Search Our Scientific Publications & Authors

J Cancer Res Clin Oncol 2020 Jun 8;146(6):1395-1404. Epub 2020 Apr 8.

The Nethersole School of Nursing, Faculty of Medicine, The Chinese University of Hong Kong, 6/F Esther Lee Building, Hong Kong, China.

Purpose: To review recent pharmacogenomics studies on breast cancer patients undergoing tamoxifen therapy, highlighting how our knowledge on cytochrome P450 2D6 (CYP2D6) can help to guide the development of adjuvant therapies for these patients.

Methods: A comprehensive literature search was conducted. Articles reporting findings pertaining to the effect of CYP2D6 on the therapeutic efficacy of tamoxifen, those reporting how targeting CYP2D6 could inform tamoxifen-based therapy development, and those on the tamoxifen effects on cell lines and animal models were included in the review. Read More

J Endocrinol 2020 May;245(2):301-314

National Institutes of Health, National Cancer Institute, Laboratory of Metabolism, Bethesda, Maryland, USA.

The CYP2D subfamily catalyses the metabolism of about 25% of prescribed drugs, including the majority of antidepressants and antipsychotics. At present, the mechanism of hepatic CYP2D regulation remains largely unknown. This study investigated the role of sex steroid hormones in CYP2D regulation. Read More

Medicine (Baltimore) 2020 Feb;99(8):e19083

The Nethersole School of Nursing, The Chinese University of Hong Kong, Hong Kong.

Background: Breast cancer is the most prevalent cancer in females and disease recurrence remains a significant problem. To prevent recurrence, tamoxifen is prescribed for at least 5 years. However, among patients who receive tamoxifen, individual responses are highly variable. Read More

Mol Psychiatry 2020 Feb 11. Epub 2020 Feb 11.

Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, 94305, USA.

Genome-wide association studies (GWAS) have successfully identified 145 loci implicated in schizophrenia (SCZ). However, the underlying mechanisms remain largely unknown. Here, we analyze 1497 RNA-seq data in combination with their genotype data and identify SNPs that are associated with expression throughout the genome by dissecting expression features to genes (eGene) and exon-exon junctions (eJunction). Read More

Drug Dev Res 2020 Jun 9;81(4):444-455. Epub 2020 Jan 9.

Institute of Zoology, Faculty of Biology, Technische Universität Dresden, Dresden, Germany.

Tamoxifen (TAM) is currently the endocrine treatment of choice for all stages of breast cancer; it has proven success in ER positive and ER negative patients. TAM is activated by endogenous CYP450 enzymes to the more biologically active metabolites 4-hydroxytamoxifen and endoxifen mainly via CYP2D6 and CYP3A4/5. CYP2D6 has been investigated for polymorphism; there is a large interindividual variation in the enzyme activity, this drastically effects clinical outcomes of tamoxifen treatment. Read More

BMC Pharmacol Toxicol 2019 12 19;20(Suppl 1):81. Epub 2019 Dec 19.

Department of Clinical Analysis, Toxicology and Food Science, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil.

Background: Tamoxifen is considered a prodrug of its active metabolite endoxifen, which is dependent on the CYP2D6 and CYP3A enzymes. Tamoxifen pharmacokinetic variability influences endoxifen exposure and, consequently, its clinical outcome. This study investigated the impact of hormonal status on the pharmacokinetics of tamoxifen and its metabolites in TAM-treated breast cancer patients. Read More

Clin Transl Sci 2020 Mar 9;13(2):284-292. Epub 2019 Nov 9.

Pontifical Catholic University of Parana, Curitiba, Brazil.

