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

4-HPR 调节 IGF-I 与乳腺癌风险

• 批准号: 2010418
• 负责人: UMBERTO VERONESI
• 金额: $ 25.65万
• 依托单位: ISTITUTO EUROPEO DI ONCOLOGIA
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-08-01 至 2000-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2010418
• 关键词: binding proteins; breast neoplasms; cancer prevention; cancer risk; chemoprevention; clinical research; clinical trials; female; gene induction /repression; human subject; insulinlike growth factor; neoplasm /cancer genetics; retinoids

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.

本申请的具体目的是验证等离子体 胰岛素样生长因子-I（IGF-1）作为 对侧乳腺癌的女性，年龄小于50岁， 用合成类维生素A 4-（羟苯基）干预 视黄酰胺（芬维A胺或4-HPR）。 这将通过 评估对侧发生率之间的关系 乳腺癌和血浆中总或 未结合的IGF-I（后者表示为IGF-I/IGF结合蛋白-3 比率）。 分析将纳入正在进行的第三阶段 每日剂量为200的4-HPR干预5年试验 mg. 以前的4-HPR试点研究已经证明， 年龄较小的女性中总IGF-I和未结合IGF-I显著降低 比50年还长。 此外，对正在进行的， III期试验涉及2，972名I期乳腺癌女性，年龄 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。 上的样品 研究将包括641名年龄小于50岁的妇女 年（377例接受4-HPR干预，264例未接受治疗的对照）， 在基线时和治疗期间， 干预期。 分析将在三个月后进行。 对侧肿瘤数量最多的年份 available. 虽然对侧乳腺癌涉及一个选定的 目标人群，验证生物标志物作为中间体 这种情况下的终点可能有助于了解乳腺癌 致癌作用 这可能有助于选择更具体的药物， 实施更有效的4-HPR干预试验， 未来，特别是更广泛的高风险受试者群体，包括 对乳腺癌和卵巢癌有遗传易感性的年轻女性 癌的