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

## TL;DR

This study shows that combining genetic testing and drug monitoring can help personalize tamoxifen treatment for better breast cancer outcomes.

## Contribution

The study demonstrates the clinical utility of combining CYP2D6 genotyping and therapeutic drug monitoring for tamoxifen therapy.

## Key findings

- Intermediate metabolizers had significantly lower endoxifen levels compared to normal metabolizers.
- Subtherapeutic endoxifen levels were more common in intermediate metabolizers.
- Combining genotyping and TDM is recommended to optimize tamoxifen treatment.

## Abstract

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.