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: 8349570
• 负责人: MARK H GREENE
• 金额: $ 180.09万
• 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/8349570
• 关键词: 19p13; 9p22.2; Algorithms; BRCA1 Mutation; BRCA1 gene; BRCA2 gene; Behavior; Behavioral; Breast; CA-125 Antigen; Cancer Genetics Network; Candidate Disease Gene; Characteristics; Chemoprevention; Clinical Data; Cohort Studies; Collaborations; DNA; Data; Decision Making; Development; Early Diagnosis; Enrollment; Estrogen receptor negative; Estrogens; Fallopian Tube Carcinoma; Family; Future; General Population; Genes; Genetic; Genetic Risk; Goals; Gynecologic Oncology Group; Hereditary Malignant Neoplasm; High Risk Woman; Histopathology; Image; Individual; Intervention; Intervention Studies; Intervention Trial; Learning; Life; Life Style; Liquid substance; Magnetic Resonance Imaging; Malignant Neoplasms; Malignant neoplasm of ovary; Mammalian Oviducts; Mammographic Density; Manuscripts; Mediation; Medical; Modeling; Molecular; Molecular Profiling; Moods; Mucous Membrane; Mutation; Natural History; Nature; Oncogenes; Operative Surgical Procedures; Outcome; Participant; Pathogenesis; Pathology; Patients; Performance; Persons; Physical activity; Physicians; Pilot Projects; Population; Preparation; Procedures; Protocols documentation; Publications; Publishing; Quality of life; Recommendation; Recruitment Activity; Reporting; Research; Research Design; Risk; Risk Reduction; Salpingo-Oophorectomy; Sampling; Screening for Ovarian Cancer; Screening procedure; Series; Serum; Staging; Stratification; Surgical Pathology; Test Result; Testing; Time; Translational Research; Validation; Vital Status; Woman; arm; base; cancer risk; cohort; experience; follow-up; genetic variant; genome wide association study; high risk; malignant breast neoplasm; mutation carrier; novel; ovarian cancer prevention; prospective; psychosocial; repository; sedentary; tool; triple-negative invasive breast carcinoma

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; (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 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 (report just published); (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. 18 published, 1 in press and 6 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. Finally, we have implemented an extended active follow-up of the entire cohort for an additional 5 years, GOG-8199 [CAS 7210], which will obtain annual follow-up data on vital status, new cancer development and new risk-reducing surgeries performed. With the conclusion of active follow-up in November 2011, we will be begin a series of primary endpoint analyses. 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 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 under review. In brief, the study intervention appeared to be feasible, although no signficiant 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.

针对卵巢癌遗传风险增加的女性的国家卵巢癌预防和早期检测研究 [CAS 7210] (GOG-199) 是 CGB 干预研究组合的基石。该研究由 Greene 博士开发和主持，是一项针对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]。这项研究于 2006 年 11 月结束新患者招募，共招募了 2605 名高危女性（1029 名手术组；1576 名筛查组）。前瞻性随访于 2011 年 11 月结束。迄今为止取得的成就包括： (1) 成功完成受试者应计； （2）完成对1500名突变未知的研究参与者的基于研究的BRCA1/2突变检测； （3）完成1037份RRSO样本的中央病理审查； (4) 发布一份报告，详细说明该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 与筛选选择的因素的初步模型； (6) 将 1,576 名筛查受试者纳入基线 CA-125 水平和 ROCA 算法性能特征的决定因素的汇总分析（与癌症遗传学网络：总计 = 4,000 名受试者）（报告刚刚发布）； (7) 为未来的转化研究创建一个独特的生物样本库； (8) 就 GOG 和 CIMBA 之间的合作进行谈判，将来自我们 1400 名突变携带者的 DNA 和临床数据贡献给乳腺癌风险的多项候选基因关联研究，以及两项全基因组关联研究 (GWAS)，其中一项用于每个 BRCA 基因。此次合作已发表 18 篇文章、出版 1 篇文章和提交 6 篇手稿，其中包括几项高影响力的发现（例如，9p22.2 处的常见遗传变异可改变 BRCA1 和 BRCA2 携带者的卵巢癌风险，这是第一个新的 BRCA 相关卵巢癌风险）确定了癌症修饰因子 [J Natl Cancer Inst]，一项全基因组关联研究确定了一个 19p13 位点，该位点可以改变 BRCA1 突变携带者患乳腺癌的风险，并且也与一般人群中雌激素受体阴性和三阴性乳腺癌[自然遗传学]）。来自另外十几个候选 SNP 的数据正处于分析和手稿准备的不同阶段。目前正在进行以下方面的辅助分析：(1) 详细描述符合条件的分析研究队列的特征； (2) 基线 RRSO 手术病理材料的组织病理学结果，强调输卵管粘膜； (3) 测试/验证与手术和筛查选择相关的医疗决策模型； (4) 研究组对基线生活质量的描述。 p53 分子特征（输卵管癌的假定分子前体）的一项合作研究正在进行中。最后，我们对整个队列进行了额外 5 年的长期主动随访，GOG-8199 [CAS 7210]，将获得有关生命状态、新癌症发展和新风险降低手术的年度随访数据执行。随着 2011 年 11 月主动随访的结束，我们将开始一系列主要终点分析。 BRCA 突变阳性家庭女性乳腺影像试点研究 [CAS 7040] 达到了 200 名 BRCA1/2 突变阳性家庭女性的累积目标；前瞻性随访于 2010 年 2 月结束（NCI 方案 01-C-0009）。基线乳房X线密度（MD）分析显示突变携带者和低风险女性之间没有差异。对携带者与非携带者的 MRI 体积以及与 MD 之间的相关性的分析已接近完成。我们的数字化乳房 X 线摄影图像被用于评估各种新颖的成像特征，这些特征可能比标准 MD 更能预测乳腺癌风险。我们描述了迄今为止报道的最大的 BRCA 突变携带者群体中 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将 BDL 作为研究/风险分层工具。突变阳性 BI 参与者的 DNA 样本已被贡献给我们与 CIMBA 的合作。根据初步数据记录，在 NAF 和 BDL 液体中均可检测到飞克数量的雌激素代谢物，一项更大规模的研究正在对同一个体的三组样本（血清、BDL、NAF）中的雌激素水平进行比较。我们发表了一系列基于该群体的心理社会分析；目前的努力针对的是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。一项针对增加乳腺癌风险久坐妇女体力活动的为期 3 个月干预措施的试点研究达到了其应计目标。它询问医生关于增加体力活动并使用计步器的建议是否会有效地增加乳腺癌风险增加的久坐女性群体的体力活动[NCI 方案#04-C-0276]。描述研究设计和招募策略的出版物已经出版，描述其结果的手稿正在审查中。简而言之，尽管在这个小型试点中没有发现各种中间终点发生重大变化，但研究干预似乎是可行的。需要进行更大规模、更有力的研究来评估干预对有临床意义的结果的影响。