Computational Treatment Simulations to Assess the Need for Personalized Tamoxifen Dosing in Breast Cancer Patients of Different Biogeographical Groups
Tamoxifen is used worldwide to treat estrogen receptor-positive breast cancer. It is extensively metabolized, and minimum steady-state concentrations of its metabolite endoxifen (C<sub>SS,min ENDX</sub>) >5.97 ng/mL have been associated with favorable outcome. Endoxifen formation is m...
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doaj-9d957ef2eeeb4189b45bffc567535d952021-06-01T00:19:25ZengMDPI AGCancers2072-66942021-05-01132432243210.3390/cancers13102432Computational Treatment Simulations to Assess the Need for Personalized Tamoxifen Dosing in Breast Cancer Patients of Different Biogeographical GroupsAnna Mueller-Schoell0Robin Michelet1Lena Klopp-Schulze2Madelé van Dyk3Thomas E. Mürdter4Matthias Schwab5Markus Joerger6Wilhelm Huisinga7Gerd Mikus8Charlotte Kloft9Department of Clinical Pharmacy and Biochemistry, Institute of Pharmacy, Freie Universitaet Berlin, 12169 Berlin, GermanyDepartment of Clinical Pharmacy and Biochemistry, Institute of Pharmacy, Freie Universitaet Berlin, 12169 Berlin, GermanyDepartment of Clinical Pharmacy and Biochemistry, Institute of Pharmacy, Freie Universitaet Berlin, 12169 Berlin, GermanyCollege of Medicine and Public Health, Flinders University, Adelaide, SA 5042, AustraliaDr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, and University Tübingen, 70376 Tübingen, GermanyDr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, 70376 Stuttgart, GermanyDepartment of Medical Oncology and Hematology, Cantonal Hospital, 9007 St. Gallen, SwitzerlandInstitute of Mathematics, University of Potsdam, 14476 Potsdam, GermanyDepartment of Clinical Pharmacy and Biochemistry, Institute of Pharmacy, Freie Universitaet Berlin, 12169 Berlin, GermanyDepartment of Clinical Pharmacy and Biochemistry, Institute of Pharmacy, Freie Universitaet Berlin, 12169 Berlin, GermanyTamoxifen is used worldwide to treat estrogen receptor-positive breast cancer. It is extensively metabolized, and minimum steady-state concentrations of its metabolite endoxifen (C<sub>SS,min ENDX</sub>) >5.97 ng/mL have been associated with favorable outcome. Endoxifen formation is mediated by the enzyme CYP2D6, and impaired CYP2D6 function has been associated with lower C<sub>SS,min</sub> <sub>ENDX</sub>. In the Women’s Healthy Eating and Living (WHEL) study proposing the target concentration, 20% of patients showed subtarget C<sub>SS,min ENDX</sub> at tamoxifen standard dosing. CYP2D6 allele frequencies vary largely between populations, and as 87% of the patients in the WHEL study were White, little is known about the risk for subtarget C<sub>SS,min ENDX</sub> in other populations. Applying pharmacokinetic simulations, this study investigated the risk for subtarget C<sub>SS,min ENDX</sub> at tamoxifen standard dosing and the need for dose individualization in nine different biogeographical groups with distinct CYP2D6 allele frequencies. The high variability in CYP2D6 allele frequencies amongst the biogeographical groups resulted in an up to three-fold difference in the percentages of patients with subtarget C<sub>SS,min ENDX</sub>. Based on their CYP2D6 allele frequencies, East Asian breast cancer patients were identified as the population for which personalized, model-informed precision dosing would be most beneficial (28% of patients with subtarget C<sub>SS,min ENDX</sub>).https://www.mdpi.com/2072-6694/13/10/2432tamoxifenbreast cancerCYP2D6polymorphismgenotypeindividualized dosing |
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DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Anna Mueller-Schoell Robin Michelet Lena Klopp-Schulze Madelé van Dyk Thomas E. Mürdter Matthias Schwab Markus Joerger Wilhelm Huisinga Gerd Mikus Charlotte Kloft |
spellingShingle |
Anna Mueller-Schoell Robin Michelet Lena Klopp-Schulze Madelé van Dyk Thomas E. Mürdter Matthias Schwab Markus Joerger Wilhelm Huisinga Gerd Mikus Charlotte Kloft Computational Treatment Simulations to Assess the Need for Personalized Tamoxifen Dosing in Breast Cancer Patients of Different Biogeographical Groups Cancers tamoxifen breast cancer CYP2D6 polymorphism genotype individualized dosing |
author_facet |
Anna Mueller-Schoell Robin Michelet Lena Klopp-Schulze Madelé van Dyk Thomas E. Mürdter Matthias Schwab Markus Joerger Wilhelm Huisinga Gerd Mikus Charlotte Kloft |
author_sort |
Anna Mueller-Schoell |
title |
Computational Treatment Simulations to Assess the Need for Personalized Tamoxifen Dosing in Breast Cancer Patients of Different Biogeographical Groups |
title_short |
Computational Treatment Simulations to Assess the Need for Personalized Tamoxifen Dosing in Breast Cancer Patients of Different Biogeographical Groups |
title_full |
Computational Treatment Simulations to Assess the Need for Personalized Tamoxifen Dosing in Breast Cancer Patients of Different Biogeographical Groups |
title_fullStr |
Computational Treatment Simulations to Assess the Need for Personalized Tamoxifen Dosing in Breast Cancer Patients of Different Biogeographical Groups |
title_full_unstemmed |
Computational Treatment Simulations to Assess the Need for Personalized Tamoxifen Dosing in Breast Cancer Patients of Different Biogeographical Groups |
title_sort |
computational treatment simulations to assess the need for personalized tamoxifen dosing in breast cancer patients of different biogeographical groups |
publisher |
MDPI AG |
series |
Cancers |
issn |
2072-6694 |
publishDate |
2021-05-01 |
description |
Tamoxifen is used worldwide to treat estrogen receptor-positive breast cancer. It is extensively metabolized, and minimum steady-state concentrations of its metabolite endoxifen (C<sub>SS,min ENDX</sub>) >5.97 ng/mL have been associated with favorable outcome. Endoxifen formation is mediated by the enzyme CYP2D6, and impaired CYP2D6 function has been associated with lower C<sub>SS,min</sub> <sub>ENDX</sub>. In the Women’s Healthy Eating and Living (WHEL) study proposing the target concentration, 20% of patients showed subtarget C<sub>SS,min ENDX</sub> at tamoxifen standard dosing. CYP2D6 allele frequencies vary largely between populations, and as 87% of the patients in the WHEL study were White, little is known about the risk for subtarget C<sub>SS,min ENDX</sub> in other populations. Applying pharmacokinetic simulations, this study investigated the risk for subtarget C<sub>SS,min ENDX</sub> at tamoxifen standard dosing and the need for dose individualization in nine different biogeographical groups with distinct CYP2D6 allele frequencies. The high variability in CYP2D6 allele frequencies amongst the biogeographical groups resulted in an up to three-fold difference in the percentages of patients with subtarget C<sub>SS,min ENDX</sub>. Based on their CYP2D6 allele frequencies, East Asian breast cancer patients were identified as the population for which personalized, model-informed precision dosing would be most beneficial (28% of patients with subtarget C<sub>SS,min ENDX</sub>). |
topic |
tamoxifen breast cancer CYP2D6 polymorphism genotype individualized dosing |
url |
https://www.mdpi.com/2072-6694/13/10/2432 |
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