Tamoxifen efficacy in breast cancer is suspected to depend on adherence and intact drug metabolism. We evaluated the role of adherence behavior and pharmacogenetics on the formation rate of (Z)-endoxifen. In 192 Brazilian patients, we assessed plasma levels of tamoxifen and its metabolites at 3, 6, and 12 months of treatment (liquid-chromatography tandem mass spectrometry), adherence behavior (Morisky, Green, and Levine medication adherence scale), and cytochrome P450 2D6 (CYP2D6) and other pharmacogene polymorphisms (matrix-assisted laser-desorption-ionization time of flight) mass spectrometry, real-time polymerase chain reaction). Read More

Clin Drug Investig 2020 Jan;40(1):25-32

Department of Pharmacy, Shengli Clinical Medical College of Fujian Medical University, Fujian Provincial Hospital, Fuzhou, Fujian, 350001, China.

Background: A CYP2D6 gene polymorphism is related to the effect of tamoxifen treatment in patient with estrogen-receptor positive (ER) positive breast cancer and CYP2D6*10 T/T can lead to a poor prognosis in Asian patients. Although one-off pharmacogenetic testing may optimize adjuvant endocrine therapy, testing prior to tamoxifen initiation incurs additional costs.

Aim: We conducted a study to assess the cost-effectiveness of CYP2D6*10 pharmacogenetic testing to guide the adjuvant endocrine therapy compared with tamoxifen without CYP2D6*10 testing in China. Read More

J Clin Med 2019 Jul 24;8(8). Epub 2019 Jul 24.

Department of Gastroenterology, Hepatology and Clinical Oncology, Centre of Postgraduate Medical Education, 01-813 Warsaw, Poland.

A certain minimum plasma concentration of ()-endoxifen is presumably required for breast cancer patients to benefit from tamoxifen therapy. In this study, we searched for DNA variants that could aid in the prediction of risk for insufficient ()-endoxifen exposure. A metabolic ratio (MR) corresponding to the ()-endoxifen efficacy threshold level was adopted as a cutoff value for a genome-wide association study comprised of 287 breast cancer patients. Read More

J Clin Oncol 2019 08 18;37(22):1981-1982. Epub 2019 Jun 18.

Hiltrud Brauch, PhD, Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany, University of Tübingen, Tübingen, Germany, and German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany; Werner Schroth, PhD and Thomas Mürdter, PhD, Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany, and University of Tübingen, Tübingen, Germany; and Matthias Schwab, MD, Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany, University of Tübingen, Tübingen, Germany, and German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany.

Toxicol Appl Pharmacol 2019 09 10;378:114619. Epub 2019 Jun 10.

National Research Institute of Chinese Medicine, Taipei, Taiwan; Department and Institute of Pharmacology, School of Medicine, National Yang-Ming University, Taipei, Taiwan; Institute of Biopharmaceutical Sciences, School of Pharmacy, National Yang-Ming University, Taipei, Taiwan; Institute of Medical Sciences, Taipei Medical University, Taipei, Taiwan. Electronic address:

Breast cancer patients with high cholesterol biosynthesis signature had poorer therapeutic outcome. Cytochrome P450 (CYP) 2D6 is crucial in the oxidation of tamoxifen to generate active metabolites, 4-hydroxytamoxifen and endoxifen. CYP2D6 variants with C100T substitution encode null or poor functional proteins. Read More

Breast 2019 Aug 6;46:52-57. Epub 2019 May 6.

Crown Princess Mary Cancer Centre, Westmead Hospital, Westmead, Australia; Faculty of Medicine and Health, The University of Sydney, Camperdown, Australia.

Objectives: Severe hot flash (HF) toxicity due to tamoxifen can compromise compliance. We previously found that HFs did not correlate with endoxifen level or CYP2D6 genotype. In this study, we reduced tamoxifen dose in patients with severe HFs to determine whether HFs were ameliorated whilst maintaining a purported therapeutic endoxifen level of >15 nM. Read More

Expert Rev Clin Pharmacol 2019 Jun 30;12(6):523-536. Epub 2019 Apr 30.

a Leiden Network for Personalised Therapeutics , Leiden University Medical Center , Leiden , The Netherlands.

