Therapeutic and Diagnostic Factors as Related to Cancer Risk

与癌症风险相关的治疗和诊断因素

基本信息

批准号：
8938231
负责人：
LOUISE BRINTON
金额：
$ 28.53万
依托单位：
DIVISION OF CANCER EPIDEMIOLOGY AND GENETICS
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/8938231
关键词：
Accounting Affect Age Anti-Inflammatory Agents Anti-inflammatory Antidiabetic Drugs Aspirin Attention Benign Cardiovascular system Cervical Chemopreventive Agent Chemoprophylaxis Child Childhood Cholesterol Chronic Clomiphene Collaborations Data Data Set Denmark Development Diabetes Mellitus Diagnostic Factor Dose Drug usage Endocrine Glands Endometrial Carcinoma Estrogens Etiology Evaluation Event Exposure to Fertility Agents Fertilization in Vitro Fibroid Tumor Fracture Gender Gynecologic Hepatotoxicity Hormonal Hormones Human papilloma virus infection Hypertension Incidence Individual Infertility Inflammation International Agency for Research on Cancer Intervention Investigation Lead Link Literature Liver diseases Long-Term Effects Malignant Neoplasms Malignant neoplasm of cervix uteri Malignant neoplasm of liver Malignant neoplasm of lung Malignant neoplasm of ovary Medical Medicare Menopause Metabolic syndrome Metformin Michigan Modeling Non-Steroidal Anti-Inflammatory Agents Obesity Oral Contraceptives Overweight Pattern Persons Pharmaceutical Preparations Population Preparation Progestin Therapy Progestins Publications Publishing Recording of previous events Regimen Reproductive History Research Research Personnel Risk Risk Factors Risk Reduction Severities Staging Therapeutic Therapeutic Intervention Thyroid Diseases United States National Institutes of Health Weight Woman Women&apos s Health base bone loss cancer risk carcinogenesis clinical practice cohort diabetic endometriosis high risk hypertension treatment insight interest leukemia malignant breast neoplasm protective effect reproductive tumor young adult

