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

SIMPLE SUMMARY: Tamoxifen is a drug often used to treat the most common type of breast cancer. Its metabolite endoxifen is formed by the liver enzyme CYP2D6, whose activity is variable and depends on a patient’s genetic profile. The frequency of CYP2D6 variants with different functional enzymatic activity varies largely between populations. To ensure sufficient efficacy of tamoxifen, a certain target concentration of endoxifen is needed, and 20% of White breast cancer patients have been shown not to reach this target concentration. However, little is known about the risk of not attaining the endoxifen target amongst other ethnic populations. This study investigated the risk for suboptimal endoxifen concentration in nine different biogeographical populations based on their distinct CYP2D6 genetic profile. The variability between the populations was high (up to three-fold), and East Asian breast cancer patients were identified as the population with the highest need for personalized tamoxifen dosing. 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 (C(SS,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 C(SS,min) (ENDX). In the Women’s Healthy Eating and Living (WHEL) study proposing the target concentration, 20% of patients showed subtarget C(SS,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 C(SS,min ENDX) in other populations. Applying pharmacokinetic simulations, this study investigated the risk for subtarget C(SS,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 C(SS,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 C(SS,min ENDX)).