: Tamoxifen dominates the anti-estrogenic therapy in the early and metastatic breast cancer setting. Tamoxifen has a complex metabolism, being mainly metabolized by CYP2D6 into its 30-100 times more potent metabolite, endoxifen. Recently, a phase I study in which endoxifen as an orally z-endoxifen hydrochloride has been successfully evaluated. Read More

Cancers (Basel) 2019 Mar 22;11(3). Epub 2019 Mar 22.

Department of Medical Oncology, Erasmus MC Cancer Institute, Dr. Molewaterplein 40, 3015 GD Rotterdam, The Netherlands.

Tamoxifen is a prodrug that is primarily metabolized into the pharmacologically active metabolite endoxifen and eventually into inactive metabolites. The herb curcumin may increase endoxifen exposure by affecting phase II metabolism. We compared endoxifen and tamoxifen exposure in breast cancer patients with or without curcumin, and with addition of the bio-enhancer piperine. Read More

Endocr Metab Immune Disord Drug Targets 2019 ;19(8):1198-1206

Department of Pharmacology and Therapeutics, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia.

Background: Tamoxifen (TAM) is a frequently used hormonal prodrug for patients with breast cancer that needs to be activated by cytochrome P450 2D6 (CYP2D6) into Zusammen-endoxifen (Z-END).

Objective: The purpose of the study was to determine the association between CYP2D6*10 (c.100C>T) genotype and attainment of the plasma steady-state Z-END minimal threshold concentration (MTC) in Indonesian women with breast cancer. Read More

Clin Pharmacol Ther 2019 09 10;106(3):585-595. Epub 2019 Apr 10.

Cancer Research Center of Toulouse (CRCT), Inserm U1037, Université Paul Sabatier, Toulouse, France.

In addition to the effect of cytochrome P450 (CYP) 2D6 genetic polymorphisms, the metabolism of tamoxifen may be impacted by other factors with possible consequences on therapeutic outcome (efficacy and toxicity). This analysis focused on the pharmacokinetic (PK)-pharmacogenetic evaluation of tamoxifen in 730 patients with adjuvant breast cancer included in a prospective multicenter study. Plasma concentrations of tamoxifen and six major metabolites, the genotype for 63 single-nucleotide polymorphisms, and comedications were obtained 6 months after treatment initiation. Read More

Breast Cancer 2019 Sep 7;26(5):535-543. Epub 2019 Feb 7.

Department of Breast Surgery, Graduate School of Medicine Kyoto University, Kyoto, Japan.

Background: An association between CYP2D6 polymorphisms and tamoxifen (TAM) efficacy has not been confirmed, partly due to unreliable prediction of active metabolite exposure solely by CYP2D6 activity. The efficacy of TAM dose escalation appears limited in poor TAM metabolizers. Since the chlorine atom on the side chain of toremifene (TOR) prevents 4-hydroxylation by CYP2D6, its contribution to active conversion of TOR is minor. Read More

J Clin Oncol 2019 03 24;37(8):636-646. Epub 2019 Jan 24.

1 Leiden University Medical Center, Leiden, the Netherlands.

Purpose: Tamoxifen is widely prescribed as adjuvant therapy in patients with early-stage breast cancer. It has been postulated that concentrations of endoxifen, the active metabolite of tamoxifen, are a better predictor of tamoxifen efficacy than CYP2D6 genotypes. Although in a retrospective study, an endoxifen threshold of 5. Read More

BMC Complement Altern Med 2019 Jan 18;19(1):23. Epub 2019 Jan 18.

Society for Cancer Research, Hiscia Institute, Arlesheim, Switzerland.

Background: Women diagnosed with breast cancer frequently seek complementary and alternative (CAM) treatment options that can help to cope with their disease and the side effects of conventional cancer therapy. Especially in Europe, breast cancer patients use herbal products containing mistletoe (Viscum album L.). Read More

Cancer Causes Control 2019 Jan 12;30(1):103-112. Epub 2018 Dec 12.

University of Washington, Seattle, WA, USA.

