Variations in plasma concentrations of tamoxifen metabolites and the effects of genetic polymorphisms on tamoxifen metabolism in Korean patients with breast cancer

Inter-individual variation in tamoxifen metabolism in breast cancer patients is caused by various genetic and clinical factors. We measured the plasma concentrations of tamoxifen and its metabolites and investigated genetic polymorphisms influencing those concentrations. We measured the concentrations of tamoxifen, endoxifen, N-desmethyltamoxifen (NDM), and 4-hydroxytamoxifen (4-OH tamoxifen) in 550 plasma specimens from 281 breast cancer patients treated with tamoxifen. Duplicate or triplicate specimens were obtained from 179 patients at 3-month intervals. In 80 patients, genotyping for tamoxifen metabolizing enzymes was performed using the DMET Plus array and long-range PCR. Plasma concentrations of tamoxifen and its metabolites showed wide variations among patients. The following genetic polymorphisms were associated with the plasma concentrations when body mass index and tamoxifen concentrations were considered as co-variables: CYP1A2 -2467delT, CYP2B6 genotype, CYP2D6 activity score (AS), and FMO3 441C>T. CYP2D6 AS and three variants in the SULT1E1 gene showed correlation with ratios of tamoxifen metabolites. CYP2D6 AS was the only variable that showed associations with both metabolite concentration and ratio: endoxifen (P < 0.001), NDM (P < 0.001), endoxifen/NDM (P < 0.001), NDM/tamoxifen (P < 0.001), and 4-OH tamoxifen/tamoxifen (P = 0.005). Serial measurements of 448 plasma concentrations in 179 patients at 3-month intervals showed wide intra-individual variation. Our study showed that genetic polymorphisms can in part determine the baseline concentrations of tamoxifen and its metabolites. However, marked intra-individual variations during follow-up monitoring were observed, and this could not be explained by genotype. Therefore, serial measurements of tamoxifen and its metabolites would be helpful in monitoring in vivo tamoxifen metabolic status.

[1]  R. Mathijssen,et al.  Individualized Tamoxifen Dose Escalation—Letter , 2016, Clinical Cancer Research.

[2]  T. Hatschek,et al.  Pronounced Interindividual But Not Intraindividual Variation in Tamoxifen and Metabolite Levels in Plasma During Adjuvant Treatment of Women With Early Breast Cancer , 2016, Therapeutic drug monitoring.

[3]  V. Gebski,et al.  Dose Escalation of Tamoxifen in Patients with Low Endoxifen Level: Evidence for Therapeutic Drug Monitoring—The TADE Study , 2016, Clinical Cancer Research.

[4]  G. Grech,et al.  Actionable pharmacogenetic markers for prediction and prognosis in breast cancer , 2015, EPMA Journal.

[5]  F. Bandrés,et al.  Impacts of the Glucuronidase Genotypes UGT1A4, UGT2B7, UGT2B15 and UGT2B17 on Tamoxifen Metabolism in Breast Cancer Patients , 2015, PloS one.

[6]  W. Zwart,et al.  Effects of Pharmacogenetics on the Pharmacokinetics and Pharmacodynamics of Tamoxifen , 2015, Clinical Pharmacokinetics.

[7]  A. Jager,et al.  Individualization of tamoxifen therapy: much more than just CYP2D6 genotyping. , 2015, Cancer treatment reviews.

[8]  H. Brauch,et al.  Tamoxifen metabolism predicts drug concentrations and outcome in premenopausal patients with early breast cancer , 2014, The Pharmacogenomics Journal.

[9]  Vered Stearns,et al.  Adjuvant endocrine therapy for women with hormone receptor-positive breast cancer: american society of clinical oncology clinical practice guideline focused update. , 2014, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[10]  S. Linn,et al.  Tamoxifen dose and serum concentrations of tamoxifen and six of its metabolites in routine clinical outpatient care , 2014, Breast Cancer Research and Treatment.

[11]  A. Gaedigk.  Complexities of CYP2D6 gene analysis and interpretation , 2013, International review of psychiatry.

[12]  T. Aas,et al.  Serum concentrations of tamoxifen and its metabolites increase with age during steady-state treatment , 2013, Breast Cancer Research and Treatment.

[13]  D. Panomvana,et al.  Effects of CYP2D6 and UGT2B7 polymorphisms on pharmacokinetics of tamoxifen in Thai breast cancer patients , 2013, Breast cancer.

[14]  A. Tejerina,et al.  Relationship between Genotypes Sult1a2 and Cyp2d6 and Tamoxifen Metabolism in Breast Cancer Patients , 2013, PloS one.

[15]  H. Putter,et al.  CYP2D6 genotype in relation to tamoxifen efficacy in a Dutch cohort of the tamoxifen exemestane adjuvant multinational (TEAM) trial , 2013, Breast Cancer Research and Treatment.

[16]  F. Bandrés,et al.  Influence of CYP2D6 Polymorphisms on Serum Levels of Tamoxifen Metabolites in Spanish Women with Breast Cancer , 2013, International journal of medical sciences.

[17]  J J Swen,et al.  Clinical Pharmacogenetics Implementation Consortium Guideline for CYP2D6 and CYP2C19 Genotypes and Dosing of Tricyclic Antidepressants , 2013, Clinical pharmacology and therapeutics.

[18]  Ming-Feng Hou,et al.  Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years after diagnosis of oestrogen receptor-positive breast cancer: ATLAS, a randomised trial , 2013, The Lancet.

