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: 8157923
• 负责人: MARK H GREENE
• 金额: $ 149.09万
• 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/8157923
• 关键词: Genetic Risk; Intervention Trial; Malignant Neoplasms; Persons

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 (including both full sequencing and testing for large deletions, rearrangements); (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 1576 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 (manuscript nearing completion); (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. Seven published and 1 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, and we are implementing plans to extend active follow-up of the entire cohort for an additional 5 years. 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 Phase II Randomized Trial of Icosahedron Acid versus Standard Care to Prevent Post-RRSO Osteopenia/Osteoporosis (GOG-215) targets one of the major complications of RRSO-related premature menopause, i.e., significant bone loss, increased risk of osteoporosis and fracture. This study is currently open at 50 sites nationwide, and has enrolled 100 participants to date. 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 in preparation.

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妇女中（GOG-199）是CGB干预研究研究组合的基石。由格林博士开发并主持，这是一项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[NCI方案#02-C-0268]。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。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（包括全测序和大缺失、重排的检测）;（3）完成1037份RRSO样本的中心病理学审查;（4）发表一份报告，详细说明研究的基本原理和设计，沿着每个队列中妇女的基线特征;（5）建立影响选择RRSO与筛选的因素的初步模型;（6）将1576名筛选受试者纳入汇总分析基线CA-125水平的决定因素和ROCA算法的性能特征（与癌症遗传学网络：总计= 4，000名受试者）（手稿即将完成）;（7）为未来的转化研究创建一个独特的生物标本库;和（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，和两个全基因组关联研究（GWAS），每个BRCA基因一个。此次合作产生了7篇已发表的论文和1篇已提交的论文，其中包括几项具有重大影响的发现（例如，9p22.2的一种常见遗传变异改变了BRCA 1和BRCA 2携带者的卵巢癌风险，第一个新的BRCA相关卵巢癌修饰因子被鉴定[J Natl Cancer Inst]，一项全基因组关联研究鉴定了一个19 p13基因座，该基因座改变了BRCA 1突变携带者的乳腺癌风险，也与一般人群中的雌激素受体阴性和三阴性乳腺癌相关[Nature Genetics]）。来自另外十几个候选SNP的数据处于分析和手稿准备的不同阶段。目前正在进行辅助分析，涉及（1）对合格分析研究队列特征的详细描述;（2）基线RRSO手术病理学材料的组织病理学结果，重点是输卵管粘膜;（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;和（4）按研究组描述基线生活质量。一项关于p53分子标记（输卵管癌的假定分子前体）的合作研究正在进行中，我们正在实施计划，将整个队列的积极随访延长5年。在BRCA突变阳性家族女性中进行的乳腺成像初步研究[CAS 7040]达到了200例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（NCI方案01-C-0009）。对基线乳腺摄影密度（MD）的分析显示，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。我们的数字化乳腺X线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是比标准MD更好的乳腺癌风险预测因子。我们已经描述了BDL在最大的BRCA突变携带者队列中的结果，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液体中均可检测到飞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样本三重（血清、BDL、NAF）中的雌激素水平。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。二十面体酸与标准护理预防RRSO后骨质减少/骨质疏松症（GOG-215）的II期随机试验针对RRSO相关过早绝经的主要并发症之一，即，严重的骨质流失，增加骨质疏松症和骨折的风险。这项研究目前在全国50个研究中心开展，迄今已招募了100名参与者。一项为期3个月的干预性研究，旨在增加有乳腺癌风险的久坐女性的身体活动，达到了其累积目标。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]。一份介绍研究设计和招募策略的出版物已经出版，一份介绍研究结果的手稿正在编写中。