Purpose: Tamoxifen is widely used to reduce the risk of breast cancer (BC) recurrence and extend disease-free survival among women with estrogen-sensitive breast cancers. Tamoxifen efficacy is thought to be attributable to its active metabolite, which is formed through a reaction catalyzed by the P450 enzyme, CYP2D6. Inhibition of tamoxifen metabolism as a result of germline genetic variation and/or use of CYP2D6-inhibiting medications ("inhibitors") is hypothesized to increase the risk of adverse BC outcomes among women taking tamoxifen. Read More

Breast Cancer Res 2018 12 10;20(1):149. Epub 2018 Dec 10.

Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Background: Tamoxifen treatment greatly reduces a woman's risk of developing a second primary breast cancer. There is, however, substantial variability in treatment response, some of which may be attributed to germline genetic variation. CYP2D6 is a key enzyme in the metabolism of tamoxifen to its active metabolites, and variants in this gene have been associated with reduced tamoxifen metabolism. Read More

Breast Cancer Res Treat 2019 Feb 8;173(3):521-532. Epub 2018 Nov 8.

BC Children's Hospital Research Institute, Vancouver, BC, Canada.

Purpose: Tamoxifen is one of the principal treatments for estrogen receptor (ER)-positive breast cancer. Unfortunately, between 30 and 50% of patients receiving this hormonal therapy relapse. Since CYP2D6 genetic variants have been reported to play an important role in survival outcomes after treatment with tamoxifen, this study sought to summarize and critically appraise the available scientific evidence on this topic. Read More

Cancer Chemother Pharmacol 2019 01 24;83(1):71-79. Epub 2018 Oct 24.

Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Pharmacy, Peking University Cancer Hospital and Institute, No.52, Fu Cheng Road, Hai Dian District, Beijing, 100142, People's Republic of China.

Purpose: Insufficient serum metabolite concentrations of tamoxifen can compromise treatment efficacy in patients with breast cancer. The purpose of this meta-analysis was to explore correlations between cytochrome P450 (CYP) 2D6*10 gene polymorphisms and serum concentrations of tamoxifen and its active metabolites in patients with breast cancer in Asia.

Methods: The study included a systematic literature search for cohort studies published before March 2018 in English databases (PubMed, Embase, Cochrane Library, and Web of Science) and Chinese databases (Chinese National Knowledge Infrastructure and Wan Fang database). Read More

PLoS One 2018 22;13(8):e0202534. Epub 2018 Aug 22.

Molecular Modeling Group, Department of Pharmaceutical Sciences, University of Basel, Basel, Switzerland.

Characterization of cytochrome P450 2D6 (CYP2D6) and the impact of the major identified allelic variants on the activity of one of the most dominating drug-metabolising enzymes is essential to increase drug safety and avoid adverse reactions. Microsecond molecular dynamics simulations have been performed to capture the dynamic signatures of this complex enzyme and five allelic variants with diverse enzymatic activity. In addition to the apo simulations, three substrates (bufuralol, veliparib and tamoxifen) and two inhibitors (prinomastat and quinidine) were included to explore their influence on the structure and dynamical features of the enzyme. Read More

Breast Cancer Res Treat 2018 Nov 17;172(2):401-411. Epub 2018 Aug 17.

Department of Clinical Pharmacy & Toxicology, Leiden University Medical Center, Albinusdreef 2, 2300 RC, Leiden, The Netherlands.

Purpose: Tamoxifen has a wide inter-variability. Recently, two SNPs in the 3'-untranslated region (UTR) of the SULT1A1 gene, rs6839 and rs1042157, have been associated with decreased SULT1A1 activity. The aim of this study is to investigate the role of the rs6839 and rs1042157 on tamoxifen metabolism and relapse-free survival (RFS) in women diagnosed with early-breast cancer receiving tamoxifen. Read More

Pharmacogenomics 2018 08 19;19(13):1027-1037. Epub 2018 Jul 19.

Department of Oncology & Pathology, Karolinska Institutet, SE171-76 Stockholm, Sweden.

Aim: We investigated the interaction of CYP2C19 and CYP2D6 genotype on clinical outcome in tamoxifen-treated breast cancer patients.

