Intervention Trials in Persons at Increased Genetic Risk

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。 全国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 0199）。这是为了解决以下问题： (a)降低风险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？和 (d)这种外科手术如何影响选择它的妇女的生活质量和非肿瘤疾病的发病率？ 选择保留卵巢的妇女正在接受一种新的卵巢癌筛查算法的筛查，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136个GOG研究中心招募患者。目前，1398例受试者已入组试验（招募目标：2000例）。本研究的筛选组已超过其招募目标（800例）;于2005年9月19日停止招募新患者。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，以评估从卵巢中采集卵巢表面上皮细胞的可行性，这些细胞被移除以降低GOG 0199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。如果试点证明了这一策略的可行性，这些细胞的收集将在有限的机构基础上添加到GOG 0199中。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）的第一阶段数据分析已经开始。在研究入组时从前600名研究受试者获得的数据用于构建预测模型;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。规划各个阶段的其他辅助分析包括： (1)对两个研究组的基线生活质量平均值进行评价; (2)a定量评价在研究进入时获得的影响CA-125血清水平的因素，合并来自GOG 0199筛选组和伴随的CGN筛选研究（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和基质的标准光学显微镜、H& E染色组织学特征。

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.