title: Tamoxifen metabolite concentrations, CYP2D6 genotype, and breast cancer outcomes.
abstract: We explored whether breast cancer outcomes are associated with endoxifen and other metabolites of tamoxifen and examined potential correlates of endoxifen concentration levels in serum including cytochrome P450 2D6 (CYP2D6) metabolizer phenotype and body mass index (BMI). Concentration levels of tamoxifen, endoxifen, 4-hydroxytamoxifen (4OH-tamoxifen), and N-desmethyltamoxifen (ND-tamoxifen) were measured from samples taken from 1,370 patients with estrogen receptor (ER)-positive breast cancer who were participating in the Women's Healthy Eating and Living (WHEL) Study. We tested these concentration levels for possible associations with breast cancer outcomes and found that breast cancer outcomes were not associated with the concentration levels of tamoxifen, 4-hydroxytamoxifen, and ND-tamoxifen. For endoxifen, a threshold was identified, with women in the upper four quintiles of endoxifen concentration appearing to have a 26% lower recurrence rate than women in the bottom quintile (hazard ratio (HR) = 0.74; 95% confidence interval (CI), (0.55-1.00)). The predictors of this higher-risk bottom quintile were poor/intermediate metabolizer genotype, higher BMI, and lower tamoxifen concentrations as compared with the mean for the cohort as a whole. This study suggests that there is a minimal concentration threshold above which endoxifen is effective against the recurrence of breast cancer and that ~80% of tamoxifen takers attain this threshold.
authors: Cancer Prevention and Control Program, Moores UCSD Cancer Center, University of California, San Diego, La Jolla, California, USA.
authors: L
authors: L
authors: Madlensky
authors: L
authors: L
authors: Natarajan
authors: S
authors: S
authors: Tchu
authors: M
authors: M
authors: Pu
authors: J
authors: J
authors: Mortimer
authors: S W
authors: SW
authors: Flatt
authors: D M
authors: DM
authors: Nikoloff
authors: G
authors: G
authors: Hillman
authors: M R
authors: MR
authors: Fontecha
authors: H J
authors: HJ
authors: Lawrence
authors: B A
authors: BA
authors: Parker
authors: A H B
authors: AH
authors: Wu
authors: J P
authors: JP
authors: Pierce
mesh_terms: D001943:Breast Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics*; D015331:Cohort Studies; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics*; D005260:Female; D005838:Genotype; D006801:Humans; D008875:Middle Aged; D010641:Phenotype; D013629:Tamoxifen / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism* / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D013629:Tamoxifen; C055492:4-hydroxy-N-desmethyltamoxifen; D019389:Cytochrome P-450 CYP2D6