A Pilot Trial of Oral Melatonin Supplementation in Breast Cancer Survivors

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DESCRIPTION (provided by applicant): Although tamoxifen has been approved by the FDA to reduce breast cancer incidence, concern remains regarding the widespread use of tamoxifen among healthy women because of its associations with endometrial cancer and thromboembolic events. Extensive epidemiologic and laboratory data suggest that melatonin may influence cancer risk. Melatonin's effect on breast cancer risk is thought to work through several different mechanisms. Firstly, melatonin acts directly at the tumor cell level, behaving both as a selective estrogen-receptor modulator (SERM) as well as an aromatase inhibitor. Secondly, melatonin blocks linoleic acid uptake and metabolism to 13- hydroxyoctadecadienoic acid, which, via down-regulation of the mitogen-activated protein/extracellular signal-regulated kinase 1/2 growth signaling pathway, is directly related to the insulin-like growth factor (IGF) system. In addition, observational studies have reported associations between an increased risk of breast cancer and night shift work, which may decrease endogenous melatonin levels from the light exposure at night. Several small single arm studies have shown that oral melatonin supplementation can decrease estrogen and possibly IGF levels, but this has not been confirmed in a randomized, placebo controlled trial. The safety of melatonin supplementation in humans has been extensively documented with no significant adverse effects reported. Estradiol, insulin-like growth factor I (IGF-I), and insulin-like growth factor binding protein 3 (IGFBP-3) have all independently been related to breast cancer risk. We propose to conduct a randomized, placebo-controlled pilot trial of oral melatonin supplementation over four months in 118 healthy survivors of early stage breast cancer without current hormonal therapy use. We will assess variations in circulating estradiol, IGF-I, and IGFBP-3 levels as surrogate biomarkers for breast cancer risk. As secondary outcomes, effects of melatonin on mood, sleep quality, and menopausal symptoms will also be evaluated. This pilot data could lay the groundwork for a large scale trial to assess the chemopreventive potential of melatonin in women, both with and without a personal history of breast cancer.