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: 8349570
• 负责人: MARK H GREENE
• 金额: $ 180.09万
• 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/8349570
• 关键词: 19p13; 9p22.2; Algorithms; BRCA1 Mutation; BRCA1 gene; BRCA2 gene; Behavior; Behavioral; Breast; CA-125 Antigen; Cancer Genetics Network; Candidate Disease Gene; Characteristics; Chemoprevention; Clinical Data; Cohort Studies; Collaborations; DNA; Data; Decision Making; Development; Early Diagnosis; Enrollment; Estrogen receptor negative; Estrogens; Fallopian Tube Carcinoma; Family; Future; General Population; Genes; Genetic; Genetic Risk; Goals; Gynecologic Oncology Group; Hereditary Malignant Neoplasm; High Risk Woman; Histopathology; Image; Individual; Intervention; Intervention Studies; Intervention Trial; Learning; Life; Life Style; Liquid substance; Magnetic Resonance Imaging; Malignant Neoplasms; Malignant neoplasm of ovary; Mammalian Oviducts; Mammographic Density; Manuscripts; Mediation; Medical; Modeling; Molecular; Molecular Profiling; Moods; Mucous Membrane; Mutation; Natural History; Nature; Oncogenes; Operative Surgical Procedures; Outcome; Participant; Pathogenesis; Pathology; Patients; Performance; Persons; Physical activity; Physicians; Pilot Projects; Population; Preparation; Procedures; Protocols documentation; Publications; Publishing; Quality of life; Recommendation; Recruitment Activity; Reporting; Research; Research Design; Risk; Risk Reduction; Salpingo-Oophorectomy; Sampling; Screening for Ovarian Cancer; Screening procedure; Series; Serum; Staging; Stratification; Surgical Pathology; Test Result; Testing; Time; Translational Research; Validation; Vital Status; Woman; arm; base; cancer risk; cohort; experience; follow-up; genetic variant; genome wide association study; high risk; malignant breast neoplasm; mutation carrier; novel; ovarian cancer prevention; prospective; psychosocial; repository; sedentary; tool; triple-negative invasive breast carcinoma

The National Ovarian Cancer Prevention and Early Detection Study [CAS 7210] among women at increased genetic risk of ovarian cancer (GOG-199) is the cornerstone of CGBs intervention studies research portfolio. Developed and chaired by Dr. Greene, it is a non-randomized natural history study of risk-reducing salpingo-oophorectomy (RRSO) versus a novel ovarian cancer screening strategy (the ROCA algorithm) [NCI Protocol #02-C-0268]. 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 ends in November 2011. Accomplishments to date include: (1) successfully completing subject accrual; (2) completing the research-based BRCA1/2 mutation testing for the 1,500 mutation-unknown study participants; (3) completing the central pathology review of 1037 RRSO samples; (4) publishing a report detailing the rationale and design of the study, along with baseline characteristics of the women in each cohort; (5) developing a preliminary model of the factors which influence the choice of RRSO versus screening; (6) contributing 1,576 screening subjects to a 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 (report just published); (7) creating a unique biospecimen repository for future translational research; and (8) negotiating a collaboration between GOG and CIMBA under which DNA and clinical data from our 1400 mutation carriers are being contributed to multiple pooled candidate gene association studies of breast cancer risk, and two genome-wide association studies (GWAS), one for each BRCA gene. 18 published, 1 in press and 6 submitted manuscripts have resulted from this collaboration, including several high-impact findings (e.g., a common genetic variant at 9p22.2 modifies ovarian cancer risks in BRCA1 and BRCA2 carriers, the first new BRCA-related ovarian cancer modifier identified [J Natl Cancer Inst], and a genome-wide association study identified a 19p13 locus that modifies the risk of breast cancer in BRCA1 mutation carriers and which is also associated with estrogen receptor-negative and triple-negative breast cancer in the general population [Nature Genetics]). Data from another dozen candidate SNPs are in various stages of analysis and manuscript preparation. Ancillary analyses are now underway related to (1) a detailed description of the characteristics of the eligible analytic study cohort; (2) histopathology findings from baseline RRSO surgical pathology material, emphasizing the fallopian tube mucosa; (3) testing/validation of the medical decision-making model related to choice between surgery and screening; and (4) a description of baseline quality of life by study arm. A collaborative study of the p53 molecular signature, a putative molecular precursor to fallopian tube carcinoma, is in development. Finally, we have implemented an extended active follow-up of the entire cohort for an additional 5 years, GOG-8199 [CAS 7210], which will obtain annual follow-up data on vital status, new cancer development and new risk-reducing surgeries performed. With the conclusion of active follow-up in November 2011, we will be begin a series of primary endpoint analyses. The Breast Imaging Pilot Study in Women from BRCA Mutation-Positive Families [CAS 7040] reached its accrual goal of 200 women from BRCA1/2 mutation-positive families; prospective follow-up ends in February 2010 (NCI Protocol 01-C-0009). Analysis of baseline mammographic density (MD) has revealed no differences between mutation carriers and low-risk women. Analyses of MRI volume in carriers versus non-carriers and correlations between with MD are nearing completion. Our digitized mammographic images are being used to evaluate various novel imaging characteristics that may prove to be better predictors of breast cancer risk than standard MD. We have described the results of BDL in the largest cohort of BRCA mutation carriers yet reported, and quantified the tolerability of the BDL procedure. Our experience has led us to abandon BDL as a research/risk stratification tool. DNA samples from mutation-positive BI participants have been contributed to our collaboration with CIMBA. Based on pilot data documenting that femtogram quantities of estrogen metabolites are detectable in both NAF and BDL fluid, a larger study comparing estrogen levels in sample trios (serum, BDL, NAF) from the same individuals is underway. We have published a series of psychosocial analyses based on this cohort; current efforts target life issues in young mutation carriers, and the impact of ambiguous screening test results on patient mood and screening behavior A Pilot Study of a 3-month Intervention for Increasing Physical Activity in Sedentary Women at Risk of Breast Cancer reached its accrual goal. It asked whether a physician recommendation for increasing physical activity along with the use of a pedometer will be effective in increasing physical activity in a sedentary population of women at increased breast cancer risk [NCI Protocol #04-C-0276]. A publication describing study design and recruiting strategies has appeared, and a manuscript describing its results is under review. In brief, the study intervention appeared to be feasible, although no signficiant change in various intermediate endpoints was identified in this small pilot. A larger, adequately-powered study is required to assess the impact of intervention on clinically meaningful outcomes.

