BackgroundWe aimed to study the pharmacokinetics and -dynamics of tamoxifen in older women with non-metastatic breast cancer.MethodsData for this analysis were derived from the CYPTAM study (NTR1509) database. Patients were stratified by age (age groups < 65 and 65 and older). Steady-state trough concentrations were measured of tamoxifen, N-desmethyltamoxifen, 4-hydroxy-tamoxifen, and endoxifen.CYP2D6andCYP3A4phenotypes were assessed for all patients by genotyping. Multiple linear regression models were used to analyze tamoxifen and endoxifen variability. Outcome data included recurrence-free survival at time of tamoxifen discontinuation (RFSt) and overall survival (OS).Results668 patients were included, 141 (21%) were 65 and older. Demographics and treatment duration were similar across age groups. Older patients had significantly higher concentrations of tamoxifen 129.4 ng/ml (SD 53.7) versus 112.2 ng/ml (SD 42.0) and endoxifen 12.1 ng/ml (SD 6.6) versus 10.7 ng/ml (SD 5.7,pall < 0.05), independently ofCYP2D6andCYP3A4gene polymorphisms. Age independently explained 5% of the variability of tamoxifen (b = 0.95,p< 0.001,R2= 0.051) and 0.1% of the variability in endoxifen concentrations (b = 0.45,p= 0.12,R2= 0.007). Older patients had worse RFSt (5.8 versus 7.3 years,p= 0.01) and worse OS (7.8 years versus 8.7 years,p= 0.01). This was not related to differences in endoxifen concentration (HR 1.0, 95% CI 0.96–1.04,p= 0.84) orCYPpolymorphisms.ConclusionSerum concentrations of tamoxifen and its demethylated metabolites are higher in older patients, independent ofCYP2D6orCYP3A4gene polymorphisms. A higher bioavailability of tamoxifen in older patients may explain the observed differences. However, clinical relevance of these findings is limited and should not lead to a different tamoxifen dose in older patients.