title: Effect of blood tamoxifen concentrations on surrogate biomarkers in a trial of dose reduction in healthy women.
abstract: OBJECTIVE
  Tamoxifen administered at 20 mg/d has been shown to decrease breast cancer incidence in at-risk women by 50%, but toxicity may limit its broad use, particularly in postmenopausal women. Because toxicity may be dose-dependent, we studied the biologic activity of low concentrations of tamoxifen to determine the plausibility of a dose reduction.
  
  
  METHODS
  We measured the blood concentrations of tamoxifen and its main metabolites in a dose titration study in 105 healthy women (placebo, tamoxifen 10 mg on alternate days, tamoxifen 10 mg/d, and tamoxifen 20 mg/d). Drug levels measured after 2 months of treatment were correlated with the changes in surrogate biomarkers of different diseases, including lipid profile, blood cell count, fibrinogen, antithrombin III, osteocalcin, and insulin-like growth factor I, a promising surrogate biomarker of breast cancer.
  
  
  RESULTS
  The means (+/- SD) for tamoxifen and N-desmethyltamoxifen (metabolite X) concentrations (ng/mL) were dose-related, being, respectively, 0 and 0 with placebo, 26.8 +/- 15.1 and 43.7 +/- 22.5 with 10 mg every other day, 51.2 +/- 24.1 and 90.7 +/- 48.0 with 10 mg/d, and 136.0 +/- 52.7 and 230.6 +/- 75.0 with 20 mg/d of tamoxifen. At variance, the biomarker changes were of comparable magnitude at any drug concentration except for platelet count and triglycerides levels, the latter showing a trend to an increase with increasing tamoxifen concentrations.
  
  
  CONCLUSIONS
  An 80% reduction in blood concentrations does not seem to affect the activity of tamoxifen on biomarkers of cardiovascular or breast cancer risk and may in fact have a more favorable safety profile. Additional studies are warranted to determine the most appropriate dose of this agent.
authors.affiliation: Chemoprevention Unit, the Division of Epidemiology and Biostatistics, and the Division of Laboratory Medicine, European Institute of Oncology, Milan, Italy. adecensi@ieo.it
authors.forename: A
authors.initials: A
authors.lastname: Decensi
authors.forename: S
authors.initials: S
authors.lastname: Gandini
authors.forename: A
authors.initials: A
authors.lastname: Guerrieri-Gonzaga
authors.forename: H
authors.initials: H
authors.lastname: Johansson
authors.forename: L
authors.initials: L
authors.lastname: Manetti
authors.forename: B
authors.initials: B
authors.lastname: Bonanni
authors.forename: M T
authors.initials: MT
authors.lastname: Sandri
authors.forename: A
authors.initials: A
authors.lastname: Barreca
authors.forename: A
authors.initials: A
authors.lastname: Costa
authors.forename: C
authors.initials: C
authors.lastname: Robertson
authors.forename: E A
authors.initials: EA
authors.lastname: Lien
mesh_terms: D018931:Antineoplastic Agents, Hormonal / Q000008:administration & dosage* / Q000097:blood*; D015415:Biomarkers / Q000097:blood; D004305:Dose-Response Relationship, Drug; D015914:Estrogen Replacement Therapy; D005260:Female; D006801:Humans; D008875:Middle Aged; D013629:Tamoxifen / Q000008:administration & dosage* / Q000097:blood*
chemical_list: D018931:Antineoplastic Agents, Hormonal; D015415:Biomarkers; D013629:Tamoxifen