Intervention Trials in Persons at Increased Genetic Risk

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。 (A)在处理携带BRCA1/2突变的妇女的许多紧迫临床问题中，预防性卵巢切除术作为一种降低风险的策略的适当作用。与妇科肿瘤学小组(GOG)和癌症遗传学网络的研究人员合作，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后续研究(临床中心议定书#02-C-0268；GOG 0199)。这涉及以下问题：(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)该手术后的原发性腹膜癌病和乳腺癌的发生率是多少？以及(D)这种外科手术对选择该手术的妇女的生活质量和非肿瘤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年夏天开始实施，目前正在全美34个地点收集患者。我们正在进行一项试点研究，以评估从卵巢中提取卵巢表面上皮细胞的可行性，这些卵巢表面上皮细胞被切除以降低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。 (B)CGB的第二个逆转项目是一项试点研究，评估乳房X光检查、核磁共振成像和PET成像作为乳腺癌遗传风险增加的妇女的筛查工具(第02-2-0009号议定书)。这一方案正在积极积累患者。这个项目还将评估月经周期对乳腺MRI成像特征的影响(协议02-C-0008)，并为我们提供一个机会来评估乳管灌洗，一种获得乳管上皮细胞的新技术，作为这种情况下的早期诊断或风险分层工具，以及作为分子遗传学研究的潜在生物材料来源。几项行为研究已被纳入乳房成像协议。这些措施包括：(1)对一种新工具(彩色生态遗传关系图)进行试点研究，以记录个人和家庭支持网络，作为遗传咨询的指南；以及(2)对坚持遵循为高危女性设计的筛查计划的突变阴性女性进行评估。 (C)我们对患有多种遗传性骨髓衰竭综合征(如Fanconi‘s贫血)家族的患者的研究现在向患者开放(临床中心协议#02-C-0052)。在这些人中过度发生的非血液病恶性肿瘤包括口腔、食道、阴唇和宫颈的鳞状细胞癌。这项研究的参与者正在接受密集的评估，以寻找可能代表癌症前兆的临床和分子异常，特别是关于头/颈部和女性生殖器癌症。人类乳头瘤病毒(HPV)在这些癌症的病因学中的作用将被探索。如果可以确定合适的临床或分子终点，将考虑制定干预计划，以这些高危家庭的患者为目标。 (D)我们正在与NCI癌症研究中心的同事合作，积极招募我们的遗传性乳腺癌/卵巢癌家族成员参加CCR最新的乳腺癌化学预防试验，这是一项使用或不使用塞来昔布的西美坦研究。 (E)计划(与亚利桑那大学癌症中心合作)在发育不良痣(一种已知的黑色素瘤前体)患者中启动一系列第二阶段临床试验，以寻找可能作为局部皮肤癌化学预防药物的生物活性化合物目前被搁置，等待招聘更多工作人员。这些研究是从亚利桑那州癌症中心的皮肤癌化学预防计划项目赠款演变而来的。将研究的候选药物包括外用维甲酸(全反式维甲酸)、9-顺式维甲酸、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记物将被用作生物活动的指示器。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。

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.