Computational treatment simulations to assess the need for personalized tamoxifen dosing in breast cancer patients of different biogeographical groups

Anna Mueller-Schoell, Robin Michelet, Lena Klopp-Schulze, Madelé van Dyk, Thomas E. Mürdter, Matthias Schwab, Markus Joerger, Wilhelm Huisinga, Gerd Mikus, Charlotte Kloft

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Abstract

Tamoxifen is used worldwide to treat estrogen receptor-positive breast cancer. It is extensively metabolized, and minimum steady-state concentrations of its metabolite endoxifen (CSS,min ENDX) >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 CSS,min ENDX. In the Women’s Healthy Eating and Living (WHEL) study proposing the target con-centration, 20% of patients showed subtarget CSS,min ENDX 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 CSS,min ENDX in other populations. Applying pharmacokinetic simulations, this study investigated the risk for subtarget CSS,min ENDX 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 CSS,min ENDX. 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 CSS,min ENDX).

Original languageEnglish
Article number2432
Number of pages13
JournalCancers
Volume13
Issue number10
DOIs
Publication statusPublished - 2 May 2021

Keywords

  • Breast cancer
  • CYP2D6
  • Genotype
  • Individualized dosing
  • Model-informed precision dosing
  • Personalized dosing
  • Polymorphism
  • Tamoxifen

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