title: Tamoxifen metabolism predicts drug concentrations and outcome in premenopausal patients with early breast cancer.
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.
authors.affiliation: 1] Dr Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany [2] University of Tübingen, Tübingen, Germany.
authors.forename: P
authors.initials: P
authors.lastname: Saladores
authors.affiliation: 1] Dr Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany [2] University of Tübingen, Tübingen, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Mürdter
authors.affiliation: 1] Faculty of Medicine, Cancer Sciences Academic Unit and University of Southampton Clinical Trials Unit, University of Southampton, Southampton, UK [2] University Hospital Southampton NHS Foundation Trust, Southampton, UK.
authors.forename: D
authors.initials: D
authors.lastname: Eccles
authors.affiliation: 1] Clinical Pharmacology Laboratory, Division of Medical Sciences, Humphrey Oei Institute of Cancer Research, National Cancer Centre Singapore, Singapore, Singapore [2] Academic Medicine Research Institute, Office of Clinical Sciences, Duke-NUS Graduate Medical School Singapore, Singapore, Singapore [3] SingHealth Clinical Pharmacology Core, Academia, Singapore Health Services, Singapore, Singapore.
authors.forename: B
authors.initials: B
authors.lastname: Chowbay
authors.affiliation: Faculty of Medicine, Department of Pharmacology and Toxicology, American University of Beirut, Beirut, Lebanon.
authors.forename: N K
authors.initials: NK
authors.lastname: Zgheib
authors.affiliation: 1] Dr Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany [2] University of Tübingen, Tübingen, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Winter
authors.affiliation: 1] Dr Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany [2] University of Tübingen, Tübingen, Germany.
authors.forename: B
authors.initials: B
authors.lastname: Ganchev
authors.affiliation: 1] Faculty of Medicine, Cancer Sciences Academic Unit and University of Southampton Clinical Trials Unit, University of Southampton, Southampton, UK [2] University Hospital Southampton NHS Foundation Trust, Southampton, UK.
authors.forename: B
authors.initials: B
authors.lastname: Eccles
authors.affiliation: 1] Faculty of Medicine, Cancer Sciences Academic Unit and University of Southampton Clinical Trials Unit, University of Southampton, Southampton, UK [2] University Hospital Southampton NHS Foundation Trust, Southampton, UK.
authors.forename: S
authors.initials: S
authors.lastname: Gerty
authors.affiliation: Hematology-Oncology Division, Department of Internal Medicine, Faculty of Medicine, American University of Beirut, Beirut, Lebanon.
authors.forename: A
authors.initials: A
authors.lastname: Tfayli
authors.affiliation: Clinical Pharmacology Laboratory, Division of Medical Sciences, Humphrey Oei Institute of Cancer Research, National Cancer Centre Singapore, Singapore, Singapore.
authors.forename: J S L
authors.initials: JS
authors.lastname: Lim
authors.affiliation: Department of Medical Oncology, Humphrey Oei Institute of Cancer Research, National Cancer Centre Singapore, Singapore, Singapore.
authors.forename: Y S
authors.initials: YS
authors.lastname: Yap
authors.affiliation: Department of Medical Oncology, Humphrey Oei Institute of Cancer Research, National Cancer Centre Singapore, Singapore, Singapore.
authors.forename: R C H
authors.initials: RC
authors.lastname: Ng
authors.affiliation: Department of Medical Oncology, Humphrey Oei Institute of Cancer Research, National Cancer Centre Singapore, Singapore, Singapore.
authors.forename: N S
authors.initials: NS
authors.lastname: Wong
authors.affiliation: Department of Medical Oncology, Humphrey Oei Institute of Cancer Research, National Cancer Centre Singapore, Singapore, Singapore.
authors.forename: R
authors.initials: R
authors.lastname: Dent
authors.affiliation: Department of Pathology and Laboratory Medicine, Faculty of Medicine, American University of Beirut, Beirut, Lebanon.
authors.forename: M Z
authors.initials: MZ
authors.lastname: Habbal
authors.affiliation: 1] Dr Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany [2] University of Tübingen, Tübingen, Germany.
authors.forename: E
authors.initials: E
authors.lastname: Schaeffeler
authors.affiliation: 1] Dr Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany [2] University of Tübingen, Tübingen, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Eichelbaum
authors.affiliation: 1] Dr Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany [2] University of Tübingen, Tübingen, Germany.
authors.forename: W
authors.initials: W
authors.lastname: Schroth
authors.affiliation: 1] Dr Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany [2] Department of Clinical Pharmacology, University Hospital Tübingen, Tübingen, Germany [3] German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Schwab
authors.affiliation: 1] Dr Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany [2] University of Tübingen, Tübingen, Germany [3] German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Brauch
mesh_terms: D000328:Adult; D018931:Antineoplastic Agents, Hormonal / Q000097:blood* / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000097:blood* / Q000175:diagnosis* / Q000188:drug therapy; D015331:Cohort Studies; D055088:Early Detection of Cancer; D005260:Female; D006801:Humans; D008875:Middle Aged; D011237:Predictive Value of Tests; D017697:Premenopause / Q000097:blood*; D011446:Prospective Studies; D013629:Tamoxifen / Q000097:blood* / Q000627:therapeutic use; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D018931:Antineoplastic Agents, Hormonal; D013629:Tamoxifen
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