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。 (a)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（临床中心方案#02-C-0268; GOG 0199）。这是解决这样的问题：（a）在降低风险的手术时，临床隐匿性卵巢癌的患病率是多少？(b)在有遗传风险的妇女的卵巢中是否存在可识别的前驱病变？(c)手术后原发性腹膜癌和乳腺癌的发生率是多少？以及（d）这种外科手术如何影响选择这种手术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34个研究中心招募患者。我们正在进行一项试点研究，以评估从卵巢中收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。 (b)广发银行的第二个研究项目是评估乳腺X线摄影、MRI和PET成像作为乳腺癌遗传风险增加的妇女筛查工具的试点研究（方案02-2-0009）。该方案正在积极增加患者。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），并为我们提供一个机会来评估乳腺导管灌洗，一种获得乳腺导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，并作为分子遗传学研究的生物材料的潜在来源。几项行为研究已纳入乳腺成像方案。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)我们的研究对象是来自患有多种遗传性骨髓衰竭综合征之一的家庭的人（例如，范可尼贫血）现在对患者招募开放（临床中心方案#02-C-0052）。在这些个体中过度发生的非血液学恶性肿瘤是口腔、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的癌症。人类乳头状瘤病毒（HPV）在这些癌症的病因中的作用将被探讨。如果能够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，这是一项关于塞来昔布联合或不联合西司坦的研究。 (e)在患有发育不良痣（一种已知的黑色素瘤前体）的患者中启动一系列II期临床试验（与亚利桑那大学癌症中心合作）的计划，以寻求可能有希望作为局部皮肤癌化学预防剂的生物活性化合物，该计划目前被搁置，等待招募更多的工作人员。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拨款演变而来的。待研究的候选药物包括局部用维甲酸（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。将采用一组替代终点生物标志物作为生物活性的指标。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。

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.