Fenretinide in young women at genetic or familial risk of breast cancer: A placebo-controlled biomarker trial.

Fenretinide, a retinoid with a low toxicity profile that accumulates in the breast, has been shown to prevent second breast cancer in young women. Fenretinide exhibits apoptotic and anti-invasive properties and it improves insulin sensitivity in overweight premenopausal women with insulin resistance. The present study aimed to further characterize its role in cancer prevention by measuring circulating biomarkers related to insulin sensitivity and breast cancer risk. Sixty-two women, aged 20 to 46 years, healthy or who had already undergone breast cancer surgery, with a known BRCA1/2 mutation or a likelihood of mutation ≥ 20% according to the BRCAPRO model, were randomly assigned to receive fenretinide (200 mg/day) or placebo for 5 years (trial registration: EudraCT Number: 2009-010260-41). Fasting blood samples were drawn at baseline, 12 and 36 months, and the following biomarkers were analyzed: retinol, leptin, adiponectin, retinol-binding protein 4, total cholesterol, HDL and LDL cholesterol, triglycerides, glucose, insulin, IGF-I, IGFBP-3, SHBG, testosterone, and VEGF. After 12 months of treatment, we observed a favorable effect of fenretinide on glucose (decrease; P=0.005), insulin (decrease; P=0.03), HOMA index (decrease; P=0.004), HDL cholesterol (increase; P=0.002), even though these effects were less prominent after 36 months. Retinol and retinol-binding protein 4 markedly decreased (P<0.0001) throughout the study. None of the other measured biomarkers changed.