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（又名GOG-199）是CGB干预研究组合的基石。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。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）。预期随访于2011年11月结束，最终的分析数据库现已完成。到目前为止，最近的成就包括：(1)将1576名筛查对象纳入已发表的汇总分析（与癌症遗传学网络一起：总共= 4,000名受试者），对基线CA-125水平的决定因素和ROCA算法的性能特征进行分析，结果表明，绝经前妇女的正常临界值上限应为52，而不是通常使用的35；(2)继续合作寻找BRCA1/2 -相关乳腺癌和卵巢癌风险的遗传修饰因子，这项工作已经发表了40篇论文，另有7篇目前正在审查中；(3)量化接受RRSO的无症状女性中临床隐匿性卵巢癌的患病率：966例GOG-09199例RRSO中有25例（2.6%）（BRCA1携带者=4.6%，BRCA2携带者=3.5%，非携带者=0.5%）；(4)记录高风险妇女将遵守卵巢癌筛查计划，该计划需要每3个月提供一次血液样本，该方案（ROCA：卵巢癌风险算法）在卵巢癌病例中产生显著的阶段下降，允许在几乎所有新病例中进行最佳手术减癌，并在超过标准CA125临界值35 IU/ml之前识别出约50%的新癌症。这些发现表明，ROCA算法可能代表了卵巢癌筛查领域的重要新进展；(5)盲法病理检查显示输卵管粘膜异型性诊断的可重复性较差，说明需要改进诊断标准；(6)通过对GOG-0199研究参与者的前瞻性随访，确定之前描述的与RRSO相关的乳腺癌保护作用可能没有之前估计的那么大。与GOG-0199相关的其余主要研究终点目前正在分析中，包括基线医疗决策和生活质量，5年前瞻性随访期间生活质量的前瞻性评估（按研究组分层），以及本研究中从筛查组过渡到手术组的381名妇女的医疗决策分析。BRCA突变阳性家庭女性的乳腺成像试点研究实现了其累积目标，前瞻性随访现已结束。该项目最近的发现包括：(1)识别计算机提取的数字乳房x线照片特征，“乳房x线照片纹理”，其存在表明受影响患者是BRCA1/2突变携带者的可能性增加了两倍；(2)与FDA的研究人员合作，开发用于乳腺MRI图像定量评估的拟人化假体；(3)证明循环雌激素及其代谢物水平与直接从乳房获得的液体（乳头抽吸液；乳腺导管冲洗上清液）测量的水平非常强烈，正相关，这一发现表明，未来的病因学研究可以利用更容易获得的血清激素水平作为可靠的替代测量暴露在组织水平。(4)继续与CIMBA合作，寻找BRCA1/2 -相关乳腺癌和卵巢癌的基因修饰因子；(5)对乳腺成像研究患者数据的社会心理分析显示，癌症筛查结果假阳性与癌症风险认知、癌症担忧或降低风险手术的增加无关。然而，癌症特异性担忧是接受降低风险手术的独立预测因素；在对高危妇女进行降低风险干预的咨询时，这一领域值得考虑；(6)以及一系列具有里程碑意义的6篇出版物，针对非常年轻（25岁以下）突变携带者的特殊需求，这一人群面临着特别具有挑战性的发展挑战，因为他们在寻找伴侣、进入工作世界、考虑组建家庭等决定人生的决定中，都是在关注BRCA相关癌症风险管理的背景下进行的。包括强化筛查和降低风险的手术。Li-Fraumeni综合征（LFS）是一种高度渗透的癌症易感性综合征，最常见的是由TP53的种系突变引起，与儿童和成人的脑癌、肾上腺癌、乳腺癌、白血病和许多其他恶性肿瘤有关。癌症筛查部分是2012年6月在美国国立卫生研究院临床中心开展的更大的LFS研究的一个组成部分。到2014年年中，超过200名TP53患者符合条件并入组。由于对开放方案的压倒性和快速反应，我们达到了临床队列的初始应计目标，并于2014年12月关闭了临床队列的应计。到目前为止，我们共筛选了115名参与者，随访时间为1-5年。乳腺癌诊断已通过乳腺MRI筛查和靶向脑MRI确定了两个脑肿瘤（低级别胶质瘤和2级星形细胞瘤）。大约7%的参与者在基线筛查研究中发现了癌症。我们将根据筛查方案检测早期癌症的能力、间隔期癌症的发展、假阳性筛查结果的频率以及参与者对这一严格时间表的依从性来分析筛查方案的有效性。我们的数据也将包括在来自多个机构的数据的更大的汇总分析中。我们的社会心理研究包括对LFS家庭的第一个CEGRM研究，其中我们发现，虽然友谊的数量变化很大，但它们通常是深刻而持久的，是信息、有形和情感支持的重要来源。计划对LFS CEGRM参与者进行纵向随访，以探讨新癌症诊断或受影响家庭成员的死亡是否会改变参与者的社会支持网络。我们计划在研究入组时描述已知或疑似LFS或LFL的个人和家庭对癌症风险和情绪健康的认知评估，并评估来自300名参与者的数据，这些参与者使用标准化问卷评估压力、痛苦、抑郁、焦虑、躯体化、应对、癌症风险评估和癌症担忧。此外，我们还纳入了对LFS家庭的定性访谈，旨在提高对他们日常挑战的理解。

The National Ovarian Cancer Prevention and Early Detection Study [CAS 7210] among women at increased genetic risk of ovarian cancer (aka GOG-199) is the cornerstone of CGB's intervention studies research portfolio. It is a non-randomized natural history study of risk-reducing salpingo-oophorectomy (RRSO) versus a novel ovarian cancer screening strategy (the ROCA algorithm). 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 ended in November 2011, and the final analytic data base is now complete. Recent accomplishments to date include: (1) contributing 1,576 screening subjects to a published 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, which demonstrated that pre-menopausal women should have an upper limit of normal cut-off=52, rather than 35 as customarily used; (2) continued our collaboration with seeking genetic modifiers of BRCA1/2 -associated breast and ovarian cancer risk, an effort which has produced 40 published manuscripts, with an additional 7 are currently under review; (3) quantification of the prevalence of clinically-occult ovarian cancers among asymptomatic women undergoing RRSO: 25 (2.6%) of 966 GOG-09199 RRSOs ( BRCA1 carriers=4.6%, BRCA2 carriers=3.5%, and non-carriers=0.5% (p=0.0006); (4) documenting that high-risk women WILL comply with an ovarian cancer screening program that entails providing a blood sample every 3 months, a regimen (ROCA: the risk of ovarian cancer algorithm) which produces a significant stage downshift among incident ovarian cancer cases, permits optimal surgical debulking in nearly all new cases, and identifies about 50% of new cancers before they exceed the standard CA125 cutoff of 35 IU/ml. These findings suggest that the ROCA algorithm may represent an important new advance in the world of ovarian cancer screening; (5) demonstrating the poor reproducibility of the diagnosis of fallopian tube mucosal atypia on blinded pathology review, illustrating the need for improved diagnostic criteria; (6) using the prospective follow-up of GOG-0199 study participants to determine that the breast cancer protective effect previously described in relation to RRSO may not be as large as previously estimated. The remaining primary study endpoints related to GOG-0199 are now under analysis, including baseline medical decision-making and quality of life, prospective evaluation of quality of life (stratified by study arm) during 5 