Therapeutic and Diagnostic Factors as Related to Cancer Risk

这个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。最近的分析已经利用我们的大型前瞻性队列研究的数据评估了更年期激素与妇科和乳腺癌风险的关系。使用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更年期激素治疗的女性患卵巢癌风险的悬而未决的问题。在使用非反对雌激素治疗10年或更长时间的女性中，卵巢癌风险的增加提供了进一步的证据，支持了更年期后雌激素水平增加会影响卵巢癌发展的假设。此外，这项研究首次提供了一些强有力的证据，明确地表明雌激素和孕激素的使用与子宫完整的女性患卵巢癌的风险增加有关。这些结果重申了对现有队列进行长期跟踪的价值，以阐明在接受更年期激素治疗的妇女中发生罕见结果(如卵巢癌)的风险增加。这项大型队列研究也被用来评估更年期激素与子宫内膜癌风险的关系。与之前一些关于雌激素+孕激素疗法可能预防这种癌症的建议相反，我们没有发现这种保护的证据。事实上，我们发现有证据表明，与不使用孕激素的女性相比，顺序使用孕激素的女性，特别是长期使用黄体酮的女性，患子宫内膜癌的风险可能会增加。此外，在这项相同的研究中，我们检查了乳腺癌的风险与雌激素单独治疗和雌激素-孕激素联合治疗有关。这项调查发现，尽管联合治疗的相关性更强，但这两种制剂的风险都增加了。荷尔蒙效应在瘦女性中更强，但联合治疗仍然是一个风险因素，即使在肥胖女性中也是如此。最后，数据被用来评估激素对不同类型的肿瘤是否有不同的关系。雌激素受体阳性肿瘤的影响最强，这些关系影响了包括组织学在内的其他临床参数。这些分析强调了在评估激素效应时考虑联合临床参数的重要性。与观察到的乳腺癌和妇科癌症的关系相反，我们没有观察到激素治疗与肺癌风险之间的关系，正如一些早期研究所表明的那样。AARP的研究也有助于评估其他药物对癌症风险的影响。分析评估了与非类固醇抗炎药(NSAIDs)有关的乳腺癌、子宫内膜和肝癌的风险，这是由一些研究刺激的，这些研究表明炎症在这些癌症部位的病因学中起着重要作用。对于所有这三个癌症站点，都有建议说非甾体抗炎药的使用可能会降低风险，尽管不同的癌症站点与所用药物的关系有所不同。我们还在评估与某些降胆固醇和糖尿病药物有关的睾丸癌风险。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被调查，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)改变与骨密度的关系的程度尚不清楚。为了详细说明这些研究问题，我们对20,000多名绝经后妇女进行了一项跟踪研究，这些妇女自愿参加骨增强药物阿仑磷酸钠的临床试验。这一庞大的队列包括关于主要乳腺癌风险因素的广泛基线信息，因此是评估与骨密度的潜在交互作用以及骨密度对其他癌症部位影响的理想选择。来自研究参与者的血清学样本的可用性也将使评估内源性激素和骨密度对后续乳腺癌风险的交互影响成为可能。

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 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. In fact, we found evidence that women who used progestins sequentially, particularly for long periods of time, might be at an increased risk of developing endometrial cancer compared to non-users. 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. In contrast to the relationships observed for breast and gynecologic cancers, we observed no relationship of hormone therapy to lung cancer risk, as had been suggested by some earlier studies. The AARP study has also been useful for evaluating effects on cancer risk of other medications. Analyses have assessed breast, endometrial and liver cancer risk in relation to non-steroidal anti-inflammatory drugs (NSAIDs), stimulated by some research that has suggested an important role for inflammation in the etiology of these cancer sites. There were suggestions for all three of these cancer site that NSAID use might reduce risk, although the relationships with the drugs used were somewhat different across cancer sites. We are also evaluating risk of testicular cancer in relation to certain cholesterol-lowering and diabetic medications. 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.