title: A randomized trial of low-dose tamoxifen on breast cancer proliferation and blood estrogenic biomarkers.
abstract: BACKGROUND
  Tamoxifen reduces the risk of breast cancer in women at high risk for the disease but increases the risk for endometrial tumors and venous thromboembolisms, possibly in a dose-dependent fashion. We compared the effects of tamoxifen at 1 mg/day and 5 mg/day with those of the standard dose of 20 mg/day on breast cancer proliferation using a surrogate endpoint marker (Ki-67 expression) and blood biomarkers associated with breast cancer, cardiovascular disease, and bone fracture risk.
  
  
  METHODS
  We randomly assigned 120 women with estrogen receptor (ER)-positive breast cancer to tamoxifen at 1, 5, or 20 mg/day for 4 weeks. Expression of the tumor proliferation marker Ki-67 and of biomarkers of breast cancer (insulin-like growth factor-I, sex hormone-binding globulin), cardiovascular disease (cholesterol, triglycerides, ultrasensitive C-reactive protein, fibrinogen, antithrombin-III), and bone fracture (type I collagen C-telopeptide) risk were determined before (baseline) and after treatment. All levels were compared with those in two nonrandomized control groups (34 women with ER-negative breast cancer and 29 additional women with ER-positive breast cancer). Data were analyzed by analysis of covariance. All statistical tests were two-sided.
  
  
  RESULTS
  Expression of Ki-67 decreased in all three tamoxifen groups, with no difference in the magnitude of reduction among groups (P =.81). Relative to baseline, Ki-67 expression decreased by a median of 15.0% (95% confidence interval = 0.0% to 24.1%) among the tamoxifen groups but increased by 12.8% (95% confidence interval = 0.0% to 19.6%) among the nonrandomized control groups. Several blood biomarkers showed dose-response relationships with tamoxifen, including decreased insulin-like growth factor-I, increased sex hormone-binding globulin, and decreased low-density lipoprotein-cholesterol, ultrasensitive C-reactive protein, fibrinogen, and antithrombin-III levels.
  
  
  CONCLUSIONS
  The effects on Ki-67 expression of lower doses of tamoxifen were comparable to those achieved with the standard dose, although the effects on blood biomarkers were variable. The effects of lower doses of tamoxifen should be assessed further in randomized trials.
authors.affiliation: Division of Chemoprevention, European Institute of Oncology, and University of Milan School of Medicine, Milan, Italy. andrea.decensi@ieo.it
authors.forename: Andrea
authors.initials: A
authors.lastname: Decensi
authors.forename: Chris
authors.initials: C
authors.lastname: Robertson
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Viale
authors.forename: Francesca
authors.initials: F
authors.lastname: Pigatto
authors.forename: Harriet
authors.initials: H
authors.lastname: Johansson
authors.forename: Elton R
authors.initials: ER
authors.lastname: Kisanga
authors.forename: Paolo
authors.initials: P
authors.lastname: Veronesi
authors.forename: Rosalba
authors.initials: R
authors.lastname: Torrisi
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Cazzaniga
authors.forename: Serena
authors.initials: S
authors.lastname: Mora
authors.forename: Maria T
authors.initials: MT
authors.lastname: Sandri
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Pelosi
authors.forename: Alberto
authors.initials: A
authors.lastname: Luini
authors.forename: Aron
authors.initials: A
authors.lastname: Goldhirsch
authors.forename: Ernst A
authors.initials: EA
authors.lastname: Lien
authors.forename: Umberto
authors.initials: U
authors.lastname: Veronesi
mesh_terms: D000328:Adult; D000368:Aged; D018931:Antineoplastic Agents, Hormonal / Q000008:administration & dosage / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000097:blood*; D001943:Breast Neoplasms / Q000097:blood / Q000737:chemistry / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D020847:Estrogen Receptor Modulators / Q000008:administration & dosage / Q000627:therapeutic use*; D004967:Estrogens / Q000097:blood*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007150:Immunohistochemistry; D019394:Ki-67 Antigen / Q000097:blood; D008875:Middle Aged; D012107:Research Design; D013629:Tamoxifen / Q000008:administration & dosage / Q000627:therapeutic use*
chemical_list: D018931:Antineoplastic Agents, Hormonal; D014408:Biomarkers, Tumor; D020847:Estrogen Receptor Modulators; D004967:Estrogens; D019394:Ki-67 Antigen; D013629:Tamoxifen