title: Adjusting the dose of tamoxifen in patients with early breast cancer and CYP2D6 poor metabolizer phenotype.
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).
  
  
  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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Medical Oncology Department, Hospital Provincial de Castellón, Castellón, Spain. Electronic address: eduardo.martinez@hospitalprovincial.es.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Martinez de Dueñas
authors.affiliation: Molecular Biopathology Laboratory, Hospital Provincial de Castellón, Castellón, Spain.
authors.forename: Enrique
authors.initials: E
authors.lastname: Ochoa Aranda
authors.affiliation: Medical Oncology Department, Hospital Clínico San Cecilio, Granada, Spain.
authors.forename: Isabel
authors.initials: I
authors.lastname: Blancas Lopez-Barajas
authors.affiliation: Molecular Biopathology Laboratory, Hospital Provincial de Castellón, Castellón, Spain.
authors.forename: Teresa
authors.initials: T
authors.lastname: Ferrer Magdalena
authors.affiliation: School of Medicine of the Universidad Complutense de Madrid, Aula de Estudios Avanzados, Fundación Tejerina, Madrid, Spain.
authors.forename: Fernando
authors.initials: F
authors.lastname: Bandrés Moya
authors.affiliation: Laboratory of Biomedicine of the Universidad Europea de Madrid, Spain.
authors.forename: Luis Miguel
authors.initials: LM
authors.lastname: Chicharro García
authors.affiliation: Clinical Biochemistry Laboratory, Hospital Clínico San Cecilio, Granada, Spain; Department of Biochemistry and Molecular Biology III and Immunology, Faculty of Medicine of Granada, Spain.
authors.forename: José A
authors.initials: JA
authors.lastname: Gómez Capilla
authors.affiliation: Clinical Biochemistry Laboratory, Hospital Clínico San Cecilio, Granada, Spain.
authors.forename: Mercedes
authors.initials: M
authors.lastname: Zafra Ceres
authors.affiliation: Clinical Biochemistry Laboratory, Hospital Clínico San Cecilio, Granada, Spain.
authors.forename: Tomás
authors.initials: T
authors.lastname: de Haro
authors.affiliation: Medical Oncology Department, Hospital Provincial de Castellón, Castellón, Spain.
authors.forename: Regina
authors.initials: R
authors.lastname: Romero Llorens
authors.affiliation: Radiotherapy Department, Hospital Provincial de Castellón, Castellón, Spain.
authors.forename: Carlos
authors.initials: C
authors.lastname: Ferrer Albiach
authors.affiliation: Pharmacy Department, Hospital General de Castellón, Castellón, Spain.
authors.forename: Rafael
authors.initials: R
authors.lastname: Ferriols Lisart
authors.affiliation: Medical Oncology Department, Hospital Provincial de Castellón, Castellón, Spain.
authors.forename: Dolores
authors.initials: D
authors.lastname: Chover Lara
authors.affiliation: Medical Oncology Department, Hospital Provincial de Castellón, Castellón, Spain.
authors.forename: Angela
authors.initials: A
authors.lastname: López Rodríguez
authors.affiliation: Medical Oncology Department, Hospital Provincial de Castellón, Castellón, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Munárriz Ferrandis
authors.affiliation: Medical Oncology Department, Hospital Provincial de Castellón, Castellón, Spain.
authors.forename: Santiago
authors.initials: S
authors.lastname: Olmos Antón
mesh_terms: D000328:Adult; D000368:Aged; D018931:Antineoplastic Agents, Hormonal / Q000008:administration & dosage* / Q000378:metabolism; D001943:Breast Neoplasms / Q000188:drug therapy*; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005838:Genotype; D006801:Humans; D008875:Middle Aged; D010641:Phenotype; D013629:Tamoxifen / Q000008:administration & dosage* / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism
chemical_list: D018931:Antineoplastic Agents, Hormonal; D013629:Tamoxifen; C055492:4-hydroxy-N-desmethyltamoxifen; D019389:Cytochrome P-450 CYP2D6
keywords: Breast cancer; CYP2D6; Dose adjustment; Endoxifen; Tamoxifen