[19]  T E Klein,et al.  Clinical Pharmacogenetics Implementation Consortium (CPIC) Guidelines for Codeine Therapy in the Context of Cytochrome P450 2D6 (CYP2D6) Genotype , 2012, Clinical pharmacology and therapeutics.

[20]  E. Wiemer,et al.  Quantification of tamoxifen and three of its phase-I metabolites in human plasma by liquid chromatography/triple-quadrupole mass spectrometry. , 2011, Journal of pharmaceutical and biomedical analysis.

[21]  R. Desnick,et al.  Increasing Tamoxifen Dose in Breast Cancer Patients Based on CYP2D6 Genotypes and Endoxifen Levels: Effect on Active Metabolite Isomers and the Antiestrogenic Activity Score , 2011, Clinical pharmacology and therapeutics.

[22]  Early Breast Cancer Trialists' Collaborative Group.  Relevance of breast cancer hormone receptors and other factors to the efficacy of adjuvant tamoxifen: patient-level meta-analysis of randomised trials , 2011, The Lancet.

[23]  L. Natarajan,et al.  Tamoxifen Metabolite Concentrations, CYP2D6 Genotype, and Breast Cancer Outcomes , 2011, Clinical pharmacology and therapeutics.

[24]  T. Fehm,et al.  Activity Levels of Tamoxifen Metabolites at the Estrogen Receptor and the Impact of Genetic Polymorphisms of Phase I and II Enzymes on Their Concentration Levels in Plasma , 2011, Clinical pharmacology and therapeutics.

[25]  Y. Yap,et al.  Impact of CYP2D6, CYP3A5, CYP2C9 and CYP2C19 polymorphisms on tamoxifen pharmacokinetics in Asian breast cancer patients. , 2011, British journal of clinical pharmacology.

[26]  C. Caldas,et al.  CYP2D6 gene variants: association with breast cancer specific survival in a cohort of breast cancer patients from the United Kingdom treated with adjuvant tamoxifen , 2010, Breast Cancer Research.

[27]  M. Beckmann,et al.  Association between CYP2D6 polymorphisms and outcomes among women with early stage breast cancer treated with tamoxifen. , 2009, JAMA.

[28]  Lei He,et al.  Association between CYP2D6 *10 genotype and survival of breast cancer patients receiving tamoxifen treatment. , 2008, Annals of oncology : official journal of the European Society for Medical Oncology.

[29]  A. Gaedigk,et al.  The CYP2D6 Activity Score: Translating Genotype Information into a Qualitative Measure of Phenotype , 2008, Clinical pharmacology and therapeutics.

[30]  Hyeong-Seok Lim,et al.  Clinical implications of CYP2D6 genotypes predictive of tamoxifen pharmacokinetics in metastatic breast cancer. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[31]  Zeruesenay Desta,et al.  Quantitative effect of CYP2D6 genotype and inhibitors on tamoxifen metabolism: Implication for optimization of breast cancer treatment , 2006, Clinical pharmacology and therapeutics.

[32]  Soo-Youn Lee,et al.  Sequence-based CYP2D6 Genotyping in the Korean Population , 2006, Therapeutic drug monitoring.

[33]  K. Muro,et al.  Quaternary ammonium-linked glucuronidation of trans-4-hydroxytamoxifen, an active metabolite of tamoxifen, by human liver microsomes and UDP-glucuronosyltransferase 1A4. , 2006, Biochemical pharmacology.

[34]  David E. Williams,et al.  The Role of Flavin-Containing Monooxygenase (FMO) in the Metabolism of Tamoxifen and Other Tertiary Amines , 2006, Drug metabolism reviews.

[35]  Y Wang,et al.  Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials , 2005, The Lancet.

[36]  David A. Flockhart,et al.  CYP2D6 genotype, antidepressant use, and tamoxifen metabolism during adjuvant breast cancer treatment. , 2005, Journal of the National Cancer Institute.

[37]  David A. Flockhart,et al.  Comprehensive Evaluation of Tamoxifen Sequential Biotransformation by the Human Cytochrome P450 System in Vitro: Prominent Roles for CYP3A and CYP2D6 , 2004, Journal of Pharmacology and Experimental Therapeutics.

[38]  T. Skaar,et al.  Pharmacological Characterization of 4-hydroxy-N-desmethyl Tamoxifen, a Novel Active Metabolite of Tamoxifen , 2004, Breast Cancer Research and Treatment.

[39]  K. Muro,et al.  Reverse geometrical selectivity in glucuronidation and sulfation of cis- and trans-4-hydroxytamoxifens by human liver UDP-glucuronosyltransferases and sulfotransferases. , 2002, Biochemical pharmacology.

[40]  S. Legha,et al.  Tamoxifen in the treatment of breast cancer. , 1988, Annals of internal medicine.

[41]  Nigel J. Clarke.  Mass Spectrometry in Precision Medicine: Phenotypic Measurements Alongside Pharmacogenomics. , 2016, Clinical chemistry.

[42]  David A. Flockhart,et al.  Tamoxifen metabolites as active inhibitors of aromatase in the treatment of breast cancer , 2011, Breast Cancer Research and Treatment.

[43]  S. Lundgren,et al.  Effects of CYP2D6 and SULT1A1 genotypes including SULT1A1 gene copy number on tamoxifen metabolism. , 2008, Annals of oncology : official journal of the European Society for Medical Oncology.

[44]  L. D. Bradford,et al.  CYP2D6 allele frequency in European Caucasians, Asians, Africans and their descendants. , 2002, Pharmacogenomics.