Cadmium Exposure and Risk of Breast Cancer in the Women's Health Initiative

描述(申请人提供)：乳腺癌流行病学已经取得了相当大的进展，但这种疾病仍然是美国女性最常见的诊断癌症，很难预防。因此，当务之急是发现潜在的新的可改变的风险因素。多条证据表明，镉是一种广泛存在的、持久的重金属环境污染物，是乳腺组织中的致癌物，但还需要更明确的流行病学调查。尽管已知的致癌风险与工业环境中发生的极高水平的镉暴露有关，但人们对一生中低水平的镉暴露的致癌性知之甚少。体外和动物实验都表明，镉具有雌激素样特性，使镉成为乳腺癌等雌激素依赖型肿瘤的合理风险因素。在之前的一项回溯性病例#对照研究中，我们发现与高尿镉相关的乳腺癌风险增加了两倍多，这一结果得到了最近第二项类似研究的支持。我们现在建议在妇女健康倡议(WHI)中对这一假设进行更明确的测试，这是一项关于绝经后妇女预防性健康实践的前瞻性队列研究。首先，我们将通过测量尿镉来评估镉暴露。大约10,000名WHI参与者在注册时捐献了尿液，截至2010年8月，这些女性中记录了567例浸润性乳腺癌病例。我们计划在一项嵌套的病例#对照研究中评估尿镉与乳腺癌风险之间的关系，将这些乳腺癌病例与大约1000名对照进行匹配。其次，我们将使用既定的方法来计算所有约161,000名WHI参与者-包括约7,000名被诊断为浸润性乳腺癌的女性-的饮食镉暴露，这些参与者完成了食物频率问卷，并估计了与饮食镉暴露相关的浸润性乳腺癌的风险。最后，为了这两个目的，我们将检查荷尔蒙定义的亚组中的关联，以了解更多关于镉可能与乳腺癌风险相关的机制。由于大多数妇女通过食用在受污染的土壤中种植的食物和通过香烟烟雾接触到镉，减少镉污染的策略可能会为降低乳腺癌发病率提供机会。拟议研究的高效和强大的设计将及时提供关于无处不在的环境污染物对浸润性乳腺癌发病率的贡献的新信息。 与公共健康相关：乳腺癌是美国女性确诊的最常见癌症。应该调查关于可改变的危险因素，包括环境化学品的有希望的线索，因为有可能制定新的预防战略。镉是一种普遍存在的环境污染物，初步证据表明，它可能与乳腺癌有关，可能是通过其雌激素效应。我们将使用之前收集的WHI生物样本和数据、最先进的镉检测和流行病学分析，在预期的妇女健康倡议队列中有效地检验这一假设。这项研究将是更全面地了解乳腺癌的可预防原因的重要一步。

DESCRIPTION (provided by applicant): Considerable advances have been made in breast cancer epidemiology, yet the disease remains the most commonly diagnosed cancer in US women and difficult to prevent. Therefore, it is imperative to pursue the discovery of potential new modifiable risk factors. Multiple lines of evidence suggest that cadmium, a widespread and persistent heavy metal environmental pollutant, is a carcinogen in breast tissue, but more definitive epidemiological investigation is required. In spite of the known carcinogenic risks associated with very high levels of cadmium exposure that occur in industrial settings, little is known about the carcinogenicity of low levels of cadmium exposure over a lifetime. Both in vitro and animal experiments show that cadmium has estrogenic properties, making cadmium a plausible risk factor for estrogen dependent tumors such as breast cancer. In a previous retrospective case#control study we found a more than two#fold increase in breast cancer risk associated with high urine cadmium, a result supported by a second recent similar study. We now propose to perform a more definitive test of this hypothesis within the Women's Health Initiative (WHI), a prospective cohort study of preventive health practices in postmenopausal women. First, we will assess cadmium exposure through measurement of urine cadmium. Approximately 10,000 participants in the WHI donated urine at enrollment, and 567 incident cases of invasive breast cancer were documented in these women through August 2010. We plan to evaluate the association between urine cadmium and breast cancer risk in a nested case#control study, matching these breast cancer cases with approximately 1,000 controls. Second, we will use established methods to calculate dietary exposure to cadmium among all ~161,000 WHI participants-including ~7,000 women diagnosed with invasive breast cancer-who completed food frequency questionnaires and estimate the hazard of invasive breast cancer associated with dietary cadmium exposure. Finally, for both of these aims we will examine associations in hormonally#defined subgroups to learn more about the mechanisms whereby cadmium may be associated with breast cancer risk. Because most women are exposed to cadmium through the consumption of foods grown in contaminated soils and through cigarette smoke, strategies that reduce cadmium pollution may present opportunities for reducing breast cancer incidence. The efficient and powerful design of the proposed study will provide timely new information on the contribution of a ubiquitous environmental contaminant to the incidence of invasive breast cancer. PUBLIC HEALTH RELEVANCE: Breast cancer is the most common cancer diagnosed in US women. Promising leads on modifiable risk factors, including environmental chemicals, should be investigated because of the potential for new prevention strategies. Cadmium is a ubiquitous environmental contaminant that preliminary evidence shows may be associated with breast cancer, possibly through its estrogenic effects. We will efficiently test this hypothesis in the prospective Women's Health Initiative cohort, using previously collected WHI bio-specimens and data, state-of-the-art cadmium assays and epidemiologic analysis. This study will be an important step toward a fuller understanding of the preventable causes of breast cancer.