Abstract 191P
Background
Tamoxifen is widely used for the treatment of estrogen receptor positive breast cancer. Endoxifen is the active metabolite of the anticancer drug tamoxifen. Several retrospective studies suggest a minimal endoxifen systemic concentration of 14–16 nM for a lower recurrence rate. Endoxifen has a large inter-individual variability in patients treated with the same dose of tamoxifen. The aim of this study was to investigate the feasibility of reaching a predefined endoxifen level (≥16 nM) over time using therapeutic drug monitoring (TDM).
Methods
In this prospective open label study, patients who started treatment with a standard dose of tamoxifen (20 mg once daily) for early breast cancer were enrolled. 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 below 16 nM after 3 or 4.5 months. Co-medication, adverse events (CTCAEv5) and compliance were closely monitored during each hospital visit. Primary endpoint of the study was the percentage of patients with an endoxifen level ≥16 nM 6 months after the start of tamoxifen compared with on literature based 80% of patients above this limit. The binomial test for one proportion was applied at a 5% significance level.
Results
In this study 145 patients were included. Results of TDM-guided dosing of tamoxifen are depicted in Table. After 6 months 89% of the patients had endoxifen levels ≥16 nM (95% CI 82–94%, p=0.007). No increase in tamoxifen related adverse events was reported after dose escalation. Table: 191P
Endoxifen levels over time using TDM
| N(%) | 3 months (T1) | 4.5 months (T2) | 6 months (T3) |
| Total tamoxifen users | 145 | 141 | 136 |
| <16 nM | 30 (21) | 18 (13) | 15 (11) |
| <16 nM besides dose escalation | 12/18 | 2/15 | |
| <16 nM T2 but ≥16 nM T1 | 5/18 | ||
| <16 nM T3 but ≥16 nM T2 | 7/15 | ||
| ≥16 nM | 115 (79) | 123 (87) | 121 (89) |
| ≥16 nM resulting from dose escalation | 15/123 | 5/121 | |
| Tamoxifen dose, N | |||
| 10 mg | 2 | 2 | |
| 20 mg | 145 | 112 | 108 |
| 30 mg | 6 | 4 | |
| 40 mg | 21 | 22 | |
| Aromatase inhibitor use | 4 | 9 | |
| Endoxifen concentration (nM) | |||
| Follow up of patients with endoxifen levels <16 nM at T1 (median; IQR) | 11.1 (11.3 – 13.1) | 19.9 (17.2 – 25.1) | 19.3 (15.3 – 25.5) |
Conclusions
The TOTAM study demonstrates that it is feasible to increase the percentage of patients with endoxifen levels ≥16 nM by means of TDM. This strategy offers a possibility to nearly halve the number of patients with endoxifen levels <16 nM.
Clinical trial identification
Netherlands Trial Register: NL6918 (NTR7113).
Editorial acknowledgement
Legal entity responsible for the study
Erasmus MC Cancer Institute, Department of Medical Oncology.
Funding
Erasmus University Medical Center Rotterdam (mRACE).
Disclosure
R.H. Mathijssen: Research grant/Funding (institution), Investigator-initiated research grants: Astellas; Research grant/Funding (institution), Investigator-initiated research grants: Bayer; Research grant/Funding (institution), Investigator-initiated research grants: Boehringer Ingelheim; Research grant/Funding (institution), Investigator-initiated research grants: Cristal Therapeutics; Research grant/Funding (institution), Investigator-initiated research grants: Pamgene; Research grant/Funding (institution), Investigator-initiated research grants: Pfizer; Research grant/Funding (institution), Investigator-initiated research grants: Novartis; Research grant/Funding (institution), Investigator-initiated research grants: Roche; Research grant/Funding (institution), Investigator-initiated research grants: Servier; Speaker Bureau/Expert testimony, Speakers fee: Novartis; Advisory/Consultancy, Advisory role: Servier. S.L. Koolen: Research grant/Funding (institution): Novartis; Research grant/Funding (institution): Cristal Therapeutics. All other authors have declared no conflicts of interest.