT vs TG + GG: 6.57 (1.99 – 13.18) vs 8.76 (3.78 – 12.80), P = 0.001]. Modest increases in the plasma concentrations of TAM and NDM were associated with 1251A>C (rs17886522). In addition to CYP2D6 polymorphisms, polymorphic variants present in the 5 upstream region of CYP2C19 were found to influence the metabolic ratios of TAM and its metabolites but not the plasma concentrations of the analytes in this exploratory study. The combinative effect of genetic variants in various phase I pharmacogenes on plasma levels of tamoxifen warrants further study.
Cancer Research 06/2012; 72(8 Supplement):2668-2668. · 9.28 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To investigate the impact of genetic polymorphisms in CYP2D6, CYP3A5, CYP2C9 and CYP2C19 on the pharmacokinetics of tamoxifen and its metabolites in Asian breast cancer patients.
A total of 165 Asian breast cancer patients receiving 20 mg tamoxifen daily and 228 healthy Asian subjects (Chinese, Malay and Indian; n= 76 each) were recruited. The steady-state plasma concentrations of tamoxifen and its metabolites were quantified using high-performance liquid chromatography. The CYP2D6 polymorphisms were genotyped using the INFINITI™ CYP450 2D6I assay, while the polymorphisms in CYP3A5, CYP2C9 and CYP2C19 were determined via direct sequencing.
The polymorphisms, CYP2D6*5 and *10, were significantly associated with lower endoxifen and higher N-desmethyltamoxifen (NDM) concentrations. Patients who were *1/*1 carriers exhibited 2.4- to 2.6-fold higher endoxifen concentrations and 1.9- to 2.1-fold lower NDM concentrations than either *10/*10 or *5/*10 carriers (P < 0.001). Similarly, the endoxifen concentrations were found to be 1.8- to 2.6-times higher in *1/*5 or *1/*10 carriers compared with *10/*10 and *5/*10 carriers (P≤ 0.001). Similar relationships were observed between the CYP2D6 polymorphisms and metabolic ratios of tamoxifen and its metabolites. No significant associations were observed with regards to the polymorphisms in CYP3A5, CYP2C9 and CYP2C19.
The present study in Asian breast cancer patients showed that CYP2D6*5/*10 and *10/*10 genotypes are associated with significantly lower concentrations of the active metabolite of tamoxifen, endoxifen. Identifying such patients before the start of treatment may be useful in optimizing therapy with tamoxifen. The role of CYP3A5, CYP2C9 and CYP2C19 seem to be minor.
British Journal of Clinical Pharmacology 05/2011; 71(5):737-50. · 3.69 Impact Factor