Premenopausal Hormone Levels and Risk of Breast Cancer

描述(由申请人提供)：乳腺癌的流行病学表明绝经前激素在病因学中起中心作用，但目前存在有限的数据表明哪些特定的激素最重要，以及风险在什么水平上增加。最近，我们观察到绝经前乳腺癌的发生与血浆性类固醇雌二醇、雄烯二酮、睾酮和脱氢表雄酮硫酸盐水平呈显著正相关。在这一应用中，我们建议扩展这些初步发现--例如，我们将更好地确定血浆水平与疾病之间的剂量-反应关系，并通过肿瘤特征评估相关性(例如，ER+/PR+与ER-/PR-)。此外，我们计划使用一种新开发的分析方法来评估尿雌激素代谢物。我们还提出了几个与类固醇激素相关的新目标，包括评估血浆肠内酯(一种植物雌激素)、25-羟基维生素D和维生素D途径中的遗传变异。最后，为了更好地了解这些因素对乳腺癌风险的贡献，我们建议评估它们对Gail和Rosner统计风险预测模型的影响。在这项研究中，我们将利用1996-99年间从29,611名参加护士健康研究II(NHSII)的参与者采集的血液和尿样，他们的年龄在32岁到54岁之间。其中18,521个样本是根据女性的月经周期确定的；对这些女性来说，早期卵泡和黄体中期血液样本都是可用的。自采集以来，样品一直保存在-130摄氏度或更低的液氮冰柜中。我们将对采血后被诊断为乳腺癌的妇女和没有患病的配对对照组的样本进行分析(即嵌套病例对照设计)，从而有效地利用这些预期收集的样本。到2009年，我们预计将确认766例乳腺癌病例，其中435例将发生在那些有定时样本的人中。NHSII是为数不多的提供了研究这些关系的理想环境的队列研究之一。全世界很少有其他研究有大量的血液和尿液样本，这些样本主要来自绝经前的女性。此外，这一队列的随访率仍然很高(98%在血液队列中)，自1989年以来收集了大量关于生殖因素、饮食、体力活动和其他变量的数据，并将继续收集(CA50385；Willett，PI)。因此，我们建议的研究应该有助于我们理解荷尔蒙和年轻女性乳腺癌之间的关系。此外，证实维生素D或肠内酯的保护性关联，这些因素可以通过生活方式的选择而改变，将对公共卫生产生重要影响。

DESCRIPTION (provided by applicant): The epidemiology of breast cancer suggests a central etiologic role for premenopausal hormones, yet limited data exist to indicate which specific hormones are of greatest importance and at what levels risk is increased. Recently, we observed significant positive associations between incident premenopausal breast cancer and plasma levels of the sex steroids estradiol, androstenedione, testosterone, and dehydroepiandrosterone sulfate. In this application, we propose to extend these initial findings - for example, we will better determine the dose-response relation between plasma levels and disease and assess associations by tumor characteristics (e.g., ER+/PR+ vs. ER-/PR-). Further, we plan to evaluate urinary estrogen metabolites using a newly developed assay. We also propose several new steroid- hormone related aims, including the assessment of plasma enterolactone (a phytoestrogen), 25-OH vitamin D, and genetic variation in the vitamin D pathway. Finally, to better understand the contribution of these factors to breast cancer risk, we propose to evaluate their addition to both the Gail and Rosner statistical risk prediction models. In this study, we will utilize blood and urine samples collected in 1996-99 from 29,611 participants in the Nurses' Health Study II (NHSII) who were 32 to 54 years of age at collection. 18,521 of these samples were timed according to the woman's menstrual cycle; for these women, both early follicular and midluteal blood samples are available. Samples have been stored at -130oC or colder in liquid nitrogen freezers since collection. We will assay samples from women who were diagnosed with breast cancer after blood collection and matched controls who remained disease-free (i.e., a nested case-control design), thus efficiently utilizing these prospectively collected samples. By 2009, we expect to confirm 766 incident cases of breast cancer, 435 of which will have occurred among those with timed samples. The NHSII is one of a few cohort studies that provides an ideal context in which to investigate these relationships. Few other studies worldwide have a large number of blood and urine samples from predominantly premenopausal women. Also, follow-up in this cohort remains high (98% in the blood cohort) and a wealth of data on reproductive factors, diet, physical activity, and other variables has been collected since 1989 and continues to be collected (CA50385; Willett, PI). Hence, our proposed study should contribute substantially to our understanding of the relationships between hormones and breast cancer in younger women. Further, confirmation of protective associations for vitamin D or enterolactone, factors amenable to change through lifestyle choices, would have important public health implications.