Materials & Methods: A cohort of 306 patients on tamoxifen treatment for a minimum of 1 year were employed to analyze the effect of genotype-predicted phenotype on relapse-free survival.

Results & Conclusion: We show that the group with worst outcome and highest risk of relapse is that of 2C19↑-2D6↓ (hazard ratio: 2. Read More

Breast Cancer Res Treat 2018 Oct 6;171(3):701-708. Epub 2018 Jul 6.

Department of Medicine, Division of Clinical Pharmacology, Western University, London, ON, N6A 5K5, Canada.

Purpose: Tamoxifen is frequently prescribed to prevent breast cancer recurrence. Tamoxifen is a prodrug and requires bioactivation by CYP2D6. Tamoxifen use is often limited by adverse effects including severe hot flashes. Read More

Int J Cancer 2018 11 19;143(10):2499-2504. Epub 2018 Sep 19.

Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.

Toremifene (TOR) is a valid and safe alternative to tamoxifen (TAM) for adjuvant endocrine therapy in breast cancer patients with a metabolic pathway that differs from that of TAM. TOR might have a therapeutic advantage in certain subgroups of patients, such as Chinese women with the CYP2D6 *10 (c.100C > T) T/T genotype, who would get less benefit when receiving adjuvant TAM treatment. Read More

CPT Pharmacometrics Syst Pharmacol 2018 07 19;7(7):474-482. Epub 2018 Jun 19.

Sugiyama Laboratory, RIKEN Innovation Center, RIKEN, Yokohama, Kanagawa, Japan.

The Tamoxifen Response by CYP2D6 Genotype-based Treatment-1 (TARGET-1) study (n = 180) was conducted from 2012-2017 in Japan to determine the efficacy of tamoxifen dosing guided by cytochrome P450 2D6 (CYP2D6) genotypes. To predict its outcomes prior to completion, we constructed the comprehensive physiologically based pharmacokinetic (PBPK) models of tamoxifen and its metabolites and performed virtual TARGET-1 studies. Our analyses indicated that the expected probability to achieve the end point (demonstrating the superior efficacy of the escalated tamoxifen dose over the standard dose in patients carrying CYP2D6 variants) was 0. Read More

Adv Pharmacol 2018 7;83:65-91. Epub 2018 May 7.

Department of Clinical Biochemistry and Pharmacology, Odense University Hospital, Odense, Denmark; Department of Clinical Research, University of Southern Denmark, Odense, Denmark.

Tamoxifen reduces the rate of breast cancer recurrence by about one-half. It is converted to more active metabolites by enzymes encoded by polymorphic genes, including cytochrome P450 2D6 (CYP2D6) and transported by ATP-binding cassette transporters. Genetic polymorphisms that confer reduced CYP2D6 activity or concurrent use of CYP2D6-inhibiting drugs may reduce the clinical efficacy of tamoxifen. Read More

Eur J Drug Metab Pharmacokinet 2018 Oct;43(5):495-508

Professor Emeritus, School of Pharmacy, University of Washington, Seattle, WA, 98195, USA.

Tamoxifen is a prodrug, and most of the therapeutic effect in treating breast cancer stems from its metabolite, endoxifen. Since cytochrome P450 (CYP) 2D6 is the most important enzyme in the production of endoxifen, drugs that inhibit CYP2D6 would be expected to reduce tamoxifen efficacy. In addition to drug-drug interactions (DDI) involving CYP2D6, there is growing evidence that enzyme inducers can substantially alter the disposition of endoxifen, reducing tamoxifen efficacy. Read More

Biol Pharm Bull 2018 May 14;41(5):722-732. Epub 2018 Feb 14.

Graduate School of Biomedical and Health Sciences, Hiroshima University.

