Intervention Trials in Persons at Increased Genetic Risk

对遗传风险增加人群的干预试验

• 批准号: 7330801
• 负责人: MARK H GREENE
• 金额: --
• 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/7330801
• 关键词: Intervention; Trials; Persons; Increased; Genetic

While the progress in identifying major cancer susceptibility genes has been gratifying, our ability to intervene at the molecular level in order to reduce the risk associated with mutations in these genes is embryonic. We are in urgent need of safe and effective strategies through which the risk of cancer in mutation carriers can be reduced now. A strategic planning process within DCEG led to a recommendation that the Division expand its activities in the area of intervention studies, a proposal which has been endorsed by the Intramural Division Directors. National Ovarian Cancer Prevention and Detection Study Among the many pressing clinical issues in the management of women who carry mutations in BRCA1/2 is the appropriate role of prophylactic oophorectomy as a risk reduction strategy. In collaboration with investigators from the Gynecologic Oncology Group (GOG) and the Cancer Genetics Network (CGN), a national, prospective follow-up study of genetically at-risk women who elect to undergo risk-reducing salpingo-oophorectomy (RRSO) has been launched (NCI Protocol #02-C-0268; GOG-199). Dr. Greene is the National Study Chair for this protocol, which is addressing the following issues: (a) What is the prevalence of clinically occult ovarian cancer at the time of risk-reducing surgery? (b) Are there identifiable precursor lesions in the ovaries of genetically at-risk women? (c) What is the incidence of primary peritoneal carcinomatosis and breast cancer subsequent to RRSO? and (d) How does this surgical procedure affect the quality of life and morbidity from non-oncologic medical conditions for the women who elect it? Women who elect to retain their ovaries are being screened with a novel ovarian cancer screening algorithm based on longitudinal changes of CA125 (and other tumor marker) levels over time. This study opened to accrual in the summer of 2003, and is presently accruing patients at 157 GOG sites in the United States and Australia. Currently, 2249 subjects have enrolled on the trial (accrual target: 2332), including 904 surgical and 1345 screening subjects. The study will close to new patient accrual on November 1, 2006. The very large task of BRCA1/2 mutation testing has begun, in order to determine the mutation status of the 60% of study participants who have not undergone prior clinical genetic testing. These data will be a critical stratification variable in the final study analysis. We are in the midst of finalizing a pilot study to assess the feasibility of harvesting ovarian surface epithelial cells from the ovaries that are removed to reduce the genetic risk of ovarian cancer in GOG-199. We are evaluating whether these cells can be used for cytology, genomic and proteomic analyses. Early data are encouraging. The data analysis targeting the medical decision-making process (regarding how women selected either surgery or screening) is in manuscript preparation. Data obtained from the first 600 study participants at the time of study entry have been used to build a predictive model; the model will then be tested/validated using data from the next cohort of 1400 subjects. Additional ancillary analyses in various stages of planning include: (1) an evaluation of baseline Quality-of-Life meansures in each of the two study groups; (2)a quantitative evaluation of factors which influence serum levels of CA-125 obtained at study entry, pooling data from the screening arms of GOG-199 and the companion CGN screening study (designated "the ROCA Trial"). (3) a detailed description of the standard light microscopy, H&E-stained histologic characteristics of fallopian tube mucosa and ovarian surface epithelium and stroma in RRSO-derived surgical material.(4) a multidisciplinary, laboratory-based assessment of the molecular biologic characteristics of ovarian and fallopian tube tissue obtained from high-risk women at the time of RRSO.

虽然在确定主要癌症易感基因方面的进展令人满意，但我们在分子水平上进行干预以降低与这些基因突变相关的风险的能力还处于萌芽状态。我们迫切需要安全和有效的战略，通过这些战略，现在可以降低突变携带者患癌症的风险。教育和性别平等司内部的一项战略规划进程导致一项建议，即该司应扩大其在干预研究领域的活动，这一建议已得到学院内各司司长的赞同。国家卵巢癌预防和检测研究在管理携带BRCA 1/2突变的妇女的许多紧迫的临床问题中，预防性卵巢切除术作为一种降低风险的策略的适当作用。与妇科肿瘤组（GOG）和癌症遗传学网络（CGN）的研究人员合作，已经启动了一项针对选择接受风险降低输卵管卵巢切除术（RRSO）的遗传风险女性的全国性前瞻性随访研究（NCI方案#02-C-0268; GOG-199）。格林博士是该方案的国家研究主席，该方案正在解决以下问题：（a）在降低风险的手术时，临床隐匿性卵巢癌的患病率是多少？(b)有遗传风险的女性卵巢中是否存在可识别的前驱病变？(c)RRSO后原发性腹膜癌病和乳腺癌的发生率是多少？以及（d）这种外科手术对选择这种手术的妇女的生活质量和非肿瘤疾病的发病率有何影响？选择保留卵巢的女性正在使用一种新型卵巢癌筛查算法进行筛查，该算法基于CA 125（和其他肿瘤标志物）水平随时间的纵向变化。这项研究于2003年夏天开始招募，目前正在美国和澳大利亚的157个GOG研究中心招募患者。目前，2249例受试者已入组试验（招募目标：2332例），包括904例手术受试者和1345例筛选受试者。本研究将于2006年11月1日结束新患者招募。BRCA 1/2突变检测的巨大任务已经开始，以确定60%未接受过临床基因检测的研究参与者的突变状态。这些数据将是最终研究分析中的关键分层变量。我们正在完成一项试点研究，以评估从卵巢中收集卵巢表面上皮细胞的可行性，这些细胞被移除以降低GOG-199中卵巢癌的遗传风险。我们正在评估这些细胞是否可用于细胞学、基因组学和蛋白质组学分析。早期数据令人鼓舞。针对医疗决策过程（关于妇女如何选择手术或筛查）的数据分析正在准备手稿。在研究入组时从前600名研究受试者获得的数据已用于构建预测模型;然后将使用下一个1400名受试者队列的数据对模型进行测试/验证。在计划的各个阶段中的附加辅助分析包括：（1）在两个研究组中的每一个中的基线生活质量平均值的评估;（2）在研究进入时获得的影响CA-125血清水平的因素的定量评估，来自GOG-199的筛选臂和伴随的CGN筛选研究（指定为“ROCA试验”）的合并数据。(3)详细描述RRSO来源的手术材料中输卵管粘膜和卵巢表面上皮和基质的标准光学显微镜、H& E染色组织学特征。(4)对RRSO时从高危女性中获得的卵巢和输卵管组织的分子生物学特征进行多学科、基于实验室的评估。