Therapeutic and Diagnostic Factors as Related to Cancer Risk

该项目的一个主要重点是确定外源性激素与随后的癌症风险的关系。最近的分析评估了绝经期激素与妇科和乳腺癌风险的关系，使用的数据来自我们的大型前瞻性队列研究。使用来自NIH-AARP饮食和健康队列研究的数据，我们澄清了一些关于使用绝经激素治疗的妇女患卵巢癌风险的未解决问题。使用无对抗性雌激素治疗10年或10年以上的女性中卵巢癌风险增加提供了进一步的证据支持绝经后雌激素水平增加可以影响卵巢癌发展的假设。此外，这项研究提供了一些第一个强有力的证据，特别是在子宫完整的妇女中，雌激素加孕激素的使用与卵巢癌风险增加有关。这些结果重申了对现有队列进行长期随访的价值，以阐明暴露于绝经期激素治疗的女性中罕见结局（如卵巢癌）的风险增加。这项大型队列研究也被用于评估绝经期激素与子宫内膜癌风险的关系。与以前的一些建议相反，雌激素加雷公藤多甙治疗可能会防止这种癌症，我们没有发现这种保护的证据。值得注意的是，在该人群中，连续或连续的雌激素加孕激素与子宫内膜癌风险均无任何统计学显著相关性。此外，在同一项研究中，我们检查了与单独使用雌激素和联合使用雌激素-孕酮治疗相关的乳腺癌风险。这项调查发现，这两种类型的制剂的风险增加，虽然联合治疗更密切相关。激素的作用在瘦的女性中更强，但即使在胖的女性中，联合治疗仍然是一个风险因素。最后，数据被用来评估激素是否对不同类型的肿瘤有不同的关系。雌激素受体阳性肿瘤的作用最强，这些关系影响其他临床参数，包括组织学。这些分析强调了在评估激素效应时考虑关节临床参数的重要性。 美国退休人员协会的研究也有助于评估其他药物对癌症风险的影响。分析还评估了与非甾体抗炎药有关的乳腺癌风险。鉴于炎症已被提出作为该癌症部位的病原体参与，该研究领域一直令人感兴趣。这些分析表明，阿司匹林的使用降低了风险，特别是雌激素受体阳性的癌症。我们还在评估某些用于治疗心血管疾病的药物对乳腺癌风险的影响，这些药物已知对DNA有去甲基化作用。 最近的队列研究表明，有骨折史或骨密度低的女性患乳腺癌的风险降低。骨丢失的严重程度和时间对风险的影响尚未研究，其他风险因素（家族史、人体测量因素、体力活动和外源性激素）在多大程度上改变与骨密度的关系尚不清楚。为了详细阐述这些研究问题，我们对超过20，000名绝经后妇女进行了一项随访研究，这些妇女自愿参加骨增强药物阿仑膦酸钠的临床试验。这个大型队列包括关于主要乳腺癌风险因素的广泛基线信息，因此非常适合评估与骨矿物质密度的潜在相互作用以及骨矿物质密度对其他癌症部位的影响。研究参与者血清学样本的可用性也将能够评估内源性激素和骨密度对随后乳腺癌风险的相互作用。

A major emphasis of this project has been to define the relationship of exogenous hormones to subsequent cancer risk. Recent analyses have assesed the relationships of menopausal hormones to gynecologic and breast cancer risk using data from our large, prospective cohort studies. Using data from the NIH-AARP Diet and Health Cohort Study, we have clarified some unresolved issues regarding ovarian cancer risk in women who use menopausal hormone therapy. Increased ovarian cancer risks among women who used unopposed estrogen therapy for 10 or more years provide further evidence to support the hypothesis that increased estrogen levels after menopause can influence the development of ovarian cancer. In addition, this study provided some of the first strong evidence that specifically links estrogen plus progestin use to increased ovarian cancer risk in women with intact uteri. These results reiterate the value of long-term follow-up of existing cohorts to elucidate increased risks of rare outcomes, such as ovarian cancer, among women who exposed to menopausal hormone therapy. This large cohort study has also been used to assess relationships of menopausal hormones to the risk of endometrial cancers. In contrast to some previous suggestions that estrogen plus progestin therapy might protect against this cancer, we found no evidence for such protection. Of note was that neither continuous nor sequential estrogen plus progestin were found to have any statistically significant associations with endometrial cancer risk in this population. Further, within this same study we examined risks of breast cancer related to both estrogens alone and with combined estrogen-progestin therapy. This investigation found elevated risks for both types of preparations, although combined therapy was more strongly related. Hormone effects were stronger among thin women, but combined therapy continued to be a risk factor even among heavy women. Finally, data were used to assess whether hormones had differential relationships on different types of tumors. The strongest effects were seen for estrogen receptor positive tumors, and these relations affected other clinical parameters, including histology. These analyses stressed the importance of considering joint clinical parameters when assessing hormone effects. The AARP study has also been useful for evaluating effects on cancer risk of other medications. Analyses have also assessed breast cancer risk in relation to non-steroidal anti-inflammatory medications. This area of research has been of interest given that inflammation has been proposed as being involved as an etiologic agent for this cancer site. These analyses showed evidence of reduced risk associated with aspirin use, particularly for estrogen receptor positive cancers. We are also evaluating effects on breast cancer risk of certain medications used in the treatment of cardiovascular diseases that are known to have demethylating effects on DNA. Recent cohort studies demonstrated reduced breast cancer risks among women with a history of fractures or low bone mineral density. The impact of the severity and timing of bone loss on risk has not yet been investigated, and the extent to which other risk factors (family history, anthropometric factors, physical activity, and exogenous hormones) modify the relationship with bone density is unknown. To elaborate on these research questions, we have conducted a follow-up study of over 20,000 postmenopausal women who volunteered for a clinical trial of the bone-enhancing drug alendronate. This large cohort includes extensive baseline information on major breast cancer risk factors, and thus is ideal for evaluating potential interactions with bone mineral density and the effects of bone mineral density on other cancer sites. The availability of serologic samples from study participants will also enable assessment of the interactive effects of endogenous hormones and bone mineral density on subsequent breast cancer risk.