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: 10918969
• 负责人: Gretchen Gierach
• 金额: $ 24.02万
• 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/10918969
• 关键词: Acceleration; 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 in Vitro; Fibroid Tumor; Fracture; Gender; Gynecologic; Health; Hepatotoxicity; Hormonal; Hormones; Hypertension; Incidence; Individual; Infertility; Inflammation; International Agency for Research on Cancer; Intervention; Investigation; 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; 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; bone loss; cancer risk; clinical practice; cohort; demethylation; endometriosis; follow-up; high risk; high risk population; hormone related cancer; hypertension treatment; insight; interest; liver development; malignant breast neoplasm; neoplasm registry; pharmacologic; 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]

该项目中我们投资组合的很大一部分集中在对癌症外源激素风险的影响上。 使用SEER数据的数据进行了描述性分析，该数据记录了2002年后的子宫内膜癌发病率的增加，当时《妇女健康计划》（WHI）试验的结果发表了。 我们假设这种反映在连续雌激素加孕激素（E+P）MHT的使用（与WHI内乳腺癌风险增加有关的疗法相关的疗法）中的广泛降低，因为这是我们以及其他人所记录的，导致了超级癌症中的子宫内膜癌风险和肥胖妇女的降低。 相比之下，在另一项分析中，我们发现长期顺序E+P使用（涉及对无源雌激素的大量暴露）与风险增加有关。这种关联仅限于较薄的正常体重女性，大概反映了其较低的内源性雌激素水平。 在针对卵巢癌的另一项研究中，我们发现顺序和连续的E+P使用都与卵巢癌风险增加有关。 实际上，在一项描述性研究中，我们注意到，在出版WHI结果后，MHT使用明显降低后，在年龄段的年龄较大的年龄段模型中，50岁以上的女性卵巢癌发病率下降了。 肝癌发生率的显着性别差异表明，激素会影响风险，从而引起对MHT使用影响的兴趣。 然而，在肝癌集合项目（LCPP）中，我们没有发现肝癌风险与MHT使用有关的证据，尽管我们对所使用的特定制剂类型的信息有限。在MHT中，我们还关心长期使用生育药物。 在对我们大型美国不孕队列的扩展后续行动中，我们没有看到克罗米芬与卵巢癌或子宫内膜癌的使用关系。 但是，暴露于12个或更多氯芬周期的妇女的侵入性乳腺癌风险增加。 在评估与以色列最大的HMO的研究人员合作进行的体外受精（IVF）的长期影响时，我们没有看到与乳腺癌，子宫内膜或卵巢癌风险的显着关联，但是宫颈癌的大幅度降低，可能会降低，可能反映了前体的监管和治疗女性的治疗，因此女性提供了增强的女性提供的疗养。 我们还合作在挪威进行了一项研究，该研究评估了IVF暴露后的癌症风险。 尽管大多数癌症的风险没有增加，尽管有些人在最长的时间内对受试者的乳腺癌风险升高。 此外，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，我们正在与国家癌症注册中心进行全国IVF生育诊所数据的回顾性联系。 一旦完成，我们将能够评估IVF治疗后的孕产妇和儿童癌症风险。在1999年，国际癌症研究机构（IARC）回顾了有关OC使用和肝细胞癌（HCC）的现有文献，并得出结论，并认为有足够的因果关系证据。 但是，综述中包括的研究数量很少，每项研究的病例数量均不足。 在涉及大量的LCPP中，我们没有发现OC使用的证据与HCC的风险增加有关。人们对慢性炎症在卵巢癌病因中的重要性的越来越多，引起了人们对使用非甾体类抗炎药（NSAID）使用的风险的兴趣。 在NIH-AARP研究中，我们评估了阿司匹林的使用和卵巢癌风险，但没有发现关联，这可能是由于使用模式的信息有限。 在对卵巢癌协会联盟（OCAC）中个人数据的大量汇总分析中，卵巢癌风险的显着降低与常规阿司匹林使用有关，证明降低的每日低剂量（100 mg）使用风险最强。 这表明，相同的阿司匹林方案被证明可以预防心血管事件，并且与降低几种癌症的风险有关可能对卵巢癌具有化学预防影响。 我们正在使用卵巢癌队列联盟（OC3）中合并的前瞻性数据（OC3）中的卵巢癌发现阿司匹林发现。 [卵巢癌研究在Z01 CP010126与激素相关的癌症中描述] HCC的大多数危险因素会导致慢性炎症；因此，我们假设使用NSAID可能与降低的风险有关。 在NIH-AARP研究中的分析中，我们发现阿司匹林（而非非阿斯皮蛋白NSAID使用）与HCC风险呈呈呈负相关。 由于大多数阿司匹林在人群中每天都使用，结果表明，为心血管化学预防剂服用80 mg剂量也可能导致HCC风险的降低。在SEER-MEDICARE数据集进行的分析中，我们证明了代谢综合征是HCC的风险因素。 由于高胆固醇水平是代谢综合征的决定性疾病之一，因此我们试图确定是否使用降低胆固醇的药物 - 将降低风险。 在密歇根州底特律的亨利·福特HMO的分析中，我们确实发现服用他汀类药物的人大大降低了患HCC的风险。 英国临床实践研究数据链接（CPRD）的随后分析证实了他汀类药物使用和肝癌风险之间的逆关联。 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肝癌。一项先前的研究表明，二甲双胍（一种抗糖尿病药物）与肝癌的发展成反比。 但是，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。 但是，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由于它是第一线治疗，我们在CPRD中进行了分析，将糖尿病的HCC病例与糖尿病对照进行了比较。 我们的分析发现，二甲双胍与HCC的发展没有密切相反，并且提供了与使用适当的比较种群有关的重要方法论见解，同时研究与药理暴露相关的癌症风险。 [肝癌研究在Z01 CP010158的稀有研究研究中描述了]

