Phthalate Metabolites and Breast Cancer Risk in the Women's Health Initiative

 描述(申请人提供)：越来越多的实验室和动物模型证据支持邻苯二甲酸盐的潜在致癌作用，邻苯二甲酸酯是一种在各种消费品(如化妆品、药物、乙烯基地板)中用作增塑剂的化学物质。邻苯二甲酸盐代谢物在近100%的美国人口中都能检测到，尽管含量差异很大，而且据报道，在人类母乳中也有邻苯二甲酸盐代谢物的存在。然而，关于邻苯二甲酸盐是否会影响人类乳腺癌风险的数据缺乏。只有一项小型回顾性病例对照研究，报告了与尿中邻苯二甲酸单乙酯水平相关的乳腺癌风险增加两倍，但与所研究的其他邻苯二甲酸乙酯代谢物没有关联或负关联。使用单一尿样的回顾性研究不太适合解决这一重要问题，因为1)诊断后测量的尿邻苯二甲酸酯代谢物水平可能在治疗期间受到邻苯二甲酸盐暴露的影响，以及2)单一测量不太可能反映与癌症风险更相关的长期暴露。因此，邻苯二甲酸盐暴露对乳腺癌风险的影响仍然知之甚少。澄清这些常见暴露的影响将为数百万关心她们乳房健康的女性提供关键信息。我们提出了一项嵌套在妇女健康倡议(WHI)中的前瞻性研究，以评估11种尿邻苯二甲酸酯代谢物水平与乳腺癌风险之间的关系。从基线和随访第三年收集的尿样可以在WHI参与者的子样本上获得，第一年的尿样也可以在一些参与者身上获得。来自调查问卷和医疗记录的大量数据，包括已知的乳腺癌风险因素，也可以在这些参与者身上获得。我们将测量500例浸润性乳腺癌患者和1,000名健康对照组重复尿样中11种邻苯二甲酸酯代谢物的水平，以解决以下具体目标：1)确定邻苯二甲酸酯代谢物水平是否与乳腺癌风险相关；2)评估邻苯二甲酸酯代谢物水平与乳腺癌之间的关联是否与：a)疾病特征，如激素受体状态；以及b)个人因素，包括年龄、绝经后激素治疗的使用和体重指数。存储的重复尿样和未来WHI队列中可用的大量伴随数据是一个独特的资源，为首次探索邻苯二甲酸盐在乳房中的作用提供了一个极好的机会 癌症风险。如果观察到邻苯二甲酸盐和乳腺癌风险之间的联系，女性可以减少对含有邻苯二甲酸盐的消费品的接触，作为一级预防手段。最终，了解邻苯二甲酸酯是否会影响乳腺癌风险，可能会促使制造商、立法机构和倡导者努力从消费品中完全去除邻苯二甲酸酯。

 DESCRIPTION (provided by applicant): Mounting laboratory and animal model evidence supports the potentially carcinogenic effects of phthalates, chemicals used as plasticizers in a wide variety of consumer products (e.g. cosmetics, medications, vinyl flooring). Phthalate metabolites are measurable in nearly 100% of the U.S. population, though levels vary widely, and also have been reported in human breast milk. However, data on whether phthalates affect human breast cancer risk is lacking. Only one small retrospective case-control study exists, which reported a two-fold increase in breast cancer risk associated with urinary levels of mono-ethyl phthalate, yet either no association or an inverse association with other phthalate metabolites studied. Retrospective studies utilizing a single urine sample are poorly suited for addressing this important question, because 1) urinary phthalate metabolite levels measured after diagnosis may have been affected by phthalate exposure during treatment, and 2) a single measurement is unlikely to reflect longer-term exposures, which are of greater relevance to cancer risk. As a result, the impact of phthalate exposure on breast cancer risk remains poorly understood. Clarifying the effects of these common exposures will provide critical information for the millions of women concerned about their breast health. We propose a prospective study nested within the Women's Health Initiative (WHI) to evaluate associations between levels of eleven urinary phthalate metabolites and breast cancer risk. Prospectively collected urine samples from baseline and year 3 of follow-up are available on a sub-sample of WHI participants with year 1 urine samples also available on some participants. Extensive data from questionnaires and medical records, including known breast cancer risk factors, also are available on these participants. We will measure levels of eleven phthalate metabolites in repeated urine samples from 500 invasive breast cancer cases diagnosed after year 3 of follow-up and 1,000 healthy matched controls to address the following Specific Aims: 1) to determine if phthalate metabolite levels are associated with breast cancer risk, and 2) to evaluate if the associations between phthalate metabolite levels and breast cancer vary by: a) disease characteristics such as hormone receptor status; and b) personal factors including age, postmenopausal hormone therapy use, and body mass index. The stored repeat urine samples and vast accompanying data available within the prospective WHI cohort are a unique resource and provide an excellent opportunity to explore for the first time the role of phthalates in breast cancer risk. If a link between phthalates and breast cancer risk were observed, women could reduce their exposure to phthalate-containing consumer products as a means of primary prevention. Ultimately, understanding if exposure to phthalates affects breast cancer risk may motivate manufacturer, legislative, and advocacy efforts to remove phthalates from consumer products altogether.