Tamoxifen Metabolite Concentrations, CYP2D6 Genotype, and Breast Cancer Outcomes
Lisa Madlensky,Loki Natarajan,S Tchu,Minya Pu,Joanne E. Mortimer,Shirley W. Flatt,DM Nikoloff,Grantland Hillman,Fontecha,HJ Lawrence,BA Parker,Ahb Wu,John P. Pierce +12 more
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TLDR
There is a minimal concentration threshold above which endoxifen is effective against the recurrence of breast cancer and that ~80% of tamoxifens takers attain this threshold, according to the Women's Healthy Eating and Living Study.Abstract:
We explored whether breast cancer outcomes are associated with endoxifen and other metabolites of tamoxifen and examined potential correlates of endoxifen concentration levels in serum including cytochrome P450 2D6 (CYP2D6) metabolizer phenotype and body mass index (BMI) Concentration levels of tamoxifen, endoxifen, 4-hydroxytamoxifen (4OH-tamoxifen), and N-desmethyltamoxifen (ND-tamoxifen) were measured from samples taken from 1,370 patients with estrogen receptor (ER)-positive breast cancer who were participating in the Women's Healthy Eating and Living (WHEL) Study We tested these concentration levels for possible associations with breast cancer outcomes and found that breast cancer outcomes were not associated with the concentration levels of tamoxifen, 4-hydroxytamoxifen, and ND-tamoxifen For endoxifen, a threshold was identified, with women in the upper four quintiles of endoxifen concentration appearing to have a 26% lower recurrence rate than women in the bottom quintile (hazard ratio (HR) = 074; 95% confidence interval (CI), (055-100)) The predictors of this higher-risk bottom quintile were poor/intermediate metabolizer genotype, higher BMI, and lower tamoxifen concentrations as compared with the mean for the cohort as a whole This study suggests that there is a minimal concentration threshold above which endoxifen is effective against the recurrence of breast cancer and that ~80% of tamoxifen takers attain this thresholdread more
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Journal ArticleDOI
Cytochrome P450 enzymes in drug metabolism: Regulation of gene expression, enzyme activities, and impact of genetic variation
TL;DR: Recent progress on drug metabolism activity profiles, interindividual variability and regulation of expression, and the functional and clinical impact of genetic variation in drug metabolizing P450s are reviewed.
Journal ArticleDOI
CYP2D6 Genotype and Tamoxifen Response in Postmenopausal Women with Endocrine-Responsive Breast Cancer: The Breast International Group 1-98 Trial
Meredith M. Regan,Brian Leyland-Jones,Mark Bouzyk,Olivia Pagani,Weining Tang,Roswitha Kammler,Patrizia Dell'Orto,Maria Olivia Biasi,Beat Thürlimann,Maria Bibi Lyng,Henrik J. Ditzel,Patrick Neven,Marc Debled,Rudolf Maibach,Karen N. Price,Richard D. Gelber,Alan S. Coates,Aron Goldhirsch,James M. Rae,Giuseppe Viale,Giuseppe Viale +20 more
TL;DR: The results of this study do not support using the presence or absence of hot flushes or the pharmacogenetic testing of CYP2D6 to determine whether to treat postmenopausal breast cancer patients with tamoxifen and support the hypothesis that reduced enzyme activity was associated with worse disease control.
Journal ArticleDOI
Review of therapeutic drug monitoring of anticancer drugs part two--targeted therapies.
Nicolas Widmer,Christophe Bardin,Etienne Chatelut,Angelo Paci,Jos H. Beijnen,Dominique Levêque,Gareth J. Veal,Alain Astier +7 more
TL;DR: Applications for TDM during oral targeted therapies may best be reserved for particular situations including lack of therapeutic response, severe or unexpected toxicities, anticipated drug-drug interactions and/or concerns over adherence treatment.
Journal ArticleDOI
Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2D6 and Tamoxifen Therapy.