项目摘要

A large part of our portfolio within this Project has focused on the effects on cancer risk of exogenous hormones. Descriptive analyses using data from SEER documented increases in endometrial cancer incidence after 2002 when results from the Womens Health Initiative (WHI) Trial were published. We hypothesized that this reflected widespread decreases in continuous estrogen plus progestin (E+P) MHT use (the therapy linked with increased breast cancer risk within WHI), given that this is an exposure that we as well as others have documented as leading to reductions in endometrial cancer risk in overweight and obese women. In contrast, in another analysis, we found long-term sequential E+P use (which involves substantial exposure to unopposed estrogens) is associated with increased risk; this association was restricted to thin-to-normal weight women, presumably reflecting their lower endogenous estrogen levels. In an additional investigation focused on ovarian cancer, we found that both sequential and continuous E+P usage was associated with ovarian cancer risk increases. In fact, in a descriptive study, we noted an accelerated decline in ovarian cancer incidence among women 50 years and older in age-period-cohort models following the marked reduction in MHT use that occurred after publication of the WHI results. The notable gender discrepancy in rates of liver cancer has suggested that hormones influence risk, leading to an interest in the effects of MHT use. However , in the LCPP, we found no evidence that liver cancer risk was related to MHT use, although we had limited information of the specific types of preparations used. Some studies, including one that we conducted, have suggested that certain hormonal and reproductive factors may affect the subsequent risk of lung cancer. This has prompted some attention regarding the effects of MHT. Although several studies have noted risk alterations associated with usage, in the NIH-AARP Study we found no evidence that risk of any type of lung cancer was affected by use of either estrogens alone or estrogen plus progestin therapies.In addition to MHT, we have also been concerned regarding the long-term use of fertility drugs. In an extended followup of our large U.S. infertility cohort, we saw no relationship of clomiphene use to either ovarian or endometrial cancers. However, women exposed to 12 or more clomiphene cycles were at an increased risk of invasive breast cancers. In an evaluation of the long-term effects of in vitro fertilization (IVF) undertaken in collaboration with investigators at one of Israelis largest HMOs, we saw no significant associations with breast, endometrial or ovarian cancer risk, but a significant reduction in cervical cancer, presumably reflecting increased surveillance and treatment of precursor conditions among women availing themselves of reproductive assistance. We also collaborated on a study in Denmark of children born to women with a history of infertility (83). There was some evidence of increases in risk of leukemia in childhood and endocrine glands tumors in young adulthood, although mechanisms underlying the associations remained unclear.The relationship of oral contraceptives to various cancers remains of interest. In a large study of women with all stages of cervical carcinogenesis, we demonstrated that OC use was associated with an increased risk of cervical precancer compared to HPV infection, but not with an increased risk of cancer compared to precancer, suggesting that hormone exposure may be particularly important at preinvasive stages. In 1999, the International Agency for Research on Cancer (IARC) reviewed the existing literature on OC use and HCC and concluded that there was sufficient evidence of a causal relationship. However, the number of studies included in the review was small and the number of cases per study modest. In the LCPP, which involved large numbers, we found no evidence that OC use was related to an increased risk of HCC. The increasing recognition of the importance of chronic inflammation in the etiology of ovarian cancer has prompted an interest in risk associated with usage of non-steroidal anti-inflammatory drug (NSAID) usage. In the NIH-AARP study, we evaluated aspirin use and ovarian cancer risk, but did not find an association, possibly due to limited information on use patterns. In a large pooled analysis of individual data within OCAC, a significant reduction in ovarian cancer risk was associated with regular aspirin use, with evidence that the reduced risk was strongest for daily low-dose (100 mg) usage. This suggested that the same aspirin regimen proven to protect against cardiovascular events and associated with risk reduction of several cancers might have chemopreventive implications for ovarian cancer.The majority of risk factors for HCC cause chronic inflammation; thus we hypothesized that use of NSAIDs might be related to reduced risk. In analyses within the NIH-AARP study, we found that aspirin, but not non-aspirin NSAID use, was significantly inversely associated with HCC risk. As most aspirin use in the population was on a daily basis, the result suggested that consuming an 80 mg dose for cardiovascular chemoprophylaxis might also lead to a reduction in HCC risk.In an analysis that we conducted in the SEER-Medicare dataset, we demonstrated that metabolic syndrome is a risk factor for HCC. As high cholesterol levels are one of the defining conditions of metabolic syndrome, we sought to determine whether use of cholesterol-lowering drugsstatins--would decrease risk. In an analysis within the Henry Ford HMO in Detroit, Michigan, we did indeed find that persons who took statins were at significantly decreased risk of developing HCC. A subsequent analysis within the U.K.s Clinical Practice Research Datalink (CPRD) confirmed the inverse association between statin use and liver cancer risk. Analyses restricted to higher-risk individuals (i.e., those with pre-existing liver disease and those with diabetes) found similarly strong inverse associations, suggesting that the observed risk reduction associated with statins was unlikely to reflect confounding by contraindication (concerns about hepatotoxicity with the use of statins that may result in biased prescribing patterns), and that statins may be beneficial even among persons at high-risk for liver cancer.A number of prior studies had suggested that use of metformin, an anti-diabetic drug, is inversely associated with development of liver cancer. Most of these studies however, have compared metformin use to that of all other anti-diabetes medications. However, anti-diabetic medications are strongly linked to diabetes duration and severity. To assess whether the apparent protective effect of metformin was due to it being a first line therapy, we conducted an analysis in the CPRD that compared HCC cases with diabetes to controls with diabetes. Our analysis found that metformin was not strongly inversely associated with the development of HCC, and has offered important methodologic insights related to the use of appropriate comparison populations while studying cancer risk associated with pharmacologic exposures.