Differentiated HepaRG cells maintain liver-specific functions such as drug-metabolizing enzymes. In this study, the feasibility of HepaRG cells as a human hepatocyte model for in vitro toxicity assessment was examined using selected hepatotoxic compounds. First, basal drug-metabolizing enzyme activities (CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP3A4, uridine 5'-diphospho-glucuronosyltransferase [UGT], and sulfotransferases [SULT]) were measured in HepaRG, human hepatocytes, and HepG2 cells. Read More

Clin Transl Sci 2018 05 13;11(3):312-321. Epub 2018 Feb 13.

Department of Biomedical and Pharmaceutical Sciences, University of Montana, Missoula, Montana, USA.

Despite evidence that pharmacogenetics can improve tamoxifen pharmacotherapy, there are few studies with American Indian and Alaska Native (AIAN) people. We examined variation in cytochrome P450 (CYP) genes (CYP2D6, CYP3A4, CYP3A5, and CYP2C9) and tamoxifen biotransformation in AIAN patients with breast cancer (n = 42) from the Southcentral Foundation in Alaska and the Confederated Salish and Kootenai Tribes in Montana. We tested for associations between CYP diplotypes and plasma concentrations of tamoxifen and metabolites. Read More

Clin Pharmacol Ther 2018 05 31;103(5):770-777. Epub 2018 Jan 31.

Department of Biomedical Data Science, Stanford University, Stanford, California, USA.

Tamoxifen is biotransformed by CYP2D6 to 4-hydroxytamoxifen and 4-hydroxy N-desmethyl tamoxifen (endoxifen), both with greater antiestrogenic potency than the parent drug. Patients with certain CYP2D6 genetic polymorphisms and patients who receive strong CYP2D6 inhibitors exhibit lower endoxifen concentrations and a higher risk of disease recurrence in some studies of tamoxifen adjuvant therapy of early breast cancer. We summarize evidence from the literature and provide therapeutic recommendations for tamoxifen based on CYP2D6 genotype. Read More

Arch Toxicol 2018 Mar 28;92(3):1099-1112. Epub 2017 Dec 28.

Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology and University of Tübingen, Auerbachstr. 112, 70376, Stuttgart, Germany.

Tamoxifen, a standard therapy for breast cancer, is metabolized to compounds with anti-estrogenic as well as estrogen-like action at the estrogen receptor. Little is known about the formation of estrogen-like metabolites and their biological impact. Thus, we characterized the estrogen-like metabolites tamoxifen bisphenol and metabolite E for their metabolic pathway and their influence on cytochrome P450 activity and ADME gene expression. Read More

Oncotarget 2017 Nov 1;8(59):100296-100311. Epub 2017 Nov 1.

Department of Clinical Pharmacology & Therapeutics, Samsung Medical Center, Seoul, Korea.

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. Read More

Breast Cancer Res 2017 Nov 28;19(1):125. Epub 2017 Nov 28.

Department of Clinical Science, University of Bergen, Bergen, Norway.

Background: Controversies exist as to whether the genetic polymorphisms of the enzymes responsible for the metabolism of tamoxifen can predict breast cancer outcome in patients using adjuvant tamoxifen. Direct measurement of concentrations of active tamoxifen metabolites in serum may be a more biological plausible and robust approach. We have investigated the association between CYP2D6 genotypes, serum concentrations of active tamoxifen metabolites, and long-term outcome in tamoxifen treated breast cancer patients. Read More

Front Pharmacol 2017 24;8:582. Epub 2017 Aug 24.

Dr. Margarete Fischer-Bosch-Institute of Clinical PharmacologyStuttgart, Germany.

Prediction of impaired tamoxifen (TAM) to endoxifen metabolism may be relevant to improve breast cancer treatment, e.g., via TAM dose increase. Read More

Pharmacogenet Genomics 2017 11;27(11):402-409

aDepartment of Clinical Pharmacy, University of Michigan College of Pharmacy, Ann Arbor, Michigan bUNC Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina cDeBartolo Family Personalized Medicine Institute, Moffitt Cancer Center, Tampa, Florida dDepartment of Clinical Pharmacology, Indiana University, Indianapolis, Indiana eBon Secours Cancer Institute, Richmond, Virginia, USA.

