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.

Therapeutic Drug Monitoring-Guided Adjuvant Tamoxifen Dosing in Patients with Early Breast Cancer: A Cost-Effectiveness Analysis from the Prospective TOTAM Trial

“…It was assumed that RFS and OS of patients with subtherapeutic endoxifen levels are equal to RFS and OS of patients who were not treated with tamoxifen in the EBCTCG study. This assumption was supported by clinical and pharmacological expert opinion [21].…”

“…However, such a trial is probably not feasible since it would require many thousands of patients to participate and a follow-up period of more than a decade [40]. To break out of this potential dead end, physicians are encouraged to implement TDM-a feasible intervention-in the meantime in clinical practice, pending further prospective data [21].…”

“…The clinical benefit of TDM was modelled based on the assumption that the RFS and OS curves of patients treated with a standard tamoxifen dose (20 mg tamoxifen once daily; without the intervention TDM) included 20% of patients with subtherapeutic endoxifen levels below 16 nM, which was reduced to 10% with TDM in line with results from TOTAM and other studies [6,9,21]. It was assumed that RFS and OS of patients with subtherapeutic endoxifen levels are equal to RFS and OS of patients who were not treated with tamoxifen in the EBCTCG study.…”

Influence of probenecid on endoxifen systemic exposure in breast cancer patients on adjuvant tamoxifen treatment

“…Despite tamoxifen dose escalation, only 36% and 79% of these patients reached the threshold, respectively. 27 Moreover, another study in 353 tamoxifen users demonstrated that dose escalation is not feasible for patients with a PM phenotype. 28 These observations stress the need for a solution, other than a dose escalation, to increase endoxifen concentrations in these patients to therapeutic concentrations.…”

Preliminary results using a kit to measure tamoxifen and metabolites concentrations in capillary blood samples from women with breast cancer

“…The metabolism of TAM involves a series of CYP450 enzymes that convert TAM to its two most active metabolites, END and 4HT, and this process may vary between patients 7 . Because these two metabolites have a 30 to 100 times greater binding affinity for the estrogen receptor than does TAM, and END achieves a 5 to 10 times higher plasma concentration than 4HT, END is thought to be the most active TAM metabolite 18 .…”