Matthew P. Goetz,Katrin Sangkuhl,Henk-Jan Guchelaar,Matthias Schwab,Michael A. Province,Michelle Whirl-Carrillo,W. Fraser Symmans,Howard L. McLeod,Mark J. Ratain,Hitoshi Zembutsu,Andrea Gaedigk,Ron H.N. van Schaik,James N. Ingle,Kelly E. Caudle,Teri E. Klein +14 more
TL;DR: Evidence from the literature is summarized and therapeutic recommendations for tamoxifen based on CYP2D6 genotype are provided, both with greater antiestrogenic potency and a higher risk of disease recurrence in some studies of tamoxIFen adjuvant therapy of early breast cancer.
Journal ArticleDOI
Pharmacogenomics of drug-metabolizing enzymes: a recent update on clinical implications and endogenous effects
TL;DR: The pharmacogenomics of DMEs is reviewed, with particular emphasis on novelties, and it is concluded that recent studies have emphasized the importance of CYP2C19 polymorphism for the effects of clopidogrel, whereas the CYP1A2 polymorphism appears to have a role in anticoagulant treatment, although inferior to VKORC1.
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Journal ArticleDOI
CYP2D6 Genotype, Antidepressant Use, and Tamoxifen Metabolism During Adjuvant Breast Cancer Treatment
Y. Jin,Zeruesenay Desta,Vered Stearns,Bryan A. Ward,Herbert Ho,K. Lee,Todd C. Skaar,Anna Maria Storniolo,Lang Li,Adjei Araba,Rebecca L. Blanchard,Anne Nguyen,Lynda Ullmer,Jill Hayden,Suzanne Lemler,Richard M. Weinshilboum,James M. Rae,Daniel F. Hayes,David A. Flockhart +18 more
TL;DR: Interactions between CYP2D6 polymorphisms and coadministered antidepressants and other drugs that are CYP 2D6 inhibitors may be associated with altered tamoxifen activity.
Journal ArticleDOI
Five Versus More Than Five Years of Tamoxifen Therapy for Breast Cancer Patients With Negative Lymph Nodes and Estrogen Receptor-Positive Tumors
Bernard Fisher,James J. Dignam,John Bryant,Arthur DeCillis,D. Lawrence Wickerham,Norman Wolmark,Joseph P. Costantino,C Redmond,Edwin R. Fisher,David M. Bowman,Luc Deschenes,Nikolay V. Dimitrov,Richard G. Margolese,André Robidoux,Henry Shibata,Jose J. Terz,Ahg Paterson,Merrill I. Feldman,William B. Farrar,James Evans,H. Lavina A. Lickley +20 more
TL;DR: The outcome of patients in the B-14 trial through 10 years of follow-up indicated that tamoxifen therapy provided substantial benefit to patients with early stage disease, and questions arose about how long the observed benefit would persist.
Journal ArticleDOI
Active Tamoxifen Metabolite Plasma Concentrations After Coadministration of Tamoxifen and the Selective Serotonin Reuptake Inhibitor Paroxetine
Vered Stearns,Michael D. Johnson,James M. Rae,James M. Rae,Alan Morocho,Antonella Novielli,Pankaj Bhargava,Pankaj Bhargava,Pankaj Bhargava,Daniel F. Hayes,Daniel F. Hayes,Zeruesenay Desta,David A. Flockhart +12 more
TL;DR: The data suggest that CYP2D6 genotype and drug interactions should be considered in women treated with tamoxifen, and the metabolite 4-hydroxy-N-desmethyl-tamox ifen is an active tamoxIFen metabolite that is generated via CYP3A4-mediated N-demethylation and CYP 2D6-mediated hydroxylation.
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Venlafaxine in management of hot flashes in survivors of breast cancer: a randomised controlled trial
Charles L. Loprinzi,John W. Kugler,Jeff A. Sloan,James A. Mailliard,Beth I. LaVasseur,Debra L. Barton,Paul J. Novotny,Shaker R. Dakhil,Kate Rodger,Teresa A. Rummans,Bradley J. Christensen +10 more
TL;DR: Venlafaxine is an effective non-hormonal treatment for hot flashes, though the efficacy must be balanced against the drug's side-effects, as well as other related antidepressants for the treatment of hot flashes.
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