Therapeutic and Diagnostic Factors as Related to Cancer

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。我们最近的分析涉及评估绝经期激素与子宫内膜癌风险的关系，使用的数据来自乳腺癌检测示范项目（一个大型的全国性乳腺筛查项目）参与者的随访研究。使用类似于以前对乳腺癌和卵巢癌风险分析的方法，我们发现风险与未使用雌激素的强烈关系，正如许多其他研究人员所观察到的那样。尽管使用雌激素-孕激素联合治疗的患者风险升高较少，但与不使用者相比，它们仍然与风险升高相关。因此，这些结果提出了关于长期使用联合替代疗法的安全性的问题。 我们还对其他激素暴露的影响感兴趣，包括用于治疗不孕症的促排卵药物。还进行了一项回顾性队列研究，评估了不同不孕原因和相关治疗对癌症风险的影响。这项研究涉及到对早在20世纪60年代就被诊断出的病人的医疗记录的详细提取，以及对获得最新健康信息的问卷调查的管理。这项研究的一个优点是收集了有关不孕症原因的详细信息。分析表明，不孕症的类型（原发性与继发性）是比不孕症的具体原因更重要的癌症风险预测因素。然而，子宫内膜异位症患者患卵巢癌的风险特别高。总的来说，该研究提供了关于使用排卵诱导剂的令人放心的结果，显示与使用克罗米芬或人绝经期促性腺激素相关的癌症风险没有显著增加。然而，在随访时间最长（15或20年以上）的受试者中，乳腺癌和卵巢癌的风险略有增加，这支持需要额外监测这些药物的长期影响。 某些医疗器械也引起了人们的兴趣，包括硅胶乳房植入物的长期安全性。考虑到乳房植入体会干扰病变的乳房X线摄影可视化，对乳腺癌风险的影响一直令人担忧。然而，在我们进行的一项大型回顾性研究中，我们没有发现乳腺癌风险改变的证据。这些患者的其他癌症部位通常也没有发生变化，尽管观察到肺癌和脑癌的风险升高，但其解释仍不清楚。在死亡率分析中，植入患者自杀死亡的风险显著升高，但其他死亡原因与一般人群相似。本研究中的患者将继续接受未来死亡事件的随访，考虑到研究人群的老龄化性质，这一点非常重要。我们最近还评估了对各种结缔组织疾病的影响。总的来说，结果相当令人放心，尽管这项调查确实强调了评估相关性的复杂性，因为大多数疾病都很罕见，而且诊断和报告存在各种困难。 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，我们正在对超过20，000名绝经后妇女进行随访研究，这些妇女自愿参加骨增强药物阿仑膦酸钠的临床试验。

A major emphasis of this project has been to define the relationship of exogenous hormones to subsequent cancer risk. Our most recently analyses have related to assessing the relationships of menopausal hormones to endometrial cancer risk using data from the follow-up study of participants in the Breast Cancer Detections Demonstration Project, a large nation-wide breast screening project. Using approaches similar to previous analyses for breast and ovarian cancer risk, we found strong relationships of risk with unopposed estrogen use, as have been observed by many other investigators. Although risks were less elevated for users of combined estrogen-progestin therapy, they contined to be associated with elevations in risk as compared with non-use. These results therefore raise questions regarding the safety of long-term use of combined replacement therapy. We have also had an interest in effects of other hormonal exposures, including ovulation stimulating drugs used to treat infertility. A retrospective cohort study was also conducted which allowed an assessment of effects on cancer risk of different causes of infertility and associated therapies. This study involved detailed abstraction of medical records of patients diagnosed as long ago as the 1960's and administration of questionnaires to obtained updated health information. A strength of the study was the detailed information collected on causes of infertility. Analyses showed that type of infertility (primary vs. secondary) was a more important predictor of cancer risk than specific causes of infertility. However, patients with endometriosis were at an especially high risk of developing ovarian cancer. In general, the study provided reassuring results regarding use of ovulation-inducing agents, showing no major increases in cancer risk relating to use of either clomiphene citrate or human menopausal gonadotropins. There were, however, slight increases in risk of both breast and ovarian cancers among the subjects followed for the longest periods of time (15 or 20+ years), supporting the need for additional monitoring of long-term effects of these agents. Certain medical devices have also been of interest, including the long-term safetly of silicone breast implants. Effects on breast cancer risk has been of concern, given that breast implants can interfere with the mammographic visualization of lesions. However, in a large retrospective study that we conducted, we found no evidence for an alteration in breast cancer risk. These patients also generally did not experience alterations in other cancer sites, although elevations were observed in the risk of lung and brain cancers, the explanation for which remains unclear. In a mortality analysis, implant patients had signficantly elevated risks of death from suicide, but other causes of death were similar to the general population. The patients in this study are continuing to be followed for future mortal events, of importance given the aging nature of the study population. We also recently assessed effects on various connective tissue diseases. In general, the results were fairly reassuring, although this investigation did highlight the complexities of evaluating the associations, given the rarity of most individual diseases, and a variety of diagnostic and reporting difficulties. 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 are conducting a follow-up study of over 20,000 postmenopausal women who volunteered for a clinical trial of the bone-enhancing drug alendronate.