国家卵巢癌预防和早期检测研究[CAS 7210]在卵巢癌遗传风险增加的女性中的研究(GOG-199)是CGB干预研究研究组合的基石。由格林博士开发并担任主席的这项研究是一项关于降低风险的输卵管卵巢切除术(RRSO)与一种新的卵巢癌筛查策略(ROCA算法)的非随机自然历史研究[NCI议定书#02-C-0268]。这项研究结束于2006年11月的新患者登记，共收集了2605名高危妇女(1029名手术组；1576名筛查组)。预期的后续行动将于2011年11月结束。迄今的成就包括：(1)成功地完成了受试者的应计；(2)完成了1500名突变未知研究参与者的基于研究的BRCA1/2突变测试；(3)完成了1037个RRSO样本的中央病理学审查；(4)发表了一份报告，详细说明了研究的基本原理和设计，以及每个队列中女性的基线特征；(5)开发了影响选择RRSO与筛查的因素的初步模型；(6)贡献1,576名筛查对象(与癌症遗传学网络：总计=4,000名对象)，对基线CA-125水平的决定因素和ROCA算法的性能特征进行汇集分析(刚刚发表的报告)；(7)创建一个独特的生物谱系资料库，用于未来的翻译研究；以及(8)与GOG和CIMBA谈判合作，根据该合作，来自我们1400名突变携带者的DNA和临床数据将被贡献给乳腺癌风险的多个汇集候选基因关联研究，以及两项全基因组关联研究(GWAS)，每个BRCA基因一项。这次合作共发表了18篇论文，其中包括多项有影响力的发现(例如，位于9p22.2的一种常见的基因变异可以改变BRCA1和BRCA2携带者中的卵巢癌风险，第一个被发现的与BRCA相关的新的卵巢癌修饰基因[J Natl Cancer Inst]，以及一项全基因组关联研究，该研究发现了一个19p13基因座可以改变BRCA1突变携带者中的乳腺癌风险，它也与普通人群中雌激素受体阴性和三阴性乳腺癌有关[自然遗传学])。另外十几个候选SNPs的数据正处于不同的分析和手稿准备阶段。目前正在进行的辅助分析涉及：(1)符合条件的分析性研究队列的特征的详细描述；(2)RRSO手术病理材料基线的组织病理学结果，重点是输卵管黏膜；(3)与手术和筛查之间的选择相关的医疗决策模型的测试/验证；(4)研究小组对基线生活质量的描述。对P53分子特征的合作研究正在进行中，P53分子特征可能是输卵管癌的分子前驱。最后，我们对整个队列实施了延长的积极跟踪，再延长5年，GOG-8199[CAS 7210]将获得有关生命状况、新的癌症发展和新的降低风险手术的年度跟踪数据。随着2011年11月积极跟进的结束，我们将开始一系列主要终点分析。BRCA突变阳性家族中的女性乳房成像先导研究[CAS 7040]达到了从BRCA1/2突变阳性家族中招募200名女性的累积目标；预期随访将于2010年2月结束(NCI议定书01-C-0009)。基线乳房X光照相密度(MD)分析显示，突变携带者和低风险女性之间没有差异。对携带者和非携带者的MRI体积以及与MD的相关性的分析已接近完成。我们的数字化乳房X光摄影图像正被用于评估各种新的成像特征，这些特征可能被证明比标准MD更能预测乳腺癌的风险。我们描述了迄今报道的最大的BRCA突变携带者队列中的BDL结果，并量化了BDL过程的耐受性。我们的经验使我们放弃了将BDL作为研究/风险分层工具。来自突变阳性BI参与者的DNA样本已被贡献给我们与CIMBA的合作。根据试点数据，在NaF和BDL液中都可以检测到毫微克量的雌激素代谢物，正在进行一项更大规模的研究，比较来自相同个体的三个样本(血清、BDL和NaF)中的雌激素水平。我们已经发表了一系列基于这一队列的心理社会分析；目前的努力针对年轻突变携带者的生活问题，以及模糊的筛查测试结果对患者情绪和筛查行为的影响一项为期3个月的干预试验的试点研究，旨在增加乳腺癌风险女性的体力活动，达到了预期目标。它询问医生建议增加体力活动并使用计步器是否会有效地增加乳腺癌风险高的久坐女性人群的体力活动[NCI议定书#04-C-0276]。一份描述研究设计和招募策略的出版物已经出版，一份描述其结果的手稿正在审查中。简而言之，这项研究干预似乎是可行的，尽管在这项小规模试验中没有发现各种中间终点的显著变化。需要一项更大的、动力充足的研究来评估干预对临床有意义的结果的影响。