title: Increasing tamoxifen dose in breast cancer patients based on CYP2D6 genotypes and endoxifen levels: effect on active metabolite isomers and the antiestrogenic activity score.
abstract: Tamoxifen (Tam), the major drug for estrogen receptor (ER)-positive breast cancer, is converted to its active metabolites, Z- and Z'-endoxifen and 4-OH-Tam isomers, primarily by cytochrome P450 CYP2D6. In 117 patients taking 20 mg/day of Tam, we determined CYP2D6 genotypes and measured the plasma levels of Tam metabolites. The Z-endoxifen levels increased while Z'-endoxifen levels decreased with increasing metabolizer phenotype activity (MPA) score (P ≤ 0.0004). The dosage in patients with endoxifen <40 nmol/l and/or CYP2D6 MPA scores of 0 was increased to 30 mg/day and their metabolite isomers were monitored for up to 90 days. Of the 24 patients on the increased dose, 90% showed an increase in active isomers by day 60; the rate of increase correlated with the MPA score. Notably, their antiestrogenic activity scores (AASs), which estimate total isomer biologic activity, increased from a baseline median of 17 to 26 at day 60. Further studies involving increasing/decreasing the Tam dosage based on the AAS may determine whether dose adjustment can optimize treatment and improve long-term survival.
authors: Division of Hematology and Medical Oncology, Department of Medicine, Mount Sinai School of Medicine, New York, New York, USA.
authors: M F
authors: MF
authors: Barginear
authors: M
authors: M
authors: Jaremko
authors: I
authors: I
authors: Peter
authors: C
authors: C
authors: Yu
authors: Y
authors: Y
authors: Kasai
authors: M
authors: M
authors: Kemeny
authors: G
authors: G
authors: Raptis
authors: R J
authors: RJ
authors: Desnick
mesh_terms: D000328:Adult; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism*; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D004965:Estrogen Antagonists / Q000008:administration & dosage*; D005260:Female; D005500:Follow-Up Studies; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D013629:Tamoxifen / Q000008:administration & dosage* / Q000031:analogs & derivatives* / Q000378:metabolism
chemical_list: D004965:Estrogen Antagonists; D013629:Tamoxifen; C055492:4-hydroxy-N-desmethyltamoxifen; D019389:Cytochrome P-450 CYP2D6