项目成果

Cancer risk among parous women following assisted reproductive technology.

• DOI: 10.1093/humrep/dev124
• 发表时间: 2015-08
• 期刊: Human reproduction (Oxford, England)
• 作者: Reigstad MM;Larsen IK;Myklebust TÅ;Robsahm TE;Oldereid NB;Omland AK;Vangen S;Brinton LA;Storeng R
• 通讯作者: Storeng R

Risk of Cancer in Children Conceived by Assisted Reproductive Technology.

• DOI: 10.1542/peds.2015-2061
• 发表时间: 2016-03
• 期刊: Pediatrics
• 影响因子: 8
• 作者: Reigstad MM;Larsen IK;Myklebust TÅ;Robsahm TE;Oldereid NB;Brinton LA;Storeng R
• 通讯作者: Storeng R

Trends in oral contraceptive and intrauterine device use among reproductive-aged women in the US from 1999 to 2017.

• DOI: 10.1007/s10552-021-01410-8
• 发表时间: 2021-06
• 期刊: Cancer causes & control : CCC
• 作者: King LA;Michels KA;Graubard BI;Trabert B
• 通讯作者: Trabert B

Ovarian cancer statistics, 2018.

• DOI: 10.3322/caac.21456
• 发表时间: 2018-07
• 期刊: CA: a cancer journal for clinicians
• 作者: Torre LA;Trabert B;DeSantis CE;Miller KD;Samimi G;Runowicz CD;Gaudet MM;Jemal A;Siegel RL
• 通讯作者: Siegel RL

Ovulation-inducing drugs and ovarian cancer risk: results from an extended follow-up of a large United States infertility cohort.

• DOI: 10.1016/j.fertnstert.2013.08.008
• 发表时间: 2013-12
• 期刊: FERTILITY AND STERILITY
• 影响因子: 6.7
• 作者: Trabert, Britton;Lamb, Emmet J.;Scoccia, Bert;Moghissi, Kamran S.;Westhoff, Carolyn L.;Niwa, Shelley;Brinton, Louise A.
• 通讯作者: Brinton, Louise A.