Objectives: Tamoxifen bioactivation to endoxifen is mediated primarily by CYP2D6; however, considerable variability remains unexplained. Our aim was to perform a comprehensive assessment of the effect of genetic variation in tamoxifen-relevant enzymes and transporters on steady-state endoxifen concentrations.

Patients And Methods: Comprehensive genotyping of CYP enzymes and transporters was performed using the iPLEX ADME PGx Pro Panel in 302 tamoxifen-treated breast cancer patients. Read More

J Clin Oncol 2017 Oct 30;35(30):3391-3400. Epub 2017 Aug 30.

Matthew P. Goetz, Vera J. Suman, Joel M. Reid, Don W. Northfelt, Michael A. Mahr, Andrew T. Ralya, Mary Kuffel, Sarah A. Buhrow, Stephanie L. Safgren, Renee M. McGovern, John Black, Travis Dockter, Tufia Haddad, Charles Erlichman, Alex A. Adjei, Dan Visscher, Benjamin R. Kipp, Minetta C. Liu, John R. Hawse, Matthew M. Ames, and James N. Ingle, Mayo Clinic, Rochester, MN; Zachary R. Chalmers and Garrett Frampton, Foundation Medicine, Cambridge, MA; and John R. Hawse, James H. Doroshow, Jerry M. Collins, and Howard Streicher, National Cancer Institute, Bethesda, MD.

Purpose Endoxifen is a tamoxifen metabolite with potent antiestrogenic activity. Patients and Methods We performed a phase I study of oral Z-endoxifen to determine its toxicities, maximum tolerated dose (MTD), pharmacokinetics, and clinical activity. Eligibility included endocrine-refractory, estrogen receptor-positive metastatic breast cancer. Read More

Eur J Clin Pharmacol 2017 Dec 28;73(12):1589-1598. Epub 2017 Aug 28.

Leiden Network for Personalised Therapeutics, Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Albinusdreef 2, Leiden, 2300, RC, The Netherlands.

Background: Tamoxifen is one of the cornerstones of endocrine therapy for breast cancer. Recently, the decreased activity CYP3A4*22 allele and the loss of function CYP3A5*3 allele have been described as potential factors that could help to explain the inter-patient variability in tamoxifen metabolism. The aim of this study is to investigate the effect of CYP3A4*22, CYP3A5*3, and CYP3A combined genotypes on tamoxifen metabolism. Read More

Chem Biodivers 2018 Jan 28;15(1). Epub 2017 Dec 28.

Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, P. R., China.

Norendoxifen, an active metabolite of tamoxifen, is a potent aromatase inhibitor. Little information is available regarding production of norendoxifen in vitro. Here, we conducted a series of kinetic and inhibition studies in human liver microsomes (HLMs) and expressed P450s to study the metabolic disposition of norendoxifen. Read More

Sci Rep 2017 08 10;7(1):7727. Epub 2017 Aug 10.

Department of Clinical Epidemiology, Aarhus University, Aarhus, Denmark.

The role of cytochrome P450 drug metabolizing enzymes in the efficacy of tamoxifen treatment of breast cancer is subject to substantial interest and controversy. CYP2D6 have been intensively studied, but the role of CYP2C19 is less elucidated, and we studied the association of CYPC19 genotype and recurrence of breast cancer. We used outcome and genotyping data from the large publicly available International Tamoxifen Pharmacogenomics Consortium (ITPC) dataset. Read More

Pharmacogenomics J 2018 04 1;18(2):201-208. Epub 2017 Aug 1.

Department of Pharmacy Practice and Translational Research, University of Houston College of Pharmacy, Houston, TX, USA.

We investigated the impact of germline CYP2D6 genotyping done using the non-tumor specimen on endoxifen concentrations and/or clinical outcomes in breast cancer (BC) patients treated with tamoxifen in published studies. We evaluated published data from 13 001 patients in 29 studies. Mean±s. Read More

Pak J Pharm Sci 2017 May;30(3(Special)):1095-1098

Fujian Provincial Cancer Hospital, Fuzhou, Fujian Province, China.

