Intervention Trials in Persons at Increased Genetic Risk of Cancer

针对癌症遗传风险增加人群的干预试验

• 批准号: 10007416
• 负责人: Sharon A. Savage
• 金额: $ 33.54万
• 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/10007416
• 关键词: Adherence; Adrenal Glands; Adult; Affect; Age; Algorithms; Anxiety; Astrocytoma; Atypia; BRCA1 gene; BRCA2 gene; Behavioral trial; Blinded; Blood specimen; Brain; Brain Neoplasms; Breast; Breast Magnetic Resonance Imaging; CA-125 Antigen; Cancer Genetics Network; Cessation of life; Characteristics; Child; Clinical; Cognitive; Collaborations; Computers; Counseling; Data; Data Analyses; Data Analytics; Databases; Decision Making; Development; Diagnosis; Diagnostic; Distress; Duct (organ) structure; Early Diagnosis; Effectiveness; Eligibility Determination; Emotional; Enrollment; Estrogens; Etiology; Evaluation; Face; Family; Family member; Frequencies; Friendships; Future; Genetic; Genetic Risk; Germ-Line Mutation; Glioma; Goals; Gynecologic Oncology Group; Hereditary Malignant Neoplasm; High Risk Woman; Hormones; Image; Individual; Institution; Intelligence; Intervention; Intervention Studies; Intervention Trial; Interview; Irrigation; Learning; Li-Fraumeni Syndrome; Life; Life Style; Liquid substance; Magnetic Resonance Imaging; Malignant Neoplasms; Malignant neoplasm of ovary; Mammalian Oviducts; Mammography; Manuscripts; Measures; Medical; Mental Depression; Molecular; Mucous Membrane; Mutation; Natural History; Oncogenes; Operative Surgical Procedures; Participant; Pathogenesis; Pathology; Patients; Performance; Persons; Pilot Projects; Population; Predisposition; Premenopause; Prevalence; Protocols documentation; Psychosocial Assessment and Care; Publications; Publishing; Quality of life; Quantitative Evaluations; Questionnaires; Regimen; Reproducibility; Research Personnel; Risk; Risk Management; Risk Reduction; Salpingo-Oophorectomy; Schedule; Screening for Ovarian Cancer; Screening for cancer; Series; Serum; Shapes; Signal Transduction; Social Change; Social support; Source; Standardization; Stress; Syndrome; TP53 gene; Test Result; Texture; Time; Tissues; Tumor Debulking; United States National Institutes of Health; Well in self; Woman; Work; arm; base; breast cancer diagnosis; breast imaging; cancer diagnosis; cancer risk; cohort; coping; design; digital; follow-up; high risk; imaging study; improved; leukemia; malignant breast neoplasm; mutation carrier; nipple aspirate fluid; novel; ovarian cancer prevention; prospective; protective effect; psychosocial; research study; response; risk perception; screening; screening program; surgical risk; uptake; Adherence; Adrenal Glands; Adult; Affect; Age; Algorithms; Anxiety; Astrocytoma; Atypia; BRCA1 gene; BRCA2 gene; Behavioral trial; Blinded; Blood specimen; Brain; Brain Neoplasms; Breast; Breast Magnetic Resonance Imaging; CA-125 Antigen; Cancer Genetics Network; Cessation of life; Characteristics; Child; Clinical; Cognitive; Collaborations; Computers; Counseling; Data; Data Analyses; Data Analytics; Databases; Decision Making; Development; Diagnosis; Diagnostic; Distress; Duct (organ) structure; Early Diagnosis; Effectiveness; Eligibility Determination; Emotional; Enrollment; Estrogens; Etiology; Evaluation; Face; Family; Family member; Frequencies; Friendships; Future; Genetic; Genetic Risk; Germ-Line Mutation; Glioma; Goals; Gynecologic Oncology Group; Hereditary Malignant Neoplasm; High Risk Woman; Hormones; Image; Individual; Institution; Intelligence; Intervention; Intervention Studies; Intervention Trial; Interview; Irrigation; Learning; Li-Fraumeni