Publication

Computational Treatment Simulations to Assess the Need for Personalized Tamoxifen Dosing in Breast Cancer Patients of Different Biogeographical Groups

Journal Paper/Review - May 18, 2021

Units
PubMed
Doi

Citation
Mueller-Schoell A, Mikus G, Huisinga W, Jörger M, Schwab M, Mürdter T, van Dyk M, Klopp-Schulze L, Michelet R, Kloft C. Computational Treatment Simulations to Assess the Need for Personalized Tamoxifen Dosing in Breast Cancer Patients of Different Biogeographical Groups. Cancers (Basel) 2021; 13
Type
Journal Paper/Review (English)
Journal
Cancers (Basel) 2021; 13
Publication Date
May 18, 2021
Issn Print
2072-6694
Brief description/objective

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) >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 . In the Women's Healthy Eating and Living (WHEL) study proposing the target concentration, 20% of patients showed subtarget C 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 in other populations. Applying pharmacokinetic simulations, this study investigated the risk for subtarget C 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. 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).