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。由Greene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协议#02-C-0268]。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）。预期随访将于2011年11月结束。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（包括全测序和大缺失、重排检测）；(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)对1576名筛选对象进行汇总分析（与癌症遗传学网络一起：总共= 4000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（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；(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。此次合作已发表了7篇论文，提交了1篇论文，其中包括几项高影响力的发现(例如：一种常见的9p22.2基因变异改变了BRCA1和BRCA2携带者的卵巢癌风险，这是第一个新的brca相关卵巢癌修饰因子被发现[J Natl cancer institute]，一项全基因组关联研究发现了一个19p13位点，它改变了BRCA1突变携带者的乳腺癌风险，并且在普通人群中也与雌激素受体阴性和三阴性乳腺癌相关[Nature Genetics])。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)对符合条件的分析研究队列特征的详细描述；(2)基线RRSO手术病理资料的组织病理学结果，强调输卵管粘膜；(3)与手术和筛查选择相关的医疗决策模型的测试/验证；(4)各组基线生活质量描述。一项关于p53分子特征的合作研究正在进行中，该分子特征被认为是输卵管癌的分子前体，我们正在实施计划，将整个队列的积极随访延长5年。BRCA突变阳性家庭女性乳腺影像学试点研究[CAS 7040]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（NCI协议01-C-0009）。基线乳房x线摄影密度（MD）分析显示突变携带者和低风险妇女之间没有差异。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。我们的数字化乳房x线摄影图像被用于评估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。根据初步数据记录，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。我们发表了一系列基于这一队列的社会心理分析；目前的努力是针对年轻突变携带者的生活问题，以及模棱两可的筛查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，即显著骨质流失，骨质疏松和骨折风险增加。这项研究目前在全国50个地点开放，到目前为止已经招募了100名参与者。一项针对有乳腺癌风险的久坐妇女进行为期3个月的增加体力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]。一份描述研究设计和招募策略的出版物已经出现，一份描述其结果的手稿正在准备中。

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.