Syndrome; Life; Life Style; Liquid substance; Magnetic Resonance Imaging; Malignant Neoplasms; Malignant neoplasm of ovary; Mammalian Oviducts; Mammography; Manuscripts; Measures; Medical; Mental Depression; Molecular; Mucous Membrane; Mutation; Natural History; Oncogenes; Operative Surgical Procedures; Participant; Pathogenesis; Pathology; Patients; Performance; Persons; Pilot Projects; Population; Predisposition; Premenopause; Prevalence; Protocols documentation; Psychosocial Assessment and Care; Publications; Publishing; Quality of life; Quantitative Evaluations; Questionnaires; Regimen; Reproducibility; Research Personnel; Risk; Risk Management; Risk Reduction; Salpingo-Oophorectomy; Schedule; Screening for Ovarian Cancer; Screening for cancer; Series; Serum; Shapes; Signal Transduction; Social Change; Social support; Source; Standardization; Stress; Syndrome; TP53 gene; Test Result; Texture; Time; Tissues; Tumor Debulking; United States National Institutes of Health; Well in self; Woman; Work; arm; base; breast cancer diagnosis; breast imaging; cancer diagnosis; cancer risk; cohort; coping; design; digital; follow-up; high risk; imaging study; improved; leukemia; malignant breast neoplasm; mutation carrier; nipple aspirate fluid; novel; ovarian cancer prevention; prospective; protective effect; psychosocial; research study; response; risk perception; screening; screening program; surgical risk; uptake

The National Ovarian Cancer Prevention and Early Detection Study [CAS 7210] among women at increased genetic risk of ovarian cancer (aka GOG-199) is the cornerstone of CGB's intervention studies research portfolio. It is a non-randomized natural history study of risk-reducing salpingo-oophorectomy (RRSO) versus a novel ovarian cancer screening strategy (the ROCA algorithm). This study closed to new patient enrollment in November 2006, having accrued 2605 high-risk women (1029 surgery arm; 1576 screening arm). Prospective follow-up ended in November 2011, and the final analytic data base is now complete. Recent accomplishments to date include: (1) contributing 1,576 screening subjects to a published pooled analysis (with the Cancer Genetics Network: total = 4,000 subjects) of determinants of baseline CA-125 levels and of the performance characteristics of the ROCA algorithm, which demonstrated that pre-menopausal women should have an upper limit of normal cut-off=52, rather than 35 as customarily used; (2) continued our collaboration with seeking genetic modifiers of BRCA1/2-associated breast and ovarian cancer risk, an effort which has produced 40 published manuscripts, with an additional 7 are currently under review; (3) quantification of the prevalence of clinically-occult ovarian cancers among asymptomatic women undergoing RRSO: 25 (2.6%) of 966 GOG-09199 RRSOs (BRCA1 carriers=4.6%, BRCA2 carriers=3.5%, and non-carriers=0.5% (p=0.0006); (4) documenting that high-risk women WILL comply with an ovarian cancer screening program that entails providing a blood sample every 3 months, a regimen (ROCA: the risk of ovarian cancer algorithm) which produces a significant stage downshift among incident ovarian cancer cases, permits optimal surgical debulking in nearly all new cases, and identifies about 50% of new cancers before they exceed the standard CA125 cutoff of 35 IU/ml. These findings suggest that the ROCA algorithm may represent an important new advance in the world of ovarian cancer screening; (5) demonstrating the poor reproducibility of the diagnosis of fallopian tube mucosal atypia on blinded