Buclin, Thierry

Csajka, Chantal

Dahmane, Elyes

Decosterd, Laurent

Eap, Chin

Galmiche, Marie

Mercier, Thomas

Zaman, Khalil

Zanolari, Boris

Serveur académique lausannois

BackgroundTAMOXIFEN METABOLISM AND THE IMPACT OF TAMOXIFEN DOSE ON THE LEVEL OF THE ACTIVE METABOLITES IN ENDOCRINE SENSITIVE BREAST CANCER PATIENTSBreast cancer (BC) is the most common cancer in women1,2. 60-70% of newly diagnosed BC have tumours that express estrogen receptor and/or progesterone receptor (ER/PR). These patients will be recommended and benefit from endocrine therapy3 .Tamoxifen is the most widely used hormonal therapy for the treatment and prevention of hormone-dependent beast cancer4. It is considered to be a “prodrug” that requires conversion, by cytochrome P450 (CYP) enzymes into its pharmacologically active metabolites, notably endoxifen (Figure 1). The clinical response to tamoxifen varies widely among patients and not all women with hormone positive breast cancer benefit from tamoxifen. The identification of the determinants of this variability is important, to predict the benefits of tamoxifen to an individual and to rational optimization of endocrine therapy5.CYP2D6 genotypes have been shown to determine the level of endoxifen and to predict outcome in patients treated with tamoxifen. This prompted to consider a potential role for CYP2D6 genotyping in therapeutic decisions. However, a large inter-patient variability in endoxifen levels still subsist even after correcting for CYP2D6 status6,7,8.Endoxifen levels could represent a better surrogate marker of tamoxifen efficacy, as its level depends also on the activity of other cytochromes (CYP3A4/5, 2C9, 2C19) and drug interacting comedications, as CYP2D6 inhibitors, frequently prescribed to treat tamoxifen-induced hot flashes.Several studies provided correlation between CYP2D6 genotype/phenotype and tamoxifen metabolism as well as between CYP2D6 genotype and clinical outcomes7,8. However, the relationship between endoxifen levels and clinical outcomes has not been evaluated, and the value of monitoring endoxifen plasma concentrations has yet to be explored.Elyes Dahmane1,2, Chantal Csajka1,2, Laurent Decosterd2, Thomas Mercier 2, Boris Zanolari 2, Chin Eap 3, Buclin Thierry 2, Marie Galmiche 4, Khalil Zaman 41Unité de Pharmacie Clinique, Section des Sciences Pharmaceutiques, Ecole de Pharmacie Genève-Lausanne, Université de Genève; 2Division de Pharmacologie et Toxicologie cliniques, 4Centre pluridisciplinaire d’Oncologie, Centre Hospitalier Universitaire Vaudois et Université de Lausanne;3Unité de Biochimie et Psychopharmacologie clinique, Département Universitaire de Psychiatrie Adulte, Hôpital de Cery, Prilly-LausanneMethodsPlasma levels of tamoxifen and its major metabolites: UPLC triple stage tandem mass spectrometry (UPLC–MS/MS) method is under development and will be validated according to the FDA recommendations (Figure 2).Pharmacogenomics:Determination of CYP2D6 genotype (*3, *4, *5, *6 variant alleles), CYP2D6 phenotype (dextromethorphan test), CYP3A phenotype (midazolam test), and other cytochromes involved in the metabolism and drug transport.Pharmacokinetic Modelling:Characterisation of population pharmacokinetic profile of tamoxifen and its metabolites using classical non-linear mixed effects modelling techniques implemented in the NONMEM® software.Patients inclusion criteria • Hormone-sensitive breast cancer patients (defined as >10% estrogenreceptor and/or >10% progesterone receptor positivity by immunohistochemistry).• Patients treated with tamoxifen and eligible for exposure to higher doses.Study design• Interventional, open label phase III trial9.• 100 to 140 patients needed to be enrolled: until at least 10 poor-metabolizers, 10 intermediate-metabolizers and 20 extensive-metabolizers(Figure 3).ReferencesPrimary ObjectivesSecondary ObjectivesDetermine how the increase of tamoxifen dose influences the level of its major metabolites in the different genotype groups (poor-, intermediate-, and extensive-metabolizers) in patients with hormone-sensitive breast cancer. • Characterize the population pharmacokinetic profile of tamoxifen and its metabolites, together with inter- and intra-patient variability, and quantify the influence of genetic and non-genetic factors on drug levels.