title: CYP2D6 genotype- and endoxifen-guided tamoxifen dose escalation increases endoxifen serum concentrations without increasing side effects.
abstract: Breast cancer patients with absent or reduced CYP2D6 activity and consequently low endoxifen levels may benefit less from tamoxifen treatment. CYP2D6 poor and intermediate metabolizers may need a personalized increased tamoxifen dose to achieve effective endoxifen serum concentrations, without increasing toxicity. From a prospective study population of early breast cancer patients using tamoxifen (CYPTAM: NTR1509), 12 CYP2D6 poor and 12 intermediate metabolizers were selected and included in a one-step tamoxifen dose escalation study during 2 months. The escalated dose was calculated by multiplying the individual's endoxifen level at baseline relative to the average endoxifen concentration observed in CYP2D6 extensive metabolizers by 20 mg (120 mg maximum). Endoxifen levels and tamoxifen toxicity were determined at baseline and after 2 months, just before patients returned to the standard dose of 20 mg. Tamoxifen dose escalation in CYP2D6 poor and intermediate metabolizers significantly increased endoxifen concentrations (p < 0.001; p = 0.002, respectively) without increasing side effects. In intermediate metabolizers, dose escalation increased endoxifen to levels comparable with those observed in extensive metabolizers. In poor metabolizers, the mean endoxifen level increased from 24 to 81 % of the mean concentration in extensive metabolizers. In all patients, the endoxifen threshold of 5.97 ng/ml (=16.0 nM) reported by Madlensky et al. was reached following dose escalation. CYP2D6 genotype- and endoxifen-guided tamoxifen dose escalation increased endoxifen concentrations without increasing short-term side effects. Whether such tamoxifen dose escalation is effective and safe in view of long-term toxic effects is uncertain and needs to be explored.
authors.affiliation: Department of Clinical Oncology, Leiden University Medical Center, Leiden, The Netherlands. v.dezentje@gmail.com.|Department of Clinical Pharmacy & Toxicology, Leiden University Medical Center, Leiden, The Netherlands. v.dezentje@gmail.com.
authors.forename: V O
authors.initials: VO
authors.lastname: Dezentjé
authors.affiliation: Department of Clinical Oncology, Leiden University Medical Center, Leiden, The Netherlands.|Department of Clinical Pharmacy & Toxicology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: F L
authors.initials: FL
authors.lastname: Opdam
authors.affiliation: Department of Clinical Oncology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: H
authors.initials: H
authors.lastname: Gelderblom
authors.affiliation: Department of Clinical Pharmacy & Toxicology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: J
authors.initials: J
authors.lastname: Hartigh den
authors.affiliation: Department of Clinical Pharmacy & Toxicology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: T
authors.initials: T
authors.lastname: Van der Straaten
authors.affiliation: Department of Surgery, Diaconessenhuis, Leiden, The Netherlands.
authors.forename: R
authors.initials: R
authors.lastname: Vree
authors.affiliation: Department of Internal Medicine, Reinier de Graaf Groep, Delft, The Netherlands.
authors.forename: E
authors.initials: E
authors.lastname: Maartense
authors.affiliation: Department of Internal Medicine, Medical Center Alkmaar, Alkmaar, The Netherlands.
authors.forename: C H
authors.initials: CH
authors.lastname: Smorenburg
authors.affiliation: Department of Medical Statistics, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: H
authors.initials: H
authors.lastname: Putter
authors.affiliation: Department of Gynaecologic Oncology, University Hospitals Leuven, Louvain, Belgium.
authors.forename: A S
authors.initials: AS
authors.lastname: Dieudonné
authors.affiliation: Department of Gynaecologic Oncology, University Hospitals Leuven, Louvain, Belgium.
authors.forename: P
authors.initials: P
authors.lastname: Neven
authors.affiliation: Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: C J H
authors.initials: CJ
authors.lastname: Van de Velde
authors.affiliation: Department of Clinical Oncology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: J W R
authors.initials: JW
authors.lastname: Nortier
authors.affiliation: Department of Clinical Pharmacy & Toxicology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: H-J
authors.initials: HJ
authors.lastname: Guchelaar
mesh_terms: D000328:Adult; D000368:Aged; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology* / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics*; D016903:Drug Monitoring; D005260:Female; D005838:Genotype; D006801:Humans; D008875:Middle Aged; D010597:Pharmacogenetics; D010641:Phenotype; D011446:Prospective Studies; D012307:Risk Factors; D013629:Tamoxifen / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D018931:Antineoplastic Agents, Hormonal; D013629:Tamoxifen; C055492:4-hydroxy-N-desmethyltamoxifen; D019389:Cytochrome P-450 CYP2D6
keywords: CYP2D6; Early breast cancer; Endoxifen