pathology review, illustrating the need for improved diagnostic criteria; (6) using the prospective follow-up of GOG-0199 study participants to determine that the breast cancer protective effect previously described in relation to RRSO may not be as large as previously estimated. The remaining primary study endpoints related to GOG-0199 are now under analysis, including baseline medical decision-making and quality of life, prospective evaluation of quality of life (stratified by study arm) during 5 years' prospective follow-up, and an analysis of medical decision-making among the 381 women who crossed over from the screening to the surgical arm of this study. The Breast Imaging Pilot Study in Women from BRCA Mutation-Positive Families achieved its accrual goal and prospective follow-up has now ended. Recent findings from this project include: (1) identification of a computer-extracted feature of digital mammograms, "mammographic texture," the presence of which signals a two-fold increase in the likelihood of an affected patient being a BRCA1/2 mutation carrier; (2) development of an anthropomorphic phantom for quantitative evaluation of breast MRI images, in collaboration with investigators from the FDA; (3) demonstrating that circulating levels of estrogen and its metabolites are very strongly, positively correlated with levels measured on fluids obtained directly from the breast (nipple aspirate fluid; breast duct lavage supernatant), a finding which suggests that future etiologic studies could utilize the more readily obtainable serum hormone levels as a reliable surrogate measure of exposure at the tissue level. (4) continued collaboration with CIMBA in search of genetic modifiers of BRCA1/2-associated breast and ovarian cancer; (5) a psychosocial analysis of data from Breast Imaging Study patients that revealed that false positive cancer screening test results were not associated with large increases in cancer risk perception, cancer worry or increased uptake of risk-reducing surgery. However, cancer-specific worry was an independent predictor of uptake of risk-reducing surgery; this domain warrants consideration when counseling high-risk women regarding risk-reducing interventions; (6) and a landmark series of 6 publications targeting the special needs of very young (less than age 25) mutation carriers, a population which faces particularly challenging developmental challenges as they navigate the life-shaping decisions of finding a partner, entering the world of work, contemplating family formation, all in the context of concerns regarding the management of their BRCA-associated cancer risk management, including intensive screening and the need for risk-reducing surgery.Li-Fraumeni syndrome (LFS) is a highly penetrant cancer predisposition syndrome most commonly caused by germline mutations in TP53 and associated with brain, adrenal gland, and breast cancers, leukemia, and many other malignancies in children and adults. The cancer-screening component is an integral part of the larger LFS study that opened at the NIH Clinical Center, in June 2012. By mid-2014, more than 200 TP53 individuals were eligible and enrolled. Due to this overwhelming and rapid response to opening the protocol, we met our initial accrual goal for the clinical cohort and closed the clinical cohort to accrual in December 2014. To date, we have screened total of 115 participants with a range of follow-up from 1-5 years. Breast cancer diagnoses have been made by breast MRI screening and targeted brain MRI identified the two brain tumors (a