Originally published as JCO Early Release 10.1200/JCO.2008.19.3797 on July 13 2009

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Randomized Double-Blind 2 x 2 Trial of Low-Dose Tamoxifen and Fenretinide for Breast Cancer Prevention in High-Risk Premenopausal Women

From the Divisions of Cancer Prevention and Genetics, Breast Surgery, Breast Diagnostics, Gynaecologic Surgery, and Pathology, European Institute of Oncology; University of Milan School of Medicine; Chemoprevention Unit, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico, Istituto Nazionale dei Tumori, Milan; Medical Oncology, E.O. Ospedali Galliera, Genoa; Medical Oncology, Ospedale S. Bortolo, Vicenza, Italy; Statistics and Modeling Science, Strathclyde University, Glasgow, Scotland, United Kingdom; Hormone Laboratory, Haukeland University Hospital; Section for Endocrinology, Institute of Medicine, University of Bergen, Bergen, Norway; and the Division of Cancer Prevention, National Cancer Institute, Bethesda, MD.

Corresponding author: Andrea Decensi, MD, Division of Medical Oncology, E.O. Ospedali Galliera, Mura delle Cappuccine 14, 16128 Genoa, Italy; e-mail: andrea.decensi{at}galliera.it.

Purpose 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.

Patients and 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 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.

Conclusion 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.

Supported by Grant No. CA-77183 from the National Cancer Institute, a contract from the Italian Foundation for Cancer Research, regional grant No. 1068 on second tumors from the Associazione Italiana per la Ricerca sul Cancro, and by Progetto Integrato Oncologia, Italian Health Ministry contracts RFPS-2006-1-339898 and RFPS-2006-1-339856.

Fenretinide was manufactured and donated by the R.W. Johnson Pharmaceutical Research Institute, Spring House, PA; tamoxifen was donated by Laboratori MAG, Garbagnate, and manufactured by Cosmo SpA, Lainate, Italy.

Presented in oral format at the Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, May 30-June 3, 2008.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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