Randomized double-blind 2x2 trial of low-dose tamoxifen and fenretinide for breast cancer prevention in high-risk premenopausal women

Andrea Decensi, Chris Robertson, Aliana Guerrieri-Gonzaga, Davide Serrano, Massimiliano Cazzaniga, Serena Mora, Marcella Gulisano, Harriet Johansson, Viviana Galimberti, Enrico Cassano, Simona M. Moroni, Franca Formelli, Ernst A. Lien, Giuseppe Pelosi, Karen A. Johnson, Bernardo Bonanni

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89 Citations (Scopus)


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. 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. 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. 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.
Original languageEnglish
Pages (from-to)3749-3756
Number of pages7
JournalJournal of Clinical Oncology
Issue number23
Publication statusPublished - 10 Aug 2009


  • tamoxifen
  • fenretinide
  • breast cancer prevention
  • premenopausal women
  • double-blind trial


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