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: 10007416
• 负责人: Sharon A. Savage
• 金额: $ 33.54万
• 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/10007416
• 关键词: Adherence; Adrenal Glands; Adult; Affect; Age; Algorithms; Anxiety; Astrocytoma; Atypia; BRCA1 gene; BRCA2 gene; Behavioral trial; Blinded; Blood specimen; Brain; Brain Neoplasms; Breast; Breast Magnetic Resonance Imaging; CA-125 Antigen; Cancer Genetics Network; Cessation of life; Characteristics; Child; Clinical; Cognitive; Collaborations; Computers; Counseling; Data; Data Analyses; Data Analytics; Databases; Decision Making; Development; Diagnosis; Diagnostic; Distress; Duct (organ) structure; Early Diagnosis; Effectiveness; Eligibility Determination; Emotional; Enrollment; Estrogens; Etiology; Evaluation; Face; Family; Family member; Frequencies; Friendships; Future; Genetic; Genetic Risk; Germ-Line Mutation; Glioma; Goals; Gynecologic Oncology Group; Hereditary Malignant Neoplasm; High Risk Woman; Hormones; Image; Individual; Institution; Intelligence; Intervention; Intervention Studies; Intervention Trial; Interview; Irrigation; Learning; Li-Fraumeni Syndrome; Life; Life Style; Liquid substance; Magnetic Resonance Imaging; Malignant Neoplasms; Malignant neoplasm of ovary; Mammalian Oviducts; Mammography; Manuscripts; Measures; Medical; Mental Depression; Molecular; Mucous Membrane; Mutation; Natural History; Oncogenes; Operative Surgical Procedures; Participant; Pathogenesis; Pathology; Patients; Performance; Persons; Pilot Projects; Population; Predisposition; Premenopause; Prevalence; Protocols documentation; Psychosocial Assessment and Care; Publications; Publishing; Quality of life; Quantitative Evaluations; Questionnaires; Regimen; Reproducibility; Research Personnel; Risk; Risk Management; Risk Reduction; Salpingo-Oophorectomy; Schedule; Screening for Ovarian Cancer; Screening for cancer; Series; Serum; Shapes; Signal Transduction; Social Change; Social support; Source; Standardization; Stress; Syndrome; TP53 gene; Test Result; Texture; Time; Tissues; Tumor Debulking; United States National Institutes of Health; Well in self; Woman; Work; arm; base; breast cancer diagnosis; breast imaging; cancer diagnosis; cancer risk; cohort; coping; design; digital; follow-up; high risk; imaging study; improved; leukemia; malignant breast neoplasm; mutation carrier; nipple aspirate fluid; novel; ovarian cancer prevention; prospective; protective effect; psychosocial; research study; response; risk perception; screening; screening program; surgical risk; uptake

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.

针对卵巢癌遗传风险增加的女性（又名 GOG-199）的国家卵巢癌预防和早期检测研究 [CAS 7210] 是 CGB 干预研究组合的基石。这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）的非随机自然历史研究。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，最终分析数据库现已完成。迄今为止取得的最新成就包括：(1) 将 1,576 名筛查受试者纳入一项已发表的汇总分析（癌症遗传学网络：总计 = 4,000 名受试者），该分析涉及基线 CA-125 水平和 ROCA 算法性能特征的决定因素，该分析表明绝经前妇女的正常截止上限应为 52，而不是通常使用的 35； (2) 继续与寻找 BRCA1/2 相关乳腺癌和卵巢癌风险的基因修饰剂合作，这项工作已发表 40 篇已发表的手稿，另外 7 篇目前正在审查中； (3) 接受 RRSO 的无症状女性中临床隐匿性卵巢癌患病率的量化：966 例 GOG-09199 RRSO 中的 25 例 (2.6%)（BRCA1 携带者=4.6%，BRCA2 携带者=3.5%，非携带者=0.5%） (p=0.0006)；(4) 记录高风险女性将遵守卵巢癌筛查该计划需要每 3 个月提供一次血液样本，一种方案（ROCA：卵巢癌风险算法）可在卵巢癌病例中产生显着的阶段下降，允许在几乎所有新病例中进行最佳手术减瘤，并识别出约 50%在新癌症超过 35 IU/ml 的标准 CA125 截止值之前，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) 证明了诊断的重复性较差。在盲法病理学审查中发现输卵管粘膜异型性，说明需要改进诊断标准 (6) 使用 GOG-0199 研究参与者的前瞻性随访来确定先前描述的与 RRSO 相关的乳腺癌保护作用可能并不像之前描述的那样正如之前估计的那样大。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）以及分析本研究中，有 381 名从筛查组转入手术组的女性进行了医疗决策。 针对 BRCA 突变阳性家庭女性的乳腺影像试点研究实现了其应计目标，前瞻性随访现已结束。该项目的最新发现包括：(1) 识别出数字乳房 X 光照片的计算机提取特征，即“乳房 X 光纹理”，该特征的存在表明受影响患者成为 BRCA1/2 突变携带者的可能性增加了两倍; (2) 与 FDA 研究人员合作，开发用于定量评估乳腺 MRI 图像的拟人模型； (3) 证明雌激素及其代谢物的循环水平与直接从乳房获得的液体（乳头抽吸液；乳腺导管灌洗上清液）测量的水平呈非常强的正相关，这一发现表明未来的病因学研究可以利用更容易获得血清激素水平作为组织水平暴露的可靠替代指标。 (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剂； (5) 对乳腺影像研究患者数据进行的心理社会分析表明，假阳性癌症筛查测试结果与癌症风险感知、癌症担忧或降低风险手术的接受率增加无关。然而，对癌症的担忧是接受降低风险手术的独立预测因素。在向高危妇女提供有关降低风险干预措施的咨询时，值得考虑这一领域； (6) 以及针对非常年轻（25 岁以下）突变携带者特殊需求的具有里程碑意义的系列出版物（共 6 份），这些人群在寻找伴侣、进入世界等塑造人生的决定时面临着特别具有挑战性的发展挑战工作、考虑组建家庭，所有这些都是出于对 BRCA 相关癌症风险管理的担忧，包括强化筛查和降低风险手术的需要。李法美尼综合征 (LFS) 是一种高度渗透性癌症易感综合征最常由 TP53 种系突变引起，并与儿童和成人的脑癌、肾上腺癌、乳腺癌、白血病以及许多其他恶性肿瘤相关。癌症筛查部分是 2012 年 6 月在 NIH 临床中心开展的大型 LFS 研究的一个组成部分。到 2014 年中期，已有 200 多名 TP53 个体符合资格并入组。由于对开放方案的反应热烈而迅速，我们实现了临床队列的初始累积目标，并于 2014 年 12 月结束了临床队列的累积。迄今为止，我们已筛选了总共 115 名参与者，并进行了一系列随访1-5年。乳腺癌诊断是通过乳腺 MRI 筛查进行的，靶向脑部 MRI 识别出两种脑肿瘤（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患有癌症。我们将根据筛查方案检测早期癌症的能力、间期癌症的发展、假阳性筛查结果的频率以及参与者遵守严格的时间表来分析筛查方案的有效性。我们的数据还将纳入对多个机构的数据进行更大规模的汇总分析。我们的心理社会研究包括第一个针对 LFS 家庭的 CEGRM 研究，其中 ee 发现，虽然友谊的数量差异很大，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，以探讨新的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。我们计划描述在参加研究时已知或疑似 LFS 或 LFL 的个人和家庭对癌症风险和情绪健康的认知评估，并正在评估 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 LFS 家庭的定性访谈，旨在加深对他们日常挑战的了解。