Breast cancer prevention with fenretinide in young women at gentic and familial risk. A phase III randomized clinical trial

The aim of the proposed trial is to assess the efficacy of fenretinide (4-hydroxyphenylretinamide, 4-HPR), a vitamin A derivative, in reducing the incidence of breast cancer (BC) in healthy young premenopausal women at increased familial/genetic risk for BC (i.e., BRCA1 or BRCA2 mutation carriers or women with a significant family risk) The primary endpoint is the incidence of invasive BC and ductal intraepithelial neoplasia (DIN).Secondary endpoints are the incidence of other non-invasive breast disorders (i.e., lobular intraneoplasia, atypical hyperplasia), ovarian cancer and other cancers. These clinical endpoints require a long follow-up. During the study we will study also several intermediate biomarkers. The biological effects of fenretinide will be assessed to provide data on its activity investigating different pathways where fenretinide may be involved. We intend to measure circulating levels of several hormones and growth factors and lipid profile parameters correlated to BC risk and metabolic syndrome, which may be indirectly involved in the carcinogenesis process and insulin resistance. In particular, we will measure circulating levels of insulin-like growth factor-I (IGF-I), its main binding protein (IGFBP-3), testosterone, insulin, glycemia, total and HDL cholesterol and triglycerides. Fenretinide and its metabolites and retinol binding protein will also be measured to investigate drug bioavailability and compliance. Furthermore we will quantify cell-free circulating DNA in plasma samples.