Therapeutic and Diagnostic Factors as Related to Cancer Risk

与癌症风险相关的治疗和诊断因素

• 批准号: 10702912
• 负责人: Gretchen Gierach
• 金额: $ 31.3万
• 依托单位: DIVISION OF CANCER EPIDEMIOLOGY AND GENETICS
• 依托单位国家: 美国
• 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/10702912
• 关键词: Age; Anti-Inflammatory Agents; Antidiabetic Drugs; Aspirin; Benign; Breast Cancer Risk Factor; Cardiovascular system; Central Nervous System Neoplasms; Chemopreventive Agent; Chemoprophylaxis; Cholesterol; Chronic; Clinic; Clomiphene; Collaborations; Consumption; Data; Data Set; Development; Diabetes Mellitus; Diagnostic Factor; Dose; Drug usage; Endometrial Carcinoma; Estrogens; Etiology; Evaluation; Event; Exposure to; Fertility; Fertility Agents; Fertilization; Fertilization in Vitro; Fibroid Tumor; Fracture; Gender; Gynecologic; Hepatotoxicity; Hormonal; Hormones; Hypertension; Incidence; Individual; Infertility; Inflammation; International Agency for Research on Cancer; Intervention; Investigation; Lead; Link; Literature; Liver diseases; Long-Term Effects; Malignant Childhood Neoplasm; Malignant Neoplasms; Malignant neoplasm of cervix uteri; Malignant neoplasm of liver; Malignant neoplasm of ovary; Medical; Medicare; Menopause; Metabolic syndrome; Metformin; Methodology; Michigan; Modeling; Non-Steroidal Anti-Inflammatory Agents; Norway; Obesity; Overweight; Pattern; Persons; Pharmaceutical Preparations; Pharmacology; Population; Preparation; Primary carcinoma of the liver cells; Progestins; Publications; Publishing; Regimen; Research; Research Personnel; Risk; Risk Factors; Risk Reduction; Severities; Therapeutic; Therapeutic Intervention; Thinness; Thyroid Diseases; Time; United States National Institutes of Health; Weight; Woman; Women' s Health; bone loss; cancer risk; clinical practice; cohort; endometriosis; follow-up; high risk; hormone related cancer; hypertension treatment; insight; interest; liver development; malignant breast neoplasm; neoplasm registry; prospective; protective effect; rare cancer; reproductive; therapeutic evaluation

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 Liver Cancer Pooling Project (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.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 Norway that evaluated cancer risk following IVF exposures. There were no increases in risk for most cancer, although some elevated risk of breast cancer for the subjects followed for the longest periods of time. In addition, some increases in risk were also observed for central nervous system tumors and for ovarian cancers among women who remained childless. To continue the evaluation of long-term cancer risks following IVF exposure, we are conducting a retrospective linkage of nationwide IVF fertility clinic data with the national cancer registry. Once completed we will be able to evaluate both maternal and childhood cancer risk following IVF treatment.In 1999, the International Agency for Research on Cancer (IARC) reviewed the existing literature on OC use and hepatocellular carcinomas (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 the ovarian cancer association consortium (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. We are following up on our aspirin finding for ovarian cancer using pooled prospective data in the ovarian cancer cohort consortium (OC3). [Ovarian cancer studies are described in Z01 CP010126 Hormone-related Cancers]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. [Liver cancer studies are described in Z01 CP010158 Studies of Rare-Cancers]

