Intervention Trials in Persons at Increased Genetic Risk of Cancer

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(GOG-199)是CGB干预研究研究组合的基石。这是一项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。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)。预期的后续行动于2011年11月结束，目前正在对最终的分析数据库进行最后的润色。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)为已发表的CA-125基线水平决定因素和ROCA算法的性能特征的汇集分析(与癌症遗传学网络：总计=4,000名受试者)贡献1,576名筛查对象；(7)为未来的翻译研究创建一个独特的生物谱系资料库；以及(8)协商GOG和CIMBA之间的合作，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。这一合作已发表了19篇手稿，其中最新的一篇发表在《自然遗传学》杂志上，并描述了一个财团对TERT基因座变异和端粒长度作为乳腺癌和卵巢癌风险修饰物的分析。一份手稿描述了30,000名BRCA突变携带者中乳腺癌和卵巢癌风险的明确基因/表型分析，目前正在审查中，另有12个候选SNPs的数据正处于分析和手稿准备的不同阶段。辅助分析目前正在进行中，涉及(1)RRSO手术病理材料基线的组织病理学发现，这将提供RRSO时临床隐匿性卵巢癌患病率的最佳可用估计(提交的手稿)；(2)在GOG-199/CGN数据集中(手稿即将完成)中ROCA卵巢癌筛查算法的性能特征分析；(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ARM对基线生活质量的描述；以及(5)基于这一队列的前瞻性随访的乳腺癌和卵巢癌的预期风险分析。多个基于生物样品的翻译研究项目正在进行中和计划中。BRCA突变阳性家族中的女性乳房成像试点研究达到了从BRCA1/2突变阳性家族中招募200名女性的预期目标；前瞻性随访于2010年2月结束。一项已发表的对基线乳房X光检查密度(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光图像已被用于与芝加哥大学的研究人员合作，以确定与BRCA突变状态密切相关的各种新的成像特征，这些特征可能被证明比标准MD更能预测乳腺癌风险。我们描述了迄今报道的最大的BRCA突变携带者队列中乳房导管灌洗(BDL)的结果，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，比较来自相同个人的三个样本(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]。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。

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.