我们在该项目中的大部分投资集中于外源激素对癌症风险的影响。使用 SEER 数据进行的描述性分析记录了 2002 年女性健康倡议 (WHI) 试验结果发布后子宫内膜癌发病率的增加。我们假设这反映了连续雌激素加孕激素 (E+P) MHT 使用（该疗法与 WHI 内乳腺癌风险增加相关）的广泛减少，因为我们和其他人都已记录到这种暴露会导致减少超重和肥胖女性患子宫内膜癌的风险。相比之下，在另一项分析中，我们发现长期连续使用 E+P（涉及大量暴露于非对抗性雌激素）与风险增加相关；这种关联仅限于体重正常的女性，这可能反映了她们的内源性雌激素水平较低。在另一项针对卵巢癌的调查中，我们发现连续和连续使用 E+P 与卵巢癌风险增加相关。事实上，在一项描述性研究中，我们注意到，在 WHI 结果发布后 MHT 使用量显着减少后，年龄-周期-队列模型中 50 岁及以上女性的卵巢癌发病率加速下降。肝癌发病率的显着性别差异表明激素会影响风险，从而引起人们对 MHT 使用效果的兴趣。然而，在 LCPP 中，我们没有发现任何证据表明肝癌风险与 MHT 的使用有关，尽管我们对所用制剂的具体类型的信息有限。一些研究，包括我们进行的一项研究，表明某些激素和生殖因素可能会影响随后患肺癌的风险。这引起了人们对 MHT 影响的关注。尽管有几项研究指出了与使用相关的风险变化，但在 NIH-AARP 研究中，我们没有发现任何证据表明单独使用雌激素或雌激素加孕激素疗法会影响任何类型肺癌的风险。还担心长期使用生育药物。在对美国不孕症大型队列的长期随访中，我们发现克罗米芬的使用与卵巢癌或子宫内膜癌没有关系。然而，接受 12 个或更多克罗米芬周期的女性患浸润性乳腺癌的风险增加。在与以色列最大的 HMO 之一的研究人员合作进行的体外受精 (IVF) 长期影响评估中，我们发现与乳腺癌、子宫内膜癌或卵巢癌风险没有显着关联，但显着降低了宫颈癌、大概反映了对接受生殖援助的妇女的先兆病症进行了更多的监测和治疗。我们还在丹麦合作开展了一项针对有不孕史的妇女所生孩子的研究 (83)。有一些证据表明儿童患白血病和成年后患内分泌腺肿瘤的风险增加，尽管这些关联的机制仍不清楚。口服避孕药与各种癌症的关系仍然令人感兴趣。在一项针对宫颈癌各阶段女性的大型研究中，我们证明，与 HPV 感染相比，使用 OC 与宫颈癌前病变风险增加相关，但与癌前病变相比，与癌症风险增加无关，这表明激素暴露可能与宫颈癌风险增加相关。在侵袭前阶段尤其重要。 1999 年，国际癌症研究机构 (IARC) 审查了有关 OC 使用和 HCC 的现有文献，并得出结论，有足够的证据表明存在因果关系。然而，纳入该评价的研究数量很少，而且每项研究的病例数也很少。在涉及大量患者的 LCPP 中，我们没有发现任何证据表明 OC 的使用与 HCC 风险增加有关。人们越来越认识到慢性炎症在卵巢癌病因学中的重要性，这引发了人们对使用非甾体抗炎药 (NSAID) 相关风险的兴趣。在 NIH-AARP 研究中，我们评估了阿司匹林的使用和卵巢癌风险，但没有发现两者之间的关联，这可能是由于有关使用模式的信息有限。在 OCAC 内对个体数据进行的大型汇总分析中，卵巢癌风险的显着降低与定期使用阿司匹林相关，有证据表明每日低剂量（100 毫克）使用阿司匹林的风险降低效果最强。这表明，相同的阿司匹林疗法已被证明可以预防心血管事件，并与降低多种癌症的风险相关，可能对卵巢癌具有化学预防作用。因此，我们假设使用非甾体抗炎药可能与降低风险有关。在 NIH-AARP 研究的分析中，我们发现阿司匹林而非非阿司匹林 NSAID 的使用与 HCC 风险呈显着负相关。由于大多数人群每天都会使用阿司匹林，因此结果表明，服用 80 毫克剂量进行心血管化学预防也可能会降低 HCC 风险。在我们对 SEER-Medicare 数据集进行的分析中，我们证明了代谢综合征是 HCC 的危险因素。由于高胆固醇水平是代谢综合征的定义条件之一，我们试图确定使用降胆固醇药物他汀类药物是否会降低风险。在密歇根州底特律 Henry Ford HMO 的一项分析中，我们确实发现服用他汀类药物的人患 HCC 的风险显着降低。英国临床实践研究数据链 (CPRD) 的后续分析证实了他汀类药物的使用与肝癌风险之间存在负相关。仅限于高风险个体（即患有既往肝病和患有糖尿病的人）的分析发现了类似的强烈负相关性，这表明观察到的与他汀类药物相关的风险降低不太可能反映禁忌症带来的混杂因素（对肝毒性的担忧）使用他汀类药物可能会导致处方模式出现偏差），而且他汀类药物甚至对肝癌高危人群也可能是有益的。许多先前的研究表明，使用他汀类药物二甲双胍是一种抗糖尿病药物，与肝癌的发展呈负相关。然而，大多数研究都将二甲双胍的使用与所有其他抗糖尿病药物的使用进行了比较。然而，抗糖尿病药物与糖尿病的持续时间和严重程度密切相关。为了评估二甲双胍的明显保护作用是否是由于它是一线治疗，我们在 CPRD 中进行了一项分析，将患有糖尿病的 HCC 病例与患有糖尿病的对照进行了比较。我们的分析发现，二甲双胍与 HCC 的发展并没有很强的负相关性，并且在研究与药物暴露相关的癌症风险时，提供了与使用适当的比较人群相关的重要方法学见解。