在这个项目中，我们的大部分投资组合都集中在外源性激素对癌症风险的影响上。使用SEER数据的描述性分析表明，2002年妇女健康倡议（WHI）试验结果发表后，子宫内膜癌发病率增加。我们假设这反映了持续使用雌激素加黄体酮（E+P） MHT （WHI内与乳腺癌风险增加相关的治疗）的广泛减少，因为我们和其他人已经记录了这种暴露导致超重和肥胖女性子宫内膜癌风险降低。相比之下，在另一项分析中，我们发现长期连续使用E+P（包括大量暴露于非拮抗雌激素）与风险增加有关；这种关联仅限于瘦到正常体重的女性，可能反映了她们较低的内源性雌激素水平。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与卵巢癌风险增加有关。事实上，在一项描述性研究中，我们注意到，在WHI结果发表后，随着MHT使用的显著减少，在年龄期队列模型中，50岁及以上妇女的卵巢癌发病率加速下降。肝癌发病率的显著性别差异表明激素影响风险，导致人们对使用MHT的影响感兴趣。然而，在肝癌汇集项目（LCPP）中，我们没有发现肝癌风险与使用MHT相关的证据，尽管我们对所使用的具体制剂类型的信息有限。除了MHT，我们还关注长期使用生育药物的问题。在对美国不孕症人群的长期随访中，我们没有发现克罗米芬的使用与卵巢癌或子宫内膜癌的关系。然而，暴露于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一项体外受精（IVF）长期影响的评估中，我们发现与乳腺癌、子宫内膜癌或卵巢癌的风险没有显著关联，但宫颈癌的风险显著降低，这可能反映了在利用生殖辅助的妇女中对前体疾病的监测和治疗的增加。我们还在挪威合作进行了一项评估体外受精后癌症风险的研究。大多数癌症的风险都没有增加，尽管一些人患乳腺癌的风险增加了很长一段时间。此外，没有孩子的女性患中枢神经系统肿瘤和卵巢癌的风险也有所增加。为了继续评估IVF暴露后的长期癌症风险，我们正在对全国IVF生育诊所数据与国家癌症登记处进行回顾性联系。一旦完成，我们将能够评估体外受精治疗后母亲和儿童患癌症的风险。1999年，国际癌症研究机构（International Agency for Research on Cancer， IARC）回顾了现有的关于口服避孕药与肝细胞癌（HCC）的文献，并得出结论，有足够的证据表明两者之间存在因果关系。然而，纳入综述的研究数量很少，每项研究的病例数量也不大。在LCPP中，涉及大量患者，我们没有发现使用OC与HCC风险增加相关的证据。人们越来越认识到慢性炎症在卵巢癌病因学中的重要性，这促使人们对使用非甾体抗炎药（NSAID）的风险产生了兴趣。在美国国立卫生研究院和美国退休人员协会的研究中，我们评估了阿司匹林的使用和卵巢癌的风险，但没有发现两者之间的联系，可能是由于使用模式的信息有限。在卵巢癌协会联合会（OCAC）对个体数据进行的大型汇总分析中，卵巢癌风险的显著降低与定期使用阿司匹林有关，有证据表明，每天低剂量（100毫克）使用阿司匹林的风险降低程度最高。这表明，同样的阿司匹林方案已被证明可以预防心血管事件，并与几种癌症的风险降低有关，可能对卵巢癌具有化学预防作用。我们正在使用卵巢癌队列联盟（OC3）的汇总前瞻性数据跟踪我们的阿司匹林对卵巢癌的发现。[卵巢癌研究在Z01 CP010126激素相关癌症中描述]HCC的大多数危险因素引起慢性炎症；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，我们发现阿司匹林与HCC风险呈显著负相关，而非非阿司匹林类非甾体抗炎药的使用。由于人群中大多数人每天服用阿司匹林，因此研究结果表明，服用80毫克的剂量用于心血管化学预防也可能导致HCC风险的降低。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的一个危险因素。由于高胆固醇水平是代谢综合征的决定性条件之一，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。在密歇根州底特律的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的风险显著降低。英国临床实践研究数据链（CPRD）的一项后续分析证实了他汀类药物的使用与肝癌风险之间的负相关。仅限于高风险个体（即既往患有肝病和糖尿病的个体）的分析发现了类似的强负相关，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的混淆（担心他汀类药物的使用可能导致处方模式偏倚），他汀类药物甚至可能对肝癌高危人群有益。许多先前的研究表明，使用抗糖尿病药物二甲双胍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由于其作为一线治疗，我们在CPRD中进行了一项分析，将HCC合并糖尿病患者与对照组合并糖尿病患者进行了比较。我们的分析发现，二甲双胍与HCC的发展没有强烈的负相关，这为在研究与药物暴露相关的癌症风险时使用适当的比较人群提供了重要的方法学见解。[肝癌研究见Z01 CP010158罕见癌症研究]