Eduardo Martinez de Dueñas1, Enrique Ochoa Aranda2, Isabel Blancas Lopez-Barajas3, Teresa Ferrer Magdalena2, Fernando Bandrés Moya4, Luis Miguel Chicharro García5, José A Gómez Capilla6, Mercedes Zafra Ceres7, Tomás de Haro7, Regina Romero Llorens8, Carlos Ferrer Albiach9, Rafael Ferriols Lisart10, Dolores Chover Lara8, Angela López Rodríguez8, Javier Munárriz Ferrandis8, Santiago Olmos Antón8. 1. Medical Oncology Department, Hospital Provincial de Castellón, Castellón, Spain. Electronic address: eduardo.martinez@hospitalprovincial.es. 2. Molecular Biopathology Laboratory, Hospital Provincial de Castellón, Castellón, Spain. 3. Medical Oncology Department, Hospital Clínico San Cecilio, Granada, Spain. 4. School of Medicine of the Universidad Complutense de Madrid, Aula de Estudios Avanzados, Fundación Tejerina, Madrid, Spain. 5. Laboratory of Biomedicine of the Universidad Europea de Madrid, Spain. 6. Clinical Biochemistry Laboratory, Hospital Clínico San Cecilio, Granada, Spain; Department of Biochemistry and Molecular Biology III and Immunology, Faculty of Medicine of Granada, Spain. 7. Clinical Biochemistry Laboratory, Hospital Clínico San Cecilio, Granada, Spain. 8. Medical Oncology Department, Hospital Provincial de Castellón, Castellón, Spain. 9. Radiotherapy Department, Hospital Provincial de Castellón, Castellón, Spain. 10. Pharmacy Department, Hospital General de Castellón, Castellón, Spain.
Abstract
BACKGROUND: CYP2D6 is a key enzyme in tamoxifen metabolism, transforming it into its main active metabolite, 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). PATIENTS AND METHODS: 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). RESULTS: 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 = 0.013) and to 9.30 ng/ml (OR 3.99; p = 0.007), respectively. These concentrations were comparable to those observed in EM patients receiving 20 mg of tamoxifen (p = 0.13 and p = 0.64, respectively). CONCLUSION: In CYP2D6 PM patients, increasing the standard tamoxifen dose two-fold or three-fold raises endoxifen concentrations to levels similar to those of patients with EM phenotype.
BACKGROUND:CYP2D6 is a key enzyme in tamoxifen metabolism, transforming it into its main active metabolite, 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). PATIENTS AND METHODS: Comprehensive CYP2D6 genotyping and plasma tamoxifen metabolite concentrations were performed among 249 breast cancerpatients 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). RESULTS: 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 = 0.013) and to 9.30 ng/ml (OR 3.99; p = 0.007), respectively. These concentrations were comparable to those observed in EM patients receiving 20 mg of tamoxifen (p = 0.13 and p = 0.64, respectively). CONCLUSION: In CYP2D6 PM patients, increasing the standard tamoxifen dose two-fold or three-fold raises endoxifen concentrations to levels similar to those of patients with EM phenotype.
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