Therapeutic Drug Monitoring of Endoxifen for Tamoxifen Precision Dosing: Feasible in Patients with Hormone-Sensitive Breast Cancer

Abstract

Background: Endoxifen is the most important active metabolite of tamoxifen. Several retrospective studies have suggested a minimal or threshold endoxifen systemic concentration of 14-16 nM is required for a lower recurrence rate. The aim of this study was to investigate the feasibility of reaching a predefined endoxifen level of ≥ 16 nM (5.97 ng/mL) over time using therapeutic drug monitoring (TDM).

Methods: This prospective open-label intervention study enrolled patients who started treatment with a standard dose of tamoxifen 20 mg once daily for early breast cancer. An outpatient visit was combined with a TDM sample at 3, 4.5, and 6 months after initiation of the tamoxifen treatment. The tamoxifen dose was escalated to a maximum of 40 mg if patients had an endoxifen concentration < 16 nM. The primary endpoint of the study was the percentage of patients with an endoxifen level ≥ 16 nM at 6 months after the start of therapy compared with historical data, in other words, 80% of patients with endoxifen levels ≥ 16 nM with standard therapy.

Results: In total, 145 patients were included. After 6 months, 89% of the patients had endoxifen levels ≥ 16 nM, compared with a literature-based 80% of patients with endoxifen levels ≥ 16 nM at baseline (95% confidence interval 82-94; P = 0.007). In patients with an affected CYP2D6 allele, it was not always feasible to reach the predefined endoxifen level of ≥ 16 nM. No increase in tamoxifen-related adverse events was reported after dose escalation.

Conclusion: This study demonstrated that it is feasible to increase the percentage of patients with endoxifen levels ≥ 16 nM using TDM. TDM is a safe strategy that offers the possibility of nearly halving the number of patients with endoxifen levels < 16 nM.

Fig. 1

Main metabolism pathway of tamoxifen into its most active metabolite, endoxifen. CYP cytochrome P450

Fig. 2

Therapeutic drug monitoring over time (n = 145). Endoxifen concentrations (nM) were stratified based on threshold: (1) < 16 nM or (2) ≥ 16 nM. AI aromatase inhibitor (i.e., letrozole, anastrozole, or exemestane), T1 3 months after start with tamoxifen, T3 6 months after start with tamoxifen

Fig. 3

(A) Pharmacokinetic profile of endoxifen levels below threshold, 3 months (n = 30), 4.5 months (n = 18) and 6 months (n = 15) after start with tamoxifen treatment. (B) Pharmacokinetic profile of endoxifen levels stratified based on CYP2D6 phenotype, 3 months (n = 145), 4.5 months (n = 141), and 6 months (n = 136) after start with tamoxifen treatment. The horizontal line represents the mean endoxifen concentration and the horizontal dashed line represents the predefined endoxifen threshold (≥ 16 nM). EM extensive metabolizer, IM intermediate metabolizer, PM poor metabolizer, T1 3 months after start with tamoxifen, T2 4.5 months after start with tamoxifen, T3 6 months after start with tamoxifen