From Genotype to Therapeutic Monitoring: Enhancing Tamoxifen Efficacy in Breast Cancer Treatment

Endoxifen is the most active metabolite of tamoxifen and plays a central role in its therapeutic efficacy. However, significant interindividual variability in endoxifen plasma concentrations, driven by both genetic and non-genetic factors, may result in subtherapeutic exposure for a substantial subset of patients. This study evaluated the influence of CYP2D6 phenotype and age on endoxifen steady-state concentrations and explored the clinical utility of therapeutic drug monitoring (TDM) to guide tamoxifen therapy. A total of 63 breast cancer patients receiving tamoxifen 20 mg daily for at least 3 months were enrolled. Patients were genotyped for CYP2D6 using TaqMan assays and classified as normal metabolizers (NMs, n = 49), intermediate metabolizers (IMs, n = 13), or ultrarapid metabolizers (UMs, n = 1). Plasma concentrations of tamoxifen and its metabolites were quantified by LC-MS/MS at steady state. Endoxifen levels were significantly lower in IMs (7.13  ng/mL; 95% CI: 3.38-15.08) compared to NMs (22.66  ng/mL; 95% CI: 18.57-27.66; P  <  .001). Subtherapeutic endoxifen concentrations (<6  ng/mL) were observed in 23.1% of IMs and 4.1% of NMs. These results support the combined use of CYP2D6 genotyping and TDM as the optimal strategy for personalizing tamoxifen therapy and minimizing the risk of subtherapeutic endoxifen exposure.