IGF-I MODULATION BY 4-HPR AND BREAST CANCER RISK

本申请的具体目的是验证血浆 胰岛素样生长因子-I(IGF-1)作为糖尿病的替代终点 50岁以下女性的对侧乳腺癌 人工合成维甲酸4-(羟基苯基)的干预 维甲酰胺(芬维甲素或4-HPR)。这将通过以下方式实现 评估对侧牙周围炎的发生率 乳腺癌与血浆总或总血药浓度的变化 未结合的IGF-I(后者表达为IGF-I/IGF结合蛋白-3 比率)。分析工作将纳入正在进行的第三阶段 每日剂量为200的4-HPR的5年干预试验 Mg.之前的4-羟丙基-1，4-羟色胺的试点研究已经证明 少龄女性血清总IGF-I和游离IGF-I水平显著降低 不只是50年。此外，对正在进行的 第三阶段试验涉及2972名年龄为1岁的I期乳腺癌妇女 30-70岁表明4-HPR减少卵巢和对侧 年轻或绝经前妇女的乳腺癌。样品放在 研究将包括641名年龄在50岁以下的女性 年(377人接受4次HPR干预，264人未接受治疗) 谁的血浆等量在基线时和在 干预期。分析将在三点后进行 对侧肿瘤数量最高的年份 可用。尽管对侧乳腺癌涉及到一种选择的 目标人群，生物标记物作为中间体的有效性 该设置中的终点可以提供对乳房的洞察 致癌。这可能有助于选择更具体的代理，并 利用4-HPR实施更有效的干预试验 未来，特别是更广泛的高风险主体群体，包括 对乳房和卵巢有遗传易感性的年轻女性 癌症。

The specific aim of the present application is to validate plasma insulin-like growth factor-I (IGF-1) as a surrogate endpoint of contralateral breast cancer in women, aged less that 50 years, on intervention with the synthetic retinoid 4-(hydroxyphenyl) retinamide (fenretinide or 4-HPR). This will be accomplished by assessing the relationship between the incidence of contralateral breast cancer and the change in plasma concentrations of total or unbound IGF-I (the latter expressed as IGF-I/IGF binding protein-3 ratio). The analysis will be integrated into the ongoing phase III trial of a five-year intervention with 4-HPR at the daily dose of 200 mg. Previous pilot studies of 4-HPR have demonstrated a significant reduction of total and unbound IGF-I in women aged less than 50 years. In addition, an interim analysis of the ongoing, phase III trial involving 2,972 stage I breast cancer women aged 30-70 years indicates that 4-HPR reduces ovarian and contralateral breast cancers in young or premenopausal women. The sample on study will include a subgroup of 641 women aged less than 50 years (377 on 4-HPR intervention and 264 untreated controls) in whom plasma aliquot are available both at baseline and during the intervention period. The analysis will be performed after three years when the highest number of contralateral tumors will be available. Although contralateral breast cancer involves a selected target population, validation of the biomarker as an intermediate endpoint in this setting may provide insight into breast carcinogenesis. This may help to select more specific agents and to implement more efficient intervention trials with 4-HPR in the future, particularly a wider group of high risk subjects, including young women with genetic susceptibility to breast and ovarian cancers.