Adjusting the dose of tamoxifen in patients with early breast cancer and CYP2D6 poor metabolizer phenotype

Abstract

CYP2D6 is a key enzyme in tamoxifen metabolism, transforming it into its main activemetabolite, endoxifen. Poor CYP2D6 metabolizers (PM) have lower endoxifen plasma concentrations and possibly benefit less from treatment with tamoxifen. We evaluated tamoxifen dose adjustment in CYP2D6 PM patients in order to obtain plasma concentrations of endoxifen comparable to patients with extensive CYP2D6 metabolism (EM). Comprehensive CYP2D6 genotyping and plasma tamoxifen metabolite concentrations were performed among 249 breast cancer patients in adjuvant treatment with tamoxifen. Tamoxifen dose was increased in PM patients to 40 mg and to 60 mg daily for a 4-month period each, repeating tamoxifen metabolite measurements on completion of each dose increase. We compared the endoxifen levels between EM and PM patients, and among the PM patients at each dose level of tamoxifen (20, 40 and 60 mg). Eleven PM patients (4.7%) were identified. The mean baseline endoxifen concentration in EM patients (11.30 ng/ml) was higher compared to the PM patients (2.33 ng/ml; p < 0.001). In relation to the 20 mg dose, increasing the tamoxifen dose to 40 and 60 mg in PM patients significantly raised the endoxifen concentration to 8.38 ng/ml (OR 3.59; p ¼ 0.013) and to 9.30 ng/ml (OR 3.99; p ¼ 0.007), respectively. These concentrations were comparable to those observed in EM patients receiving 20 mg of tamoxifen (p ¼ 0.13 and p ¼ 0.64, respectively). In CYP2D6 PM patients, increasing the standard tamoxifen dose two-fold or three-fold raisesendoxifen concentrations to levels similar to those of patients with EM phenotype.