title: Preliminary results on safety and activity of a randomized, double-blind, 2 x 2 trial of low-dose tamoxifen and fenretinide for breast cancer prevention in premenopausal women.
abstract: OBJECTIVE
  To determine whether low-dose tamoxifen and fenretinide have a synergistic effect on surrogate biomarkers, including circulating insulin-like growth factor I (IGF-I) and mammographic density, in premenopausal women at risk for breast cancer and to study drug safety.
  
  
  METHODS
  Premenopausal women (n = 235) were randomly assigned in a double-blind four-arm trial to receive tamoxifen 5 mg/d, fenretinide 200 mg/d, both agents, or placebo for 2 years. The present analysis refers to preliminary data on safety, IGF-I, and breast cancer events.
  
  
  RESULTS
  Patients were included if they had an excised ductal carcinoma-in-situ (57%), lobular carcinoma-in-situ (13%), minimal invasive breast cancer (7%), or a 5-year Gail risk > or = 1.3% (23%). After a median follow-up of 40 months, there was a reduction of 13%, 2%, 20%, and 1% in IGF-I levels for patients on tamoxifen, fenretinide, tamoxifen plus fenretinide, and placebo, respectively. Recruitment was stopped based on the lack of an interaction on IGF-I levels, which was a primary end point for the study. Thirty-six patients have dropped out of the study, 17 because of adverse events and 19 for various other reasons. One stage I endometrial cancer occurred in a patient on fenretinide, and one optic nerve ischemia and one deep venous thrombosis occurred on tamoxifen. There was no difference in menopausal symptoms, endometrial thickness, polyps, or ovarian cysts among treatment arms. To date, 24 breast cancers have been observed, without differences among arms.
  
  
  CONCLUSIONS
  The combination of low-dose tamoxifen and fenretinide is safe but not synergistic in lowering IGF-I levels in premenopausal women. The clinical implications require further follow-up.
authors.affiliation: Division of Chemoprevention, European Institute of Oncology, Milan, Italy.
authors.forename: Aliana
authors.initials: A
authors.lastname: Guerrieri-Gonzaga
authors.forename: Chris
authors.initials: C
authors.lastname: Robertson
authors.forename: Bernardo
authors.initials: B
authors.lastname: Bonanni
authors.forename: Davide
authors.initials: D
authors.lastname: Serrano
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Cazzaniga
authors.forename: Serena
authors.initials: S
authors.lastname: Mora
authors.forename: Marcella
authors.initials: M
authors.lastname: Gulisano
authors.forename: Harriet
authors.initials: H
authors.lastname: Johansson
authors.forename: Franca
authors.initials: F
authors.lastname: Formelli
authors.forename: Mattia
authors.initials: M
authors.lastname: Intra
authors.forename: Antuono
authors.initials: A
authors.lastname: Latronico
authors.forename: Dorella
authors.initials: D
authors.lastname: Franchi
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Pelosi
authors.forename: Karen
authors.initials: K
authors.lastname: Johnson
authors.forename: Andrea
authors.initials: A
authors.lastname: Decensi
mesh_terms: D000328:Adult; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000517:prevention & control*; D004311:Double-Blind Method; D004717:Endometrium / Q000187:drug effects / Q000473:pathology; D005260:Female; D017313:Fenretinide / Q000008:administration & dosage / Q000009:adverse effects; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000032:analysis; D008875:Middle Aged; D017697:Premenopause; D013629:Tamoxifen / Q000008:administration & dosage / Q000009:adverse effects; D014801:Vitamin A / Q000097:blood
chemical_list: D000970:Antineoplastic Agents; D013629:Tamoxifen; D014801:Vitamin A; D017313:Fenretinide; D007334:Insulin-Like Growth Factor I