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: 8763620
• 负责人: MARK H GREENE
• 金额: $ 153.71万
• 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/8763620
• 关键词: Algorithms; BRCA1 gene; Behavior; Behavioral; Breast; CA-125 Antigen; Cancer Genetics Network; Candidate Disease Gene; Characteristics; Chemoprevention; Chicago; Clinical Data; Collaborations; DNA; Data; Data Set; Databases; Decision Making; Duct (organ) structure; Early Diagnosis; Enrollment; Estrogens; Family; Future; Genes; Genetic; Genetic Risk; Genotype; Goals; Gynecologic Oncology Group; Hereditary Malignant Neoplasm; High Risk Woman; Histopathology; Image; Individual; Intervention; Intervention Studies; Intervention Trial; Irrigation; Learning; Length; Life; Life Style; Liquid substance; Magnetic Resonance Imaging; Malignant Neoplasms; Malignant neoplasm of ovary; Mammographic Density; Manuscripts; Mediation; Medical; Modeling; Molecular; Moods; Mutation; Natural History; Nature; Oncogenes; Operative Surgical Procedures; Outcome; Participant; Pathogenesis; Pathology; Patients; Performance; Persons; Phenotype; Physical activity; Physicians; Pilot Projects; Population; Preparation; Prevalence; Procedures; Protocols documentation; Publishing; Quality of life; Recommendation; Recruitment Activity; Reporting; Research; Research Design; Research Personnel; Research Project Grants; Risk; Risk Reduction; Salpingo-Oophorectomy; Sampling; Screening for Ovarian Cancer; Series; Serum; Staging; Stratification; Surgical Pathology; Test Result; Testing; Time; Touch sensation; Translational Research; Universities; Validation; Variant; Woman; arm; base; cancer risk; cohort; experience; follow-up; genome wide association study; high risk; malignant breast neoplasm; mutation carrier; novel; ovarian cancer prevention; prospective; psychosocial; repository; screening; sedentary; telomere; tool

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 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 finishing touches are now being put on the final analytic data base. 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 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; (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. 19 published manuscripts have resulted from this collaboration, the most recent of which appeared in Nature Genetics and described a consortium of consortia analysis of TERT locus variants and telomere length as modifiers of breast and ovarian cancer risk. A manuscript describing what will be the definitive genotype/phenotype analysis of breast and ovarian cancer risk in 30,000 BRCA mutation carriers is now under review, and data from another dozen candidate SNPs are in various stages of analysis and manuscript preparation. Ancillary analyses are now underway related to (1) histopathology findings from baseline RRSO surgical pathology material, which will provide the best available estimate of the prevalence of clinically-occult ovarian cancer at the time of RRSO (manuscript submitted); (2) an analysis of the performance characteristics of the ROCA ovarian cancer screening algorithm in the pooled GOG-199/CGN data set (manuscript nearing completion); (3) testing/validation of the medical decision-making model related to choice between surgery and screening; (4) a description of baseline quality of life by study arm; and (5) an analysis of the prospective risk of breast and ovarian cancer based on the prospective follow-up of this cohort. Multiple biospecimen-based translational research projects are both underway and planned. The Breast Imaging Pilot Study in Women from BRCA Mutation-Positive Families reached its accrual goal of 200 women from BRCA1/2 mutation-positive families; prospective follow-up ended in February 2010. A published 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 have been used in a collaboration with investigators from the University of Chicago to identify various novel imaging characteristics that are are strongly correlated with BRCA mutation status and which may prove to be better predictors of breast cancer risk than standard MD. We have described the results of breast duct lavage (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 (manuscript under review). 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]. In brief, the study intervention appeared to be feasible, although no significant 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发现研究[CAS 7210]在卵巢癌遗传风险增加的妇女中（GOG-199）是广发银行干预研究组合的基石。这是一项关于降低风险的输卵管卵巢切除术（RRSO）与新型卵巢癌筛查策略（ROCA算法）的非随机自然史研究。该研究于2006年11月结束新患者入组，共纳入2605例高危女性（手术组1029例;筛查组1576例）。前瞻性随访于2011年11月结束，目前正在对最终分析数据库进行最后的润色。迄今取得的成就包括：（1）成功完成受试者招募;（2）完成1,500例突变未知研究参与者的研究性BRCA 1/2突变检测;（3）完成1037例RRSO样本的中心病理学审查;（4）发表报告，详细说明研究的原理和设计，沿着每个队列中女性的基线特征;（5）建立影响RRSO与筛查选择的因素的初步模型;（6）将1，576名筛查受试者纳入已发表的汇总分析（与癌症遗传学网络：总共= 4，000名受试者）基线CA-125水平的决定因素和ROCA算法的性能特征;（7）为未来的转化研究创建一个独特的生物样本库;（8）谈判GOG和CIMBA之间的合作，根据该合作，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合并候选基因关联研究，以及两个全基因组关联研究（GWAS），每个BRCA基因一个。这项合作产生了19篇已发表的手稿，其中最近的一篇发表在《自然遗传学》上，描述了一个财团对作为乳腺癌和卵巢癌风险修饰因子的TERT基因座变异和端粒长度的分析。一份描述30，000名BRCA突变携带者中乳腺癌和卵巢癌风险的决定性基因型/表型分析的手稿正在审查中，另外十几个候选SNP的数据正在分析和手稿准备的各个阶段。目前正在进行辅助分析，涉及（1）基线RRSO手术病理学材料的组织病理学结果，这将提供RRSO时临床隐匿性卵巢癌患病率的最佳估计值（已提交手稿）;（2）GOG-199/CGN汇总数据集中ROCA卵巢癌筛查算法的性能特征分析（手稿即将完成）;（3）与手术和筛查之间选择相关的医疗决策模型的测试/验证;（4）按研究组描述基线生活质量;和（5）基于该队列前瞻性随访的乳腺癌和卵巢癌前瞻性风险分析。多个基于生物技术的转化研究项目正在进行和计划中。 BRCA突变阳性家族女性的乳腺成像初步研究达到了200名BRCA 1/2突变阳性家族女性的入组目标;前瞻性随访于2010年2月结束。一项已发表的基线乳腺摄影密度（MD）分析显示，突变携带者和低风险妇女之间没有差异。对携带者与非携带者的MRI体积以及与MD之间的相关性的分析即将完成。我们的数字化乳房X线摄影图像已被用于与芝加哥大学的研究人员合作，以确定各种新的成像特征，这些特征与BRCA突变状态密切相关，并且可能被证明是比标准MD更好的乳腺癌风险预测因子。我们已经描述了乳腺导管灌洗（BDL）的结果，在最大的队列BRCA突变携带者尚未报告，并量化了BDL程序的耐受性。我们的经验使我们放弃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。基于初步数据，证明在NAF和BDL液体中均可检测到Femtogram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样本三组（血清、BDL、NAF）中的雌激素水平（手稿正在审查中）。我们已经发表了一系列基于该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。它询问医生建议增加身体活动沿着使用计步器是否能有效增加乳腺癌风险增加的久坐女性人群的身体活动[NCI方案#04-C-0276]。简而言之，研究干预似乎是可行的，尽管在该小型试验中未发现各种中间终点的显著变化。需要一个更大的，有足够把握度的研究来评估干预对临床有意义的结果的影响。