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

 描述（由申请方提供）：越来越多的实验室和动物模型证据支持邻苯二甲酸酯的潜在致癌作用，邻苯二甲酸酯是在各种消费品（例如化妆品、药物、乙烯基地板）中用作增塑剂的化学品。邻苯二甲酸酯代谢物在近100%的美国人口中是可测量的，尽管水平差异很大，并且在人类母乳中也有报道。然而，关于邻苯二甲酸酯是否会影响人类乳腺癌风险的数据还缺乏。只有一个小的回顾性病例对照研究存在，其中报告了乳腺癌的风险增加了两倍，与尿中的邻苯二甲酸单乙酯水平，但没有相关性或与其他邻苯二甲酸酯代谢物研究的负相关。使用单一尿液样本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受到治疗期间邻苯二甲酸酯暴露的影响，2）单一测量不太可能反映长期暴露，这与癌症风险更相关。因此，邻苯二甲酸酯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注其乳房健康的妇女提供关键信息。我们提出了一项前瞻性研究嵌套在妇女健康倡议（WHI），以评估11个尿邻苯二甲酸酯代谢物和乳腺癌风险之间的关联。从基线和随访第3年收集的尿液样本可用于WHI参与者的子样本，部分参与者也可用于第1年的尿液样本。来自问卷调查和医疗记录的大量数据，包括已知的乳腺癌风险因素，也可用于这些参与者。我们将测量500例随访3年后诊断的浸润性乳腺癌病例和1，000例健康匹配对照的重复尿液样本中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，以及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因以下因素而异：a）疾病特征，如激素受体状态;和B）个人因素，包括年龄、绝经后激素治疗使用和体重指数。前瞻性WHI队列中储存的重复尿样和大量伴随数据是一种独特的资源，为首次探索邻苯二甲酸酯在乳腺癌中的作用提供了极好的机会。 癌症风险。如果邻苯二甲酸酯和乳腺癌风险之间的联系被观察到，妇女可以减少接触含邻苯二甲酸酯的消费品作为一种初级预防手段。最终，了解邻苯二甲酸酯暴露是否会影响乳腺癌风险可能会促使制造商，立法和宣传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.