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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

From the Divisions of Chemoprevention, Breast Surgery, Breast Diagnostics, Gynaecologic Surgery, and Pathology, European Institute of Oncology; Chemoprevention Unit, National Cancer Institute, Milan; Division of Medical and Preventive Oncology, E.O. Ospedali Galliera, Genoa; Division of Medical Oncology, Ospedale S. Bortolo, Vicenza, Italy; Department of Statistics and Modelling Science, Strathclyde University, Glasgow, Scotland, United Kingdom; and Division of Cancer Prevention, National Cancer Institute, Bethesda, MD

Address reprint requests to Andrea Decensi, MD, Division of Chemoprevention, European Institute of Oncology, via Ripamonti, 435, 20141 Milan, Italy; e-mail: andrea.decensi{at}ieo.it

PURPOSE: 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.

PATIENTS AND 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 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.

CONCLUSION: 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.

Supported by National Cancer Institute grant No. CA-77188, a contract from the Italian Foundation for Cancer Research, and regional grant No. 1068/2005 on second tumors from the Associazione Italiana per la Ricerca sul Cancro.

Presented in part at the American Association for Cancer Research Prevention Meeting, Phoenix, AZ, October 26-30, 2003; and at the 40th Annual American Society of Clinical Oncology Meeting, New Orleans, LA, June 5-8, 2004.

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

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