The purpose of the present research work was to study the CYP2D6 gene polymorphism survival outcome after breast cancer patient received the toremifene and tamoxifen treatment. Seventy-eight patients who received radical mastectomy and toremifene and tamoxifen treatment after operation were divided into three groups: CYP2D6*1/*1 group (13 cases), CYP2D6*1/*10 group (28cases) and CYP2D6*10/*10 group (35 cases), according to the gene polymorphism of blood serum CYP2D6. The results of treatment of three groups were compared. Read More

Clin Pharmacokinet 2018 02;57(2):229-242

Department of Clinical Pharmacy and Biochemistry, Institute of Pharmacy, Freie Universitaet Berlin, Kelchstr. 31, 12169, Berlin, Germany.

Background And Objectives: A better understanding of the highly variable pharmacokinetics (PK) of tamoxifen and its active metabolite endoxifen in breast cancer patients is crucial to support individualised treatment. This study used a modelling and simulation approach to quantitatively assess the influence of cytochrome P450 (CYP) 2D6 activity and other relevant factors on tamoxifen and endoxifen PK to identify subgroups at risk for subtherapeutic endoxifen concentrations.

Methods: Simulations were performed using two previously published PK models jointly describing tamoxifen and endoxifen with CYP2D6 and CYP3A4/5 enzyme activities implemented as covariates. Read More

Anticancer Agents Med Chem 2017 ;17(13):1805-1813

Division of Chemical Pathology, Department of Pathology Faculty of Medicine and Health Sciences, Stellenbosch University and the National Health Laboratory Service, Tygerberg Hospital, Tygerberg. South Africa.

Background: Genetics play a significant role in drug metabolism of endocrine therapy of breast cancer. These aspects have been studied extensively in patients on tamoxifen, but the pharmacogenetics of aromatase inhibitors are less established. In contrast to the protective effect of tamoxifen, aromatase inhibitors are linked with an increased risk for bone loss and fractures. Read More

Breast Cancer (Dove Med Press) 2017 6;9:111-120. Epub 2017 Mar 6.

Institute of Biochemistry, Molecular Biology and Biotechnology (IBMBB), University of Colombo, Colombo, Sri Lanka.

Introduction And Aims: Tamoxifen is an adjuvant drug effective in treating hormone receptor - positive breast cancer. However, 30%-50% of patients relapse and many develop adverse effects, such as hot flashes and fatty liver. Allelic variations altering the activity of cytochrome P450-2D6 enzyme affect response to tamoxifen by modulating metabolism of tamoxifen into its pharmacologically active metabolite endoxifen. Read More

Oncotarget 2017 Mar;8(13):20925-20938

Department of Surgery, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan.

In this study, we investigated whether single nucleotide polymorphisms (SNPs) identified by genome-wide association study (GWAS) (MAP3K1, FGFR2, TNRC9, HCN1, and 5p12), and SNPs involved in the metabolism of estrogen (CYP19, COMT, ESR1, and UGT1A1), tamoxifen (CYP2C9, CYP2C19, CYP3A5, and CYP2D6), and chemotherapeutic agents (ABCB1, ALDH3A1, and CYP2B6) are associated with the prognoses of 414 hormone receptor (HR)-positive early breast cancers with negative or 1 to 3 nodal metastases. At a median follow-up period of 10.6 years, 363 patients were alive, and 51 (12. Read More

Klin Onkol 2016 ;29 Suppl 3:S29-38

Ovarian suppression or ovarian ablation used in treatment of breast carcinoma results in temporary or permanent menopause and associated menopausal symptoms - most frequently vasomotoric symptoms (hot flashes, sweats), vaginal atrophy, sleep disturbances. Patients can also experience frequent decrease in bone density (osteopenia, osteoporosis), mood swings or depression, less frequently cardiac toxicity. Managements of these symptoms is complex. Read More