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妇女中（GOG-199）是CGB干预研究组合的基石。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名高危女性（手术组1029名，筛查组1576名）。预期随访于2011年11月结束，目前正在对最后的分析数据库进行最后的润色。迄今为止的成就包括：(1)成功完成科目应计；(2)对1500名突变未知的研究参与者完成基于研究的BRCA1/2突变检测；(3)完成1037份RRSO样本的中心病理复查；(4)发表一份报告，详细说明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)建立影响RRSO选择与筛查的因素的初步模型；(6)将1576名筛查对象提供给已发表的汇总分析（与癌症遗传学网络一起：总共= 4,000名受试者），以确定基线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标本库；(8)协商GOG和CIMBA之间的合作，根据该合作，来自我们1400个突变携带者的DNA和临床数据将用于乳腺癌风险的多个候选基因关联研究，以及两个全基因组关联研究（GWAS），每个BRCA基因一个。这次合作已经发表了19篇论文，其中最近的一篇发表在《自然遗传学》上，描述了TERT位点变异和端粒长度作为乳腺癌和卵巢癌风险修饰因子的联盟分析。一份描述30,000名BRCA突变携带者乳腺癌和卵巢癌风险的最终基因型/表型分析的手稿目前正在审查中，另外12个候选snp的数据正处于不同的分析和手稿准备阶段。相关的辅助分析正在进行中：(1)基线RRSO手术病理材料的组织病理学发现，这将提供RRSO时临床隐匿性卵巢癌患病率的最佳估计（手稿提交）；(2)在GOG-199/CGN汇总数据集上ROCA卵巢癌筛查算法的性能特征分析（论文接近完成）；(3)与手术和筛查选择相关的医疗决策模型的测试/验证；(4)各组基线生活质量的描述；(5)基于本队列前瞻性随访的乳腺癌和卵巢癌前瞻性风险分析。多个基于生物标本的转化研究项目正在进行和计划中。BRCA突变阳性家庭女性乳腺影像学试点研究达到了200名BRCA1/2突变阳性家庭女性的累积目标；预期随访于2010年2月结束。一项已发表的基线乳房x线摄影密度（MD）分析显示，突变携带者和低风险女性之间没有差异。携带者与非携带者的MRI体积分析以及与MD之间的相关性已接近完成。我们与芝加哥大学的研究人员合作，使用数字化乳房x线摄影图像来识别与BRCA突变状态密切相关的各种新的影像学特征，这些特征可能比标准MD更好地预测乳腺癌风险。我们描述了迄今为止报道的最大BRCA突变携带者队列中乳腺导管灌洗（BDL）的结果，并量化了BDL手术的耐受性。我们的经验使我们放弃了BDL作为研究/风险分层工具。突变阳性BI参与者的DNA样本已提供给我们与CIMBA的合作。根据试点数据记录，在NAF和BDL液体中均可检测到雌激素代谢物的飞图量，一项更大规模的研究正在进行中，比较来自同一个体的三组样本（血清、BDL、NAF）中的雌激素水平（手稿正在审查中）。我们发表了一系列基于这一队列的社会心理分析；目前的研究目标是年轻突变携带者的生活问题，以及不明确的筛查结果对患者情绪和筛查行为的影响。一项针对久坐有乳腺癌风险的女性进行为期3个月的增加身体活动干预的初步研究达到了预期目标。它询问医生建议增加体力活动并使用计步器是否对久坐的乳腺癌风险增加的女性人群增加体力活动有效[NCI协议#04-C-0276]。简而言之，研究干预似乎是可行的，尽管在这个小型试点中没有发现各种中间终点的显著变化。需要一个更大的、足够有力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.