title: Randomized dose-ranging trial of tamoxifen at low doses in hormone replacement therapy users.
abstract: OBJECTIVE
  The combination of hormone replacement therapy (HRT) and low-dose tamoxifen may retain the benefits while reducing the risks of either agent. We assessed the optimal biologic dose and schedule of tamoxifen in HRT users using surrogate end point biomarkers and menopausal symptoms.
  
  
  METHODS
  Two hundred ten current or de novo HRT users were randomly assigned to one of the following four arms: tamoxifen 1 mg/day and placebo/week, placebo/day and tamoxifen 10 mg/week, tamoxifen 5 mg/day and placebo/week, or both placebos for 12 months. The primary end point was the change of plasma insulinlike growth factor 1 (IGF-I) through 12 months, and secondary end points were IGF-I/IGF binding protein-3 (IGFBP-3) ratio, fibrinogen, antithrombin III, C reactive protein, C-telopeptide, mammographic percent density, and endometrial thickness. Endometrial proliferation was assessed by Pipelle biopsy in superficial, deep glandular, and stromal compartments after 12 months.
  
  
  RESULTS
  Compared with placebo, IGF-I declined in all tamoxifen arms (P = .005), with a greater change on 5 mg/day (P = .019 v 10 mg/week or 1 mg/day). Tamoxifen increased IGFBP-3 and lowered antithrombin-III, C reactive protein, and mammographic density, with greater effects of 5 mg/day. Tamoxifen increased endometrial thickness but not Ki-67 expression, which was lower on 5 mg/day among the three doses. Menopausal symptoms were not significantly worsened by tamoxifen.
  
  
  CONCLUSIONS
  Doses of tamoxifen < or = 5 mg/day modulate favorably biomarkers of breast carcinogenesis and cardiovascular risk in HRT users with no increase of endometrial proliferation and menopausal symptoms. A dose of 5 mg/day was the most effective and has been selected for a phase III trial in HRT users.
authors: Division of Chemoprevention, European Institute of Oncology, Milan, Italy. andrea.decensi@galliera.it
authors: Andrea
authors: A
authors: Decensi
authors: Sara
authors: S
authors: Gandini
authors: Davide
authors: D
authors: Serrano
authors: Massimiliano
authors: M
authors: Cazzaniga
authors: Maria
authors: M
authors: Pizzamiglio
authors: Fausto
authors: F
authors: Maffini
authors: Giuseppe
authors: G
authors: Pelosi
authors: Cristina
authors: C
authors: Daldoss
authors: Umberto
authors: U
authors: Omodei
authors: Harriet
authors: H
authors: Johansson
authors: Debora
authors: D
authors: Macis
authors: Matteo
authors: M
authors: Lazzeroni
authors: Mauro
authors: M
authors: Penotti
authors: Laura
authors: L
authors: Sironi
authors: Simona
authors: S
authors: Moroni
authors: Vanda
authors: V
authors: Bianco
authors: Gabriella
authors: G
authors: Rondanina
authors: Jennifer
authors: J
authors: Gjerde
authors: Aliana
authors: A
authors: Guerrieri-Gonzaga
authors: Bernardo
authors: B
authors: Bonanni
mesh_terms: D000328:Adult; D018931:Antineoplastic Agents, Hormonal / Q000008:administration & dosage*; D014408:Biomarkers, Tumor; D002097:C-Reactive Protein / Q000378:metabolism; D049109:Cell Proliferation; D004334:Drug Administration Schedule; D004717:Endometrium / Q000378:metabolism; D005260:Female; D020249:Hormone Replacement Therapy / Q000379:methods*; D006801:Humans; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000096:biosynthesis; D008875:Middle Aged; D010919:Placebos; D013629:Tamoxifen / Q000008:administration & dosage*
chemical_list: D018931:Antineoplastic Agents, Hormonal; D014408:Biomarkers, Tumor; D018972:Insulin-Like Growth Factor Binding Protein 3; D010919:Placebos; D013629:Tamoxifen; D007334:Insulin-Like Growth Factor I; D002097:C-Reactive Protein