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.

在卵巢癌遗传风险增加（GOG-199）的女性中，全国卵巢癌的预防和早期检测研究[CAS 7210]是CGBS干预研究研究组合的基石。由格林博士开发和主持，这是一项非随机自然历史研究，对降低风险的Salpingo-opophororcormosy（RRSO）与一种新型的卵巢癌筛查策略（ROCA算法）[NCI方案＃02-C-0268]。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）。预期后续活动于2011年11月结束。迄今为止的成就包括：（1）成功完成主题应计； （2）完成基于研究的BRCA1/2突变测试，以进行1,500个未知的研究参与者； （3）完成1037个RRSO样品的中央病理评论； （4）发表一份报告，详细介绍了研究的理由和设计，以及每个队列中妇女的基线特征； （5）开发一个影响RRSO选择与筛选的因素的初步模型； （6）对基线CA-125水平的决定因素以及ROCA算法的绩效特征（报告刚刚发布的报告），对1,576名筛查受试者进行了汇总分析（具有癌症遗传网络：总= 4,000名受试者）； （7）为未来的翻译研究创建一个独特的生物测量存储库； （8）谈判GOG和CIMBA之间的合作，根据该协作，我们的1400个突变携带者的DNA和临床数据正在为乳腺癌风险的多个综合候选基因关联研究和两项全基因组关联研究（GWAS）（一个BRCA基因研究）提供了贡献。 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 BRCA1突变载体中的乳腺癌，也与普通人群中的雌激素受体阴性和三阴性乳腺癌有关[自然遗传学]）。来自另外十几个候选SNP的数据处于分析和手稿准备的各个阶段。现在正在进行辅助分析与（1）符合条件分析研究队列的特征的详细描述； （2）基线RRSO手术病理学材料的组织病理学发现，强调输卵管粘膜； （3）与手术和筛查之间选择有关的医疗决策模型的测试/验证； （4）研究部门对基线生活质量的描述。 p53分子签名的合作研究是输卵管癌的推定分子前体。最后，我们已经实施了整个队列的延长积极随访5年，即GOG-8199 [CAS 7210]，该数据将获得有关生命状况，新的癌症发展和新的降低风险降低手术的年度随访数据。随着2011年11月积极随访的结论，我们将开始进行一系列主要终点分析。来自BRCA突变阳性家族女性的乳房成像试验研究[CAS 7040]达到了BRCA1/2突变阳性家族的200名女性的应计目标。预期随访于2010年2月（NCI协议01-C-0009）。基线乳腺X线X摄影密度（MD）的分析显示，突变携带者和低风险女性之间没有差异。对载体与非载波的MRI体积的分析以及与MD之间的相关性接近完成。我们数字化的乳房X线照片图像用于评估各种新型的成像特征，这些成像特征可能比标准MD更好地预测乳腺癌风险。我们已经描述了尚未报告的BRCA突变载体队列中BDL的结果，并量化了BDL程序的耐受性。我们的经验使我们放弃了BDL作为研究/风险分层工具。来自突变阳性BI参与者的DNA样品已为我们与CIMBA的合作做出了贡献。基于试点数据记录，在NAF和BDL液中可以检测到雌激素代谢产物的数量，这是一项更大的研究，比较了同一个体的样本三重点（血清，BDL，NAF）中的雌激素水平。我们已经根据该队列发表了一系列的社会心理分析。当前的努力针对年轻突变载体中的生命问题，以及模棱两可的筛查测试结果对患者情绪和筛查行为的影响，一项针对3个月干预措施的试点研究，以增加患有乳腺癌风险的久坐妇女的体育活动，达到了其目标。它询问医生是否建议增加体育活动以及使用计步器的使用将有效增加乳腺癌风险增加的久坐女性人群的体育活动[NCI方案＃04-C-0276]。一份描述研究设计和招聘策略的出版物已经出现，并且正在审查描述其结果的手稿。简而言之，研究干预似乎是可行的，尽管在这个小型飞行员中未发现各种中间终点的刻薄变化。需要一项更大的，足够的动力研究来评估干预对临床有意义的结果的影响。