title: Randomized double-blind 2 x 2 trial of low-dose tamoxifen and fenretinide for breast cancer prevention in high-risk premenopausal women.
abstract: OBJECTIVE
  Tamoxifen and fenretinide are active in reducing premenopausal breast cancer risk and work synergistically in preclinical models. The authors assessed their combination in a two-by-two biomarker trial.
  
  
  METHODS
  A total of 235 premenopausal women with pT1mic/pT1a breast cancer (n = 21), or intraepithelial neoplasia (IEN, n = 160), or 5-year Gail risk > or = 1.3% (n = 54) were randomly allocated to either tamoxifen 5 mg/d, fenretinide 200 mg/d, their combination, or placebo. We report data for plasma insulin-like growth factor I (IGF-I), mammographic density, uterine effects, and breast neoplastic events after 5.5 years.
  
  
  RESULTS
  During the 2-year intervention, tamoxifen significantly lowered IGF-I and mammographic density by 12% and 20%, respectively, fenretinide by 4% and 10% (not significantly), their combination by 20% and 22%, with no evidence for a synergistic interaction. Tamoxifen increased endometrial thickness principally in women becoming postmenopausal, whereas fenretinide decreased endometrial thickness significantly. The annual rate of breast neoplasms (n = 48) was 3.5% +/- 1.0%, 2.1% +/- 0.8%, 4.7% +/- 1.3%, and 5.2% +/- 1.3% in the tamoxifen, fenretinide, combination, and placebo arms, respectively, with hazard ratios (HRs) of 0.70 (95% CI, 0.32 to 1.52), 0.38 (95% CI, 0.15 to 0.90), and 0.96 (95% CI, 0.46 to 1.99) relative to placebo (tamoxifen x fenretinide adverse interaction P = .03). There was no clear association with tumor receptor type. Baseline IGF-I and mammographic density did not predict breast neoplastic events, nor did change in mammographic density.
  
  
  CONCLUSIONS
  Despite favorable effects on plasma IGF-I levels and mammographic density, the combination of low-dose tamoxifen plus fenretinide did not reduce breast neoplastic events compared to placebo, whereas both single agents, particularly fenretinide, showed numerical reduction in annual odds of breast neoplasms. Further follow-up is indicated.
authors: Division of Medical Oncology, EO Ospedali Galliera, Mura delle Cappuccine 14, 16128 Genoa, Italy. andrea.decensi@galliera.it
authors: Andrea
authors: A
authors: Decensi
authors: Chris
authors: C
authors: Robertson
authors: Aliana
authors: A
authors: Guerrieri-Gonzaga
authors: Davide
authors: D
authors: Serrano
authors: Massimiliano
authors: M
authors: Cazzaniga
authors: Serena
authors: S
authors: Mora
authors: Marcella
authors: M
authors: Gulisano
authors: Harriet
authors: H
authors: Johansson
authors: Viviana
authors: V
authors: Galimberti
authors: Enrico
authors: E
authors: Cassano
authors: Simona M
authors: SM
authors: Moroni
authors: Franca
authors: F
authors: Formelli
authors: Ernst A
authors: EA
authors: Lien
authors: Giuseppe
authors: G
authors: Pelosi
authors: Karen A
authors: KA
authors: Johnson
authors: Bernardo
authors: B
authors: Bonanni
mesh_terms: D000328:Adult; D016588:Anticarcinogenic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000627:therapeutic use*; D018931:Antineoplastic Agents, Hormonal / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000097:blood*; D001943:Breast Neoplasms / Q000097:blood / Q000000981:diagnostic imaging / Q000473:pathology* / Q000517:prevention & control*; D002285:Carcinoma, Intraductal, Noninfiltrating / Q000517:prevention & control; D018275:Carcinoma, Lobular / Q000517:prevention & control; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D004357:Drug Synergism; D005260:Female; D017313:Fenretinide / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000627:therapeutic use*; D006801:Humans; D015994:Incidence; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000097:blood; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D008327:Mammography; D008875:Middle Aged; D015999:Multivariate Analysis; D016017:Odds Ratio; D017697:Premenopause / Q000097:blood; D016016:Proportional Hazards Models; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism; D020845:Selective Estrogen Receptor Modulators / Q000627:therapeutic use; D013629:Tamoxifen / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives / Q000097:blood / Q000627:therapeutic use*; D016896:Treatment Outcome; D014801:Vitamin A / Q000097:blood
chemical_list: D016588:Anticarcinogenic Agents; D018931:Antineoplastic Agents, Hormonal; D014408:Biomarkers, Tumor; D017313:Fenretinide; D018972:Insulin-Like Growth Factor Binding Protein 3; D007334:Insulin-Like Growth Factor I; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D020845:Selective Estrogen Receptor Modulators; D013629:Tamoxifen; D014801:Vitamin A; C055492:4-hydroxy-N-desmethyltamoxifen; C508053:ERBB2 protein, human