Implementation of model-informed precision dosing for tamoxifen therapy in patients with breast cancer: A prospective intervention study
Ruben Y.M. van Nijnatten,
Sanne M. Buijs,
Bram C. Agema,
Raphaël M.J. Fischer,
Inge Ghobadi Moghaddam-Helmantel,
Caroline M.E. Contant,
Felix E. de Jongh,
Auke M.T. Huijben,
Manon Kop,
Annemieke van der Padt-Pruijsten,
Hanneke J.M. Zuetenhorst,
Ron H.N. van Schaik,
Birgit C.P. Koch,
A. Jager,
Stijn L.W. Koolen,
Ron H.J. Mathijssen
Affiliations
Ruben Y.M. van Nijnatten
Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands
Sanne M. Buijs
Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands; Corresponding author. Department of Medical Oncology, Erasmus MC Cancer Institute Dr. Molewaterplein 40, PO Box 2040, CN, 3015, the Netherlands.
Bram C. Agema
Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands
Raphaël M.J. Fischer
Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands
Inge Ghobadi Moghaddam-Helmantel
Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands
Caroline M.E. Contant
Department of Surgery, Maasstad Hospital, Rotterdam, the Netherlands
Felix E. de Jongh
Department of Internal Medicine, Breast Cancer Center South Holland South, Ikazia Hospital, Rotterdam, the Netherlands
Auke M.T. Huijben
Department of Internal Medicine, Breast Cancer Center South Holland South, Maasstad Hospital, Rotterdam, the Netherlands
Manon Kop
Department of Internal Medicine, IJsselland Hospital, Capelle aan den IJssel, the Netherlands
Annemieke van der Padt-Pruijsten
Department of Internal Medicine, Breast Cancer Center South Holland South, Spijkenisse Medical Center, Spijkenisse, the Netherlands
Hanneke J.M. Zuetenhorst
Department of Internal Medicine, Franciscus Gasthuis & Vlietland, Schiedam, the Netherlands
Ron H.N. van Schaik
Department of Clinical Chemistry, Erasmus University Medical Center, Rotterdam, the Netherlands
Birgit C.P. Koch
Department of Hospital Pharmacy, Erasmus University Medical Center, Rotterdam, the Netherlands
A. Jager
Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands
Stijn L.W. Koolen
Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands; Department of Hospital Pharmacy, Erasmus University Medical Center, Rotterdam, the Netherlands
Ron H.J. Mathijssen
Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands
Tamoxifen is an estrogen-receptor (ER) antagonist, used as adjuvant treatment of ER-positive breast cancer. It is converted by CYP2D6 into endoxifen, its most active metabolite. Patients with endoxifen plasma concentrations <16 nM face a higher risk of recurrence. The use of a priori model-informed precision dosing (MIPD) may lead to faster target attainment and thus potentially improve patient outcomes.In total, 106 evaluable patients were prospectively included in this single-arm MIPD-intervention study. Patients received a model-predicted tamoxifen dose when starting tamoxifen-treatment (65.1 % of patients received 20 mg, 16.0 % received 30 mg and 18.9 % received 40 mg). Seventy-five percent of the 40 mg group was predicted to be unable to reach the threshold of 16 nM despite receiving the highest registered dose. After attaining steady-state, 84.0 % of patients reached endoxifen levels ≥16 nM, which was not significantly higher compared to a historical control cohort (77.9 %, p = 0.17). The model showed adequate performance and correctly identified patients requiring 40 mg tamoxifen. Endoxifen samples that were acquired 4–6 weeks after treatment initiation, are informative of steady-state endoxifen levels and can be used to inform MIPD and adjust tamoxifen dosing prior to steady-state attainment.In this first MIPD implementation study for patients treated with tamoxifen, MIPD did lead to more patients achieving endoxifen levels ≥16 nM as compared to the one-dose-fits-all strategy, albeit insignificant. This may partly be explained by a larger proportion of patients who were recommended to switch to an aromatase inhibitor (AI) in the intervention cohort. In conclusion, MIPD seems beneficial compared to one-size-fits-all-dosing, but TDM still remains an important addition.
