A Pilot Trial of Oral Melatonin Supplementation in Breast Cancer Survivors

描述（由申请人提供）：尽管他莫昔芬已被FDA批准用于降低乳腺癌发病率，但由于其与子宫内膜癌和血栓栓塞事件相关，因此在健康女性中广泛使用他莫昔芬仍令人担忧。广泛的流行病学和实验室数据表明，褪黑激素可能会影响癌症的风险。褪黑激素对乳腺癌风险的影响被认为是通过几种不同的机制起作用的。首先，褪黑激素直接作用于肿瘤细胞水平，作为选择性雌激素受体调节剂（SERM）以及芳香化酶抑制剂。其次，褪黑激素阻断亚油酸摄取和代谢为13-羟基十八碳二烯酸，其通过下调促分裂原活化蛋白/细胞外信号调节激酶1/2生长信号传导途径与胰岛素样生长因子（IGF）系统直接相关。此外，观察性研究报告了乳腺癌风险增加与夜班工作之间的关联，夜班工作可能会降低夜间光照导致的内源性褪黑激素水平。几项小型单臂研究表明，口服褪黑激素补充剂可以降低雌激素和可能的IGF水平，但这尚未在随机安慰剂对照试验中得到证实。褪黑激素补充剂在人类中的安全性已被广泛记录，没有显著的不良反应报告。胰岛素样生长因子I（IGF-I）和胰岛素样生长因子结合蛋白3（IGFBP-3）都与乳腺癌风险独立相关。我们建议在118名目前未使用激素治疗的早期乳腺癌健康幸存者中进行一项为期4个月的口服褪黑激素补充剂的随机、安慰剂对照试点试验。我们将评估循环雌二醇、IGF-I和IGFBP-3水平的变化，作为乳腺癌风险的替代生物标志物。作为次要结果，还将评估褪黑激素对情绪、睡眠质量和更年期症状的影响。这些试验数据可以为大规模试验奠定基础，以评估褪黑激素在有和没有乳腺癌个人史的女性中的化学预防潜力。

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.