low-grade glioma and a grade 2 astrocytoma). Approximately 7% of participants have had an incident cancer identified at the baseline screening study. We will analyze the effectiveness of the screening protocol based on its ability to detect early stage cancers, the development of interval cancers, the frequency of false positive screening findings, and participant adherence to this rigorous schedule. Our data will also be included in larger pooled analyses of data from multiple institutions. Our psychosocial studies included the first CEGRM study of LFS families in which ee found that while the number of friendships varied widely, they were usually deep and enduring and were important sources of informational, tangible and emotional support. Longitudinal follow-up of LFS CEGRM participants is planned to explore whether new cancer diagnoses or the death of affected family members changes the social support networks of participants. We plan to describe the cognitive appraisal of cancer risk and emotional well being in individuals and families with known or suspected LFS or LFL at enrollment in the study and are evaluating data from 300 participants assessed using standardized questionnaires for stress, distress, depression, anxiety, somatization, coping, cancer risk appraisal, and cancer worry. Additionally, we have also incorporated qualitative interviews of LFS families designed to improve understanding of their day-to-day challenges.

在卵巢癌遗传风险增加的女性中，全国卵巢癌的预防和早期检测研究[CAS 7210]（又名GOG-199）是CGB干预研究研究组合的基石。这是一项非随机自然历史研究，对降低风险的salpingo-opophororto术（RRSO）与一种新型的卵巢癌筛查策略（ROCA算法）。这项研究于2006年11月关闭了新的患者入学，并获得了2605名高危女性（1029手术组； 1576年筛查组）。预期的随访于2011年11月结束，最终的分析数据库现已完成。迄今为止的最新成就包括：（1）对基线Ca-125水平的决定因素的出版汇总分析（带有癌症遗传网络：总受试者）的1,576名筛查受试者以及ROCA算法的性能特征，而Roca算法的性能特征则表明，预先妇女应具有正常的上限，而不是正常的355255255。 （2）继续我们与寻求BRCA1/2相关乳腺癌和卵巢癌风险的遗传修饰符的合作，这项工作已经产生了40份发表的手稿，目前正在审查另外7个手稿； （3）无症状妇女中临床诊断卵巢癌患病率的量化：966 GOG-09199 RRSO中的25（2.6％）RRSO（BRCA1携带者= 4.6％，BRCA2携带者，BRCA2携带者= 3.5％，非携带者= 3.5％，非携带者和非官员= 0.5％（p = 0.0006）（p = 0.0006）；每3个月提供一次血液样本，一种疗法（ROCA：卵巢癌算法的风险），在发生卵巢癌病例中会产生明显的阶段降档，允许在几乎所有新病例中最佳的手术pluble，并在所有新癌症中识别出大约50％的新癌症，而不是标准的CA125 CATOFF建议。卵巢癌筛查的新进展；（5）表明，在盲人病理学评论中，诊断为输卵管粘膜的诊断性不佳，说明了使用GOG-0199研究参与者的前瞻性随访的诊断标准的需要。与GOG-0199相关的剩余主要研究终点现在正在分析中，包括基线医疗决策和生活质量，预期的生活质量评估（由研究部门分层）在5年的前瞻性随访中，以及对从筛查到这项研究的手术组的381名妇女的医疗决策分析。 来自BRCA突变阳性家庭的女性的乳房成像试点研究实现了其应计目标和前瞻性随访。该项目的最新发现包括：（1）鉴定数字乳房X线照片的计算机提取特征，“乳房X线图纹理”，该特征的存在表明，受影响患者是BRCA1/2突变携带者的可能性增加了两倍。 （2）与FDA的研究人员合作开发用于乳腺MRI图像的拟态性评估的拟态幻影； （3）证明雌激素及其代谢产物的循环水平非常强，与直接从乳房获得的液体（乳头抽吸流体；乳房导管灌洗级别的级别）获得的水平呈正相关，这一发现表明，未来的病因学研究可以利用更易于获得的血清群量均可衡量的水平，以实验性地衡量衡量水平。 （4）继续与CIMBA合作寻找BRCA1/2相关乳腺癌和卵巢癌的遗传修饰剂； （5）对乳房成像研究患者的数据的社会心理分析表明，假阳性癌症筛查测试结果与癌症风险感知，癌症的忧虑或增加降低风险的手术的吸收的大幅增加无关。然而，癌症特定的担忧是降低风险手术的摄取的独立预测指标。在为降低风险的干预措施咨询高危妇女时，该领域需要考虑； （6）和一个具有里程碑意义的六个出版物，针对非常年轻（25岁）突变携带者的特殊需求，这是一个人口，当他们在寻找合作伙伴，进入工作世界的生活塑造决策时，面临着特别具有挑战性的发展挑战LI-Fraumeni综合征（LFS）是一种高度渗透性的癌症易感综合征，最常见于TP53中的种系突变引起，与大脑，肾上腺和乳腺癌，白血病以及儿童和成人的许多其他恶性肿瘤有关。癌症筛选成分是2012年6月在NIH临床中心开业的较大LFS研究的组成部分。到2014年中，有200多名TP53个人符合条件并参与其中。由于对打开协议的压倒性和快速响应，我们实现了临床队列的最初应计目标，并在2014年12月关闭了临床队列。迄今为止，我们已经筛选了115名参与者，其中有1 - 5年的随访范围。乳腺癌的诊断是通过乳房MRI筛查进行的，靶向大脑MRI鉴定了两个脑肿瘤（低度胶质瘤和2级星形胶质细胞瘤）。在基线筛查研究中，大约7％的参与者患有事件癌。我们将根据检测早期癌症的能力，间隔癌的发展，假阳性筛查发现的频率以及参与者遵守此严格的时间表的能力来分析筛查协议的有效性。我们的数据还将包含在多个机构的大量汇总数据中。我们的社会心理研究包括对LFS家族的首次CEGRM研究，其中EE发现友谊的数量差异很大，但它们通常是深刻而持久的，并且是信息，有形和情感支持的重要来源。计划对LFS CEGRM参与者进行纵向随访，以探讨新的癌症诊断或受影响家庭成员的死亡改变参与者的社会支持网络。我们计划在研究中描述具有已知或疑似LFS或LFL的个人和家庭对癌症风险和情绪健康的认知评估，并正在评估来自300名参与者的数据，并使用标准调查表评估了对压力，痛苦，抑郁，焦虑，焦虑，躯体化，躯体化，躯体化，疾病，COPING，COPING，COPTING，COPTING，CAPCER CAPSING，CAPCER风险评估以及癌症的忧虑。此外，我们还对LFS家庭进行了定性访谈，旨在提高对日常挑战的了解。