Interventions for People at Increased Risk of Cancer

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)在这一进程的同时，我们已经开始努力支持NCI癌症研究中心目前正在进行的乳腺癌和结肠癌化学预防试验，方法是敦促我们的癌症高发家庭成员参与这些重要的研究，并协调有兴趣的人的转介。目前正在招收患者的试验包括使用选择性雌激素受体调节剂雷洛昔芬的第二阶段乳腺癌预防试验[对乳腺癌风险增加的女性开放]，以及使用选择性COX-2抑制剂塞来昔布的第二阶段结肠癌试验[针对遗传性非息肉病性结直肠癌综合征家族成员]。(B)还在讨论在发育不良痣患者中启动一系列第二阶段临床试验的可能性(与亚利桑那大学癌症中心合作)，这是一种已知的黑色素瘤前体，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。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。(C)一项关于在1000名患有前列腺癌的德系以色列人中BRCA1/2创始人突变的流行率的研究为前列腺癌是BRCA突变男性疾病谱的一部分的假设提供了额外的支持。现在已经开始与泌尿外科肿瘤学分部/癌症研究中心的合作者讨论设计一项前列腺癌干预试验的可能性，该试验将针对CGB突变阳性遗传性乳腺癌/卵巢癌家族中的男性。(D)我们对患有多种遗传性骨髓衰竭综合症(例如范可尼氏贫血)家族的患者的研究将于2002年初开始。在这些人中过度发生的非血液病恶性肿瘤包括口腔和食道的鳞状细胞癌。这项研究的参与者将接受密集的评估，以寻找可能代表癌症前期的临床和分子异常。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。(E)有待解决的一个问题是，CGB可能在规划、进行和分析针对遗传高危人群的国家、多机构第三阶段干预试验方面发挥作用，或许可以与癌症遗传学网络、乳腺癌、结肠癌家庭合作登记中心、早期检测资源网络、特定地点孢子等组织合作。目前，美国还没有一个组织具备开展此类研究所需的全部能力。临床试验合作小组拥有与进行大型随机研究相关的专业知识、资源和基础设施，但从历史上讲，他们无法接触到遗传高危人群。同样，CGN和CFR可以接触到合适的研究对象，但没有进行临床试验的经验。临床遗传学分部可能处于最有利的位置，在这类研究中发挥核心作用。

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) Concurrent with this process, we have initiated efforts to support the breast cancer and colon cancer chemoprevention trials currently underway within NCI's Center for Cancer Research by urging members of our cancer-prone families to participate in these important studies, and coordinating referrals for those who are interested. Trials currently accruing patients include a Phase II breast cancer prevention trial [open to women at increased risk of breast cancer] utilizing the selective estrogen receptor modulator raloxifene, and a Phase II colon cancer trial [targeting members of hereditary nonpolyposis colorectal cancer syndrome families] employing the selective COX-2 inhibitor, celecoxib. (b) Also under discussion is the possibility of initiating 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. 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. (c) A study of the prevalence of BRCA1/2 founder mutations is among 1000 Ashkenazi Israelis with prostate cancer has provided additional support for the hypothesis that prostate cancer is part of the disease spectrum for men with BRCA mutations. Discussions have now begun with collaborators from the Urological Oncology Branch/Center for Cancer Research regarding the possibility of designing a prostate cancer intervention trial that would target the men from CGB's cohort of mutation-positive hereditary breast/ovarian cancer families. (d) Our study of persons from families with one of a variety of inherited bone marrow failure syndromes (e.g., Fanconi's anemia) will open to patient accrual in early 2002. Among the non-hematologic malignancies which occur excessively in these individuals are squamous cell carcinomas of the oral cavity and esophagus. Participants in this study will undergo intensive evaluation in search of both clinical and molecular abnormalities which might represent cancer precurosrs. 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. (e) An issue yet to be resolved is the role that CGB might play in the planning, conduct and analysis of national, multi-institutional Phase III intervention trials which target genetically high-risk populations, perhaps in collaboration with such organizations as the Cancer Genetics Network, the Cooperative Family Registries for Breast, Colon Cancer, the Early Detection Resource Network, site-specific SPORES, etc. This issue is most likely to require formal consideration with regard to the possibility of mounting a Phase III randomized chemoprevention trial for women who are carriers of mutations in the BRCA1/2 genes. At present, there is no single organization in the United States with all of the capabilities required to undertake such a study. The clinical trials cooperative groups have expertise, resources and infrastructure relative to the conduct of large randomized studies, but historically have not had access to genetically high-risk populations. Similarly, CGN and CFR have access to the right kind of study subjects, but no experience in the conduct of clinical trials. The Clinical Genetics Branch may be optimally positioned to play a central role in such studies.