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) 在这一进程的同时，我们已开始努力支持目前在 NCI 癌症研究中心正在进行的乳腺癌和结肠癌化学预防试验，敦促我们的易患癌症家庭的成员参与这些重要的研究，并协调感兴趣者的转诊。目前正在招募患者的试验包括一项使用选择性雌激素受体调节剂雷洛昔芬的 II 期乳腺癌预防试验（对乳腺癌风险增加的女性开放），以及一项使用选择性 COX-2 抑制剂塞来昔布的 II 期结肠癌试验（针对遗传性非息肉病性结直肠癌综合征家族成员）。 (b) 还在讨论的还有是否有可能在发育不良痣（一种已知的黑色素瘤前兆）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。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。将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。 (c) 一项关于 1000 名患有前列腺癌的阿什肯纳兹以色列人中 BRCA1/2 创始人突变患病率的研究为前列腺癌是具有 BRCA 突变的男性疾病谱的一部分这一假设提供了额外的支持。现在已经开始与泌尿肿瘤科/癌症研究中心的合作者讨论设计前列腺癌干预试验的可能性，该试验将针对来自 CGB 突变阳性遗传性乳腺癌/卵巢癌家族队列的男性。 (d) 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将于 2002 年初开放给患者招募。这些人中过度发生的非血液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深入评估，以寻找可能代表癌症前兆的临床和分子异常。我们将探讨人乳头状瘤病毒 (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。 (e) 一个有待解决的问题是，CGB 在针对遗传高危人群的国家、多机构 III 期干预试验的规划、实施和分析中可能发挥的作用，可能与癌症遗传学网络、乳腺癌、结肠癌合作家谱登记处、早期检测资源网络、特定地点 SPORES 等组织合作。这个问题很可能需要正式考虑针对以下妇女开展 III 期随机化学预防试验的可能性：是 BRCA1/2 基因突变的携带者。目前，美国还没有一个组织具备进行此类研究所需的全部能力。临床试验合作小组拥有与开展大型随机研究相关的专业知识、资源和基础设施，但历史上无法接触到遗传高危人群。同样，CGN 和 CFR 可以获得合适的研究对象，但没有进行临床试验的经验。临床遗传学分支可能处于最佳位置，可以在此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.