years' prospective follow-up, and an analysis of medical decision-making among the 381 women who crossed over from the screening to the surgical arm of this study. The Breast Imaging Pilot Study in Women from BRCA Mutation-Positive Families achieved its accrual goal and prospective follow-up has now ended. Recent findings from this project include: (1) identification of a computer-extracted feature of digital mammograms, "mammographic texture," the presence of which signals a two-fold increase in the likelihood of an affected patient being a BRCA1/2 mutation carrier; (2) development of an anthropomorphic phantom for quantitative evaluation of breast MRI images, in collaboration with investigators from the FDA; (3) demonstrating that circulating levels of estrogen and its metabolites are very strongly, positively correlated with levels measured on fluids obtained directly from the breast (nipple aspirate fluid; breast duct lavage supernatant), a finding which suggests that future etiologic studies could utilize the more readily obtainable serum hormone levels as a reliable surrogate measure of exposure at the tissue level. (4) continued collaboration with CIMBA in search of genetic modifiers of BRCA1/2 -associated breast and ovarian cancer; (5) a psychosocial analysis of data from Breast Imaging Study patients that revealed that false positive cancer screening test results were not associated with large increases in cancer risk perception, cancer worry or increased uptake of risk-reducing surgery. However, cancer-specific worry was an independent predictor of uptake of risk-reducing surgery; this domain warrants consideration when counseling high-risk women regarding risk-reducing interventions; (6) and a landmark series of 6 publications targeting the special needs of very young (less than age 25) mutation carriers, a population which faces particularly challenging developmental challenges as they navigate the life-shaping decisions of finding a partner, entering the world of work, contemplating family formation, all in the context of concerns regarding the management of their BRCA -associated cancer risk management, including intensive screening and the need for risk-reducing surgery.Li-Fraumeni syndrome (LFS) is a highly penetrant cancer predisposition syndrome most commonly caused by germline mutations in TP53 and associated with brain, adrenal gland, and breast cancers, leukemia, and many other malignancies in children and adults. The cancer-screening component is an integral part of the larger LFS study that opened at the NIH Clinical Center, in June 2012. By mid-2014, more than 200 TP53 individuals were eligible and enrolled. Due to this overwhelming and rapid response to opening the protocol, we met our initial accrual goal for the clinical cohort and closed the clinical cohort to accrual in December 2014. To date, we have screened total of 115 participants with a range of follow-up from 1-5 years. Breast cancer diagnoses have been made by breast MRI screening and targeted brain MRI identified the two brain tumors (a low-grade glioma and a grade 2 astrocytoma). Approximately 7% of participants have had an incident cancer identified at the baseline screening study. We will analyze the effectiveness of the screening protocol based on its ability to detect early stage cancers, the development of interval cancers, the frequency of false positive screening findings, and participant adherence to this rigorous schedule. Our data will also be included in larger pooled analyses of data from multiple institutions. Our psychosocial studies included the first CEGRM study of LFS families in which ee found that while the number of friendships varied widely, they were usually deep and enduring and were important sources of informational, tangible and emotional support. Longitudinal follow-up of LFS CEGRM participants is planned to explore whether new cancer diagnoses or the death of affected family members changes the social support networks of participants. We plan to describe the cognitive appraisal of cancer risk and emotional well being in individuals and families with known or suspected LFS or LFL at enrollment in the study and are evaluating data from 300 participants assessed using standardized questionnaires for stress, distress, depression, anxiety, somatization, coping, cancer risk appraisal, and cancer worry. Additionally, we have also incorporated qualitative interviews of LFS families designed to improve understanding of their day-to-day challenges.