A DNA biomarker of oral cancer metastasis

描述（由申请人提供）：对于没有临床明显颈部转移的早期口腔癌患者，确定转移风险对生存至关重要。病理学和分子生物学技术不能准确预测转移。即使是早期口腔癌，隐匿性颈部转移率也大于20%。通常，如果转移的风险为20%或更高，则进行预防性颈清扫术。外科医生通常选择预防性颈淋巴结清扫术，尽管该手术存在风险，因为在癌症诊断时未能手术切除隐匿性（未检测到）颈部转移导致5年生存率降低50%。然而，与该手术相关的风险是令人生畏的：3-4小时的大手术涉及关键解剖结构和发病率，包括中风。尽管如此，对于大多数患者来说，这一程序是一个不必要的，但务实的解决办法所构成的困境隐现的幽灵隐匿性转移。我们的实验室最近发现了一种潜在的基因组生物标志物，可以识别低风险患者 转移。该生物标志物是二元的，如果患者缺乏基因组DNA拷贝数改变+3q、-8p、+8q和+20，则可以识别出低转移风险的患者。这些低风险患者中的肿瘤是所谓的非3q 8 pq 20亚型，而携带一种或多种这些畸变的肿瘤是3q 8 pq 20亚型，并且与转移的实质风险相关。3q 8 pq 20状态是一种有前途的生物标志物，其灵敏度为96%，假阴性率为7%。这项前瞻性生物标志物临床评价研究的主要目标是确定非3q 8 pq 20状态在识别N 0肿瘤患者转移低风险方面的准确性。次要目标是：（a）在存在单个协变量的情况下评估生物标志物的影响。我们将评估我们的生物标志物在存在潜在重要临床因素（患者年龄、性别、烟草和酒精）的情况下是否更有效或更无效。 病史、口腔SCC部位、肿瘤厚度、临床和病理学特征，（B）将3q 8 pq 20生物标志物与其它目前使用的隐匿性转移的预测因子进行比较，和（c）评估生物标志物在预测其它关键临床结果方面是否准确。本R34应用程序的目的是：a）设计和制定临床方案，B）准备基本文件/监管文件夹，c）制定数据管理方案大纲，以满足NIDCR数据管理注意事项文件中详述的“最佳实践建议”（一旦获得适当的资金，将在U 01期间开发基于网络的数据库），d）建立数据安全和监测计划，e）培训和校准研究团队，以实现方案程序、数据收集和数据输入的标准化，以及f）建立研究委员会结构，其中包括执行委员会和独立监督委员会。这些文件、参与者校准和成立的委员会将是R34的可交付成果。

DESCRIPTION (provided by applicant): For patients with early-stage oral cancer who do not have clinically evident neck metastasis, determination of risk for metastasis is critical for survival. Pathologic and molecular techniques do not accurately predict metastasis. Even for early-stage oral cancers, the rate of occult neck metastasis is greater than 20%. Typically a prophylactic neck dissection is performed if the risk for metastasis is 20% or more. Surgeons usually opt for a prophylactic neck dissection despite the risks of the procedure because failure to surgically resect occult (undetected) neck metastasis at the time of cancer diagnosis results in a 50% reduction in 5 year survival. However, risks associated with this procedure are daunting: a 3-4 hour major surgical procedure involving critical anatomic structures and morbidity including stroke. Nonetheless, for most patients this procedure is an unneeded but pragmatic solution to the dilemma posed by the looming specter of occult metastasis. Our laboratories recently discovered a potential genomic biomarker that identifies patients at low risk of metastasis. The biomarker is binary and identifies patients at low risk of metastasis if they lack the genomic DNA copy number alterations +3q, -8p, +8q and +20. Tumors in these low risk patients are of the so-called non- 3q8pq20 subtype, whereas tumors harboring one or more of these aberrations are of the 3q8pq20 subtype and associated with a substantial risk of metastasis. The 3q8pq20 status is a promising biomarker with a sensitivity of 96% and a false negative rate of 7%. The primary goal of this prospective biomarker clinical evaluation study is to determine the accuracy of non-3q8pq20 status in identifying a low risk of metastasis in patients with N0 tumors. Secondary goals are to: (a) assess the impact of the biomarker in the presence of single covariates. We will evaluate whether our biomarker is more or less effective in the presence of potentially important clinical factors: patient age, gender, tobacco and alcohol history, oral SCC site, tumor thickness, clinical and pathologic features, (b) compare the 3q8pq20 biomarker to other currently used predictors of occult metastasis, and (c) assess whether the biomarker is accurate at predicting other key clinical outcome. The Aim of this R34 application is to: a) design and develop the clinical protocol, b) prepare the Essential Documents/Regulatory Binder, c) develop an outline for the data management protocol to meet the "Best Practice Recommendations" detailed in the NIDCR Data Management Considerations document (the web- based database will be developed during the U01 once appropriate funds are available), d) establish a Data Safety and Monitoring plan, e) train and calibrate the research team for standardization of protocol procedures, data collection and data entry, and f) establish the committee structure for the study, which will include an Executive Committee and an Independent Oversight Committee. These documents, participant calibration, and the established committees will be the deliverables for the R34.