• Investigate the role of the other CYPs (CYP3A4, CYP2C19), conjugation enzymes, and drug transporters in the pharmacokinetics of tamoxifen, and the impact of their polymorphism on drug and metabolites levels.• Confirm a relation between hot flashes and CYP2D6 genotypes and/or active metabolites levels, and evaluate the role of this clinical symptom assessment in the monitoring of tamoxifen treatment. • Explore the correlation between genotypes/metabolites levels and clinical outcomes in terms of tumor relapse. • Assess the feasibility, efficacy, and safety of concentration-guided adjustment of tamoxifen dosage in CYP2D6 poor metabolizers (PM).1. A. Jemal et al, CA. Cancer J. Clin. 2009.2. Swiss Association of Cancer Registries. Statistics. Available at http://www.asrt.ch.3. C. K. Osborne, N. Engl. J. Med. 1998.4. V. C.  Jordan, Steroids 2007.5. S. Borges et al, Clin. Pharmacol. Ther. 2006.6. M.P. Goetz et al, Clin Pharmacol Ther. 2008.7. V. Stearns V et al, Expert Rev. Mol. Med. 2008.8. Hoskins JM Nat Rev Cancer. 20099. Clinical trial summary.  http://clinicaltrials.gov/ct2/show/NCT00963209.RT: 0.00 - 10.00 SM: 15B0 1 2 3 4 5 6 7 8 9 10Time (min)050100050100050100050100050100050100050100050100RT: 7.53RT: 6.74RT: 7.48RT: 7.18RT: 6.38RT: 7.13RT: 1.02RT: 4.13RT: 3.84 RT: 8.00RT: 4.09RT: 3.81RT: 3.88RT: 3.59RT: 7.53RT: 3.84RT: 3.56NL: 4.52E7TIC F: + c ESI SRM ms2 372.300 [71.850-72.350]  MS  ICIS Tam011_17NL: 4.12E5TIC F: + c ESI SRM ms2 377.300 [71.850-72.350]  MS  ICIS Tam011_17NL: 1.78E7TIC F: + c ESI SRM ms2 358.300 [57.850-58.350]  MS  ICIS Tam011_17NL: 3.75E5TIC F: + c ESI SRM ms2 363.300 [57.850-58.350]  MS  ICIS Tam011_17NL: 4.08E7TIC F: + c ESI SRM ms2 388.300 [71.850-72.350]  MS  ICIS Tam011_17NL: 9.88E5TIC F: + c ESI SRM ms2 393.300 [71.950-72.450]  MS  ICIS Tam011_17NL: 2.71E6TIC F: + c ESI SRM ms2 374.300 [57.750-58.250]  MS  ICIS Tam011_17NL: 3.98E5TIC F: + c ESI SRM ms2 379.300 [57.950-58.450]  MS  ICIS Tam011_17TamoxifenTamoxifen-d5(internal standard)N-desmethyl-tamoxifenN-desmethyl-tamoxifen-d5(internal standard)4-hydroxy-tamoxifenZ-Endoxifen-d5(internal standard)Z-EndoxifenE-Endoxifen-d5(internal standard)E-Endoxifen4-hydroxy-tamoxifen-d5(internal standard)Figure 2. UPLC-ESI-MS/MS chromatogram of the highest calibration sample containing tamoxifen and its major metabolites. Corresponding deuterated analogues are used as internal standards.Figure 1. Biotransformation of tamoxifen and its metabolites. CYP3A4/5 is the major CYP isoform responsible for the formation of N-desmethyltamoxifen, whereas the generation of the more potent metabolites 4-hydroxytamoxifen and endoxifen (4-hydroxy-N-desmethyl-tamoxifen) are predominantly catalyzed by CYP2D6. Other CYP isoforms, including CYP2C19, CYP2C9, and CYP2B6, appear to play less important roles in tamoxifenmetabolism in vitro. Phase II enzymes may also play a role in endoxifen clearance. SULT1A1: sulphotransferase1A1; UGT: uridine diphosphate glucuronosyltransferase5.0 1 2 3 4Tamoxifen 20 mg dailyTamoxifen 20 mg daily or alternative therapyTamoxifen 40 mg daily*MonthsInclusionGenotyping Tamoxifen and metabolites levelsPhenotypingBlood sampleFigure 3. Study design. Patients receive tamoxifen (20 mg BID) daily for 4 months in the absence of disease progression or toxicity. Blood samples are collected for genotyping, phenotyping, and quantification of tamoxifenand its metabolites. The results of the CYP2D6 genotyping may be communicated to the patients who are PM, at the end of the 4 months and the opportunity of alternative endocrine therapy (e.g. Aromatase inhibitors) will be discussed.

Tamoxifen metabolism and the impact of Tamoxifen dose on the level of the active metabolites in endocrine sensitive breast cancer patients

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Tamoxifen metabolism and the impact of Tamoxifen dose on the level of the active metabolites in endocrine sensitive breast cancer patients

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