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: 7288885
• 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/7288885
• 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 0199). This 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 136 GOG sites in the United States and Australia. Currently, 1398 subjects have enrolled on the trial (accrual target: 2000). The screening arm of this study has surpassed its accrual goal (800); it closed to new patient enrollment September 19, 2005. 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 0199. We are evaluating whether these cells can be used for cytology, genomic and proteomic analyses. If the pilot demonstrates the feasibility of this strategy, the collection of these cells will be added to GOG 0199 on a limited institution basis. Early data are encouraging. The first phase of data analysis targeting the medical decision-making process (regarding how women selected either surgery or screening) has begun. Data obtained from the first 600 study participants at the time of study entry are being 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 0199 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.

虽然在识别主要癌症易感基因方面取得了可喜的进展，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阶段。我们迫切需要安全有效的策略，通过这些策略可以降低突变携带者患癌症的风险。咨询委员会内部的战略规划进程导致了一项建议，即该司扩大干预研究领域的活动，这一建议已得到内部司司长的赞同。 国家卵巢癌预防与检测研究 在对携带BRCA1/2突变的妇女的管理中，许多紧迫的临床问题是预防性卵巢切除术作为一种降低风险的策略的适当作用。与妇科肿瘤学小组(GOG)和癌症遗传学网络(CGN)的研究人员合作，对选择接受降低风险的输卵管卵巢切除术(RRSO)的遗传高危女性启动了一项全国性的前瞻性随访研究(NCI议定书#02-C-0268；GOG 0199)。这将解决以下问题： (A)在降低风险手术时，临床上隐匿性卵巢癌的患病率是多少？ (B)遗传高危妇女的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病率是多少？和 (D)这种外科手术对选择手术的妇女的生活质量和非肿瘤性疾病的发病率有何影响？ 选择保留卵巢的女性正在接受一种新的卵巢癌筛查算法，该算法基于CA125(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，目前正在美国和澳大利亚的136个GOG站点收集患者。目前，已有1398名受试者参加试验(应计目标：2000人)。这项研究的筛查部门已经超过了其应计目标(800人)；它于2005年9月19日关闭了新患者登记。BRCA1/2突变检测的巨大任务已经开始，以确定60%的研究参与者的突变状态，这些参与者之前没有接受过临床基因检测。这些数据将是最终研究分析中的关键分层变量。 我们正在完成一项初步研究，以评估从卵巢中获取卵巢表面上皮细胞的可行性，这些细胞被切除以降低GOG0199中卵巢癌的遗传风险。我们正在评估这些细胞是否可以用于细胞学、基因组和蛋白质组分析。如果试点证明了这一战略的可行性，这些单元的收集将在有限的机构基础上添加到GOG 0199。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)的数据分析的第一阶段已经开始。在研究进入时，从前600名研究参与者那里获得的数据被用来建立预测模型；然后，将使用来自下一批1400名受试者的数据来测试/验证该模型。在规划的不同阶段进行的其他辅助分析包括： (1)对两个研究组的基线生活质量均值进行评估； (2)定量评估在研究开始时获得的影响血清CA-125水平的因素，合并来自GOG 0199的筛查分支和配套的CGN筛查研究(称为“ROCA试验”)的数据。 (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及间质的标准光镜、HE染色的组织学特征。