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

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}).