Intervention Trials in Persons w/ Genetic Risk of Cancer

对有癌症遗传风险的人进行的干预试验

• 批准号: 7065526
• 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/7065526
• 关键词: bone marrow disorder; brca gene; breast neoplasms; cancer prevention; cancer risk; chemoprevention; clinical research; clinical trials; disease /disorder etiology; early diagnosis; family genetics; genetic screening; genetic susceptibility; human genetic material tag; human papillomavirus; human subject; medical outreach /case finding; neoplasm /cancer epidemiology; neoplasm /cancer genetics; neoplasm /cancer radiodiagnosis; ovariectomy; ovary neoplasms; patient oriented research; peritoneum neoplasm; squamous cell carcinoma; virus related neoplasm /cancer

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. (a) 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, a national, prospective follow-up study of genetically at-risk women who elect to undergo risk-reducing salpingo-oophorectomy (RRSO) has been launched (Clinical Center Protocol #02-C-0268; GOG 0199). This is addressing such issues as: (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 this operation? 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 34 sites around the United States. We are in the midst of conducting 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. (b) CGB's second invervention project is a pilot study assessing mammography, MRI and PET imaging as screening tools for women at increased genetic risk of breast cancer (Protocol 02-2-0009). This protocol is actively accruing patients. This project will also assess the impact of menstrual cycle timing on breast MRI imaging characteristics (Protocol 02-C-0008), and provide us with an opportunity to evaluate breast duct lavage, a new technique for obtaining breast duct epithelial cells, as an early diagnosis or risk stratification tool in this setting, and as a potential source of biological materials for molecular genetic studies. Several behavioral studies have been incorporated into the Breast Imaging protocol. These include: (1) a pilot study of a novel tool (the Colored EcoGenetic Relations Map) for documenting individual and family support networks as a guide to genetic counseling; and (2) an assessment of mutation-negative women who persist in following screening programs designed for high-risk women. (c) Our study of persons from families with one of a variety of inherited bone marrow failure syndromes (e.g., Fanconi's anemia) is now open to patient accrual (Clinical Center Protocol #02-C-0052). Among the non-hematologic malignancies which occur excessively in these individuals are squamous cell carcinomas of the oral cavity, esophagus, labia and cervix. Participants in this study are undergoing intensive evaluation in search of both clinical and molecular abnormalities which might represent cancer precursors, particularly with regard to cancers of the head/neck and female genitals. The role of the human papilloma virus (HPV) in the etiology of these cancers will be explored. If suitable clinical or molecular endpoints can be identified, consideration will be given to the development of an intervention program which would target persons from these high-risk families. (d) We are collaborating with colleagues in NCI's Center for Cancer Research by actively recruiting members of our hereditary breast/ovarian cancer families into CCR's newest breast cancer chemoprevention trial, a study of exemestane with or without celecoxib. (e) Plans to initiate a series of Phase II clinical trials (in collaboration with the University of Arizona Cancer Center) among patients with dysplastic nevi, a known melanoma precursor, to seek biologically active compounds which might hold promise as topical skin cancer chemoprevention agents is currently on hold, pending recruitment of additional staff. These studies have evolved from the Arizona Cancer Center's Skin Cancer Chemoprevention Program Project Grant. Candidate agents which would be studied include topical tretinoin (all-trans retinoic acid), 9-cis retinoic acid, diflouromethylornithine (DFMO), epigallotcatechin gallate, perillyl alcohol and sodium salicylate. A panel of surrogate endpoint biomarkers would be employed as indicators of biological activity. This project would represent a natural evolution of DCEG's long-standing interests in hereditary melanoma and melanoma precursors

虽然在识别主要癌症易感基因方面取得的进展令人欣喜，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。我们现在迫切需要安全有效的策略来降低突变携带者患癌症的风险。 DCEG 内部的战略规划过程提出了一项建议，即该司扩大其在干预研究领域的活动，该建议已得到校内司司长的认可。 (a) 在管理携带 BRCA1/2 突变的女性方面，许多紧迫的临床问题之一是预防性卵巢切除术作为降低风险策略的适当作用。与妇科肿瘤学组 (GOG) 和癌症遗传学网络的研究人员合作，一项针对选择接受降低风险输卵管卵巢切除术 (RRSO) 的遗传风险女性的全国性前瞻性随访研究已经启动（临床中心协议#02-C-0268；GOG 0199）。这解决了以下问题：(a) 进行降低风险手术时临床隐匿性卵巢癌的患病率是多少？ (b) 有遗传风险的妇女的卵巢是否存在可识别的先兆病变？ (c) 该手术后原发性腹膜癌和乳腺癌的发生率是多少？ (d) 这种外科手术如何影响选择该手术的女性的生活质量和非肿瘤疾病的发病率？选择保留卵巢的女性正在接受一种新型卵巢癌筛查算法的筛查，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 年夏天开始招募患者，目前正在美国 34 个地点招募患者。我们正在进行一项试点研究，以评估从 GOG 0199 中切除的卵巢中采集卵巢表面上皮细胞的可行性，以降低卵巢癌的遗传风险。我们正在评估这些细胞是否可用于细胞学，基因组和蛋白质组分析。如果试点证明了这一策略的可行性，这些细胞的集合将在有限的机构基础上添加到GOG 0199中。早期数据令人鼓舞。 (b) CGB 的第二个发明项目是一项试点研究，评估乳房 X 线摄影、MRI 和 PET 成像作为乳腺癌遗传风险增加的妇女的筛查工具（方案 02-2-0009）。该方案正在积极招募患者。该项目还将评估月经周期时间对乳腺 MRI 成像特征的影响（方案 02-C-0008），并为我们提供评估乳腺导管灌洗的机会，这是一种获取乳腺导管上皮细胞的新技术，作为早期诊断方法。在这种情况下诊断或风险分层工具，并作为分子遗传学研究的生物材料的潜在来源。多项行为研究已纳入乳房成像方案中。其中包括：（1）一项新工具（彩色生态遗传关系图）的试点研究，用于记录个人和家庭支持网络，作为遗传咨询的指南； (2) 对坚持遵循专为高危女性设计的筛查计划的突变阴性女性进行评估。 (c) 我们对来自患有多种遗传性骨髓衰竭综合征（例如范科尼贫血）之一的家庭的人的研究现已开放给患者应计（临床中心方案#02-C-0052）。在这些个体中过度发生的非血液恶性肿瘤包括口腔、食道、阴唇和子宫颈的鳞状细胞癌。这项研究的参与者正在接受深入评估，以寻找可能代表癌症前兆的临床和分子异常，特别是头/颈癌和女性生殖器癌症。我们将探讨人乳头瘤病毒 (HPV) 在这些癌症病因学中的作用。如果可以确定合适的临床或分子终点，将考虑制定针对这些高危家庭人员的干预计划。 (d) 我们正在与 NCI 癌症研究中心的同事合作，积极招募遗传性乳腺癌/卵巢癌家族成员参加 CCR 最新的乳腺癌化学预防试验，这是一项联合或不联合塞来昔布的依西美坦研究。 (e) 计划在发育异常痣（一种已知的黑色素瘤前体）患者中启动一系列 II 期临床试验（与亚利桑那大学癌症中心合作），以寻找可能有望作为局部皮肤癌化学预防剂的生物活性化合物目前处于搁置状态，等待招聘更多工作人员。这些研究源自亚利桑那州癌症中心的皮肤癌化学预防计划项目拨款。待研究的候选药物包括外用维A酸（全反式视黄酸）、9-顺式视黄酸、二氟甲基鸟氨酸（DFMO）、表没食子儿茶素没食子酸酯、紫苏醇和水杨酸钠。一组替代终点生物标志物将被用作生物活性的指标。该项目将代表 DCEG 对遗传性黑色素瘤和黑色素瘤前体的长期兴趣的自然演变