Autoantibodies in NSCLC as Markers for Disease

描述(由申请人提供)：在基于人群的CT筛查试验中，仅使用年龄和吸烟史作为选择标准，以高昂的成本提供了低产量的癌症检测。此外，在CT筛查中对不确定肺结节的常规识别通常需要额外的检查，放大了成本，并增加了相关介入诊断程序的潜在发病率。我们已经开发了一种用于非小细胞肺癌的血液检测，当整合到早期检测范例中时，可能会解决这些限制。具体地说，我们利用肺癌患者的扩张性自身抗体库来开发一种补偿非小细胞肺癌异质性的多标记物分析。捕获蛋白是使用患者血浆中的抗体从cdna肿瘤文库中选择出来的，然后用来测量肿瘤相关抗体作为疾病的标志。采用荧光微阵列作为平台，以适应多标记方法。通过病例样本和对照样本之间的统计差异对单个标记进行排序，并使用接收器操作特征(ROC)来统计地定义具有较高区分值的标记的最佳组合。然后，在已知的病例和对照样本上建立组合标记集的分类器，并用于预测可用样本中的疾病。性能结果表明，该系统具有很好的临床应用潜力。在成功完成该项目的生物标记物发现阶段后，目前的建议有三个主要目标：1)评估在扩大的临床人群中诊断的已确诊肺癌的检测性能；2)确定该检测在不依赖于筛查研究的放射学识别的不确定肺结节的管理中的作用；以及3)确认表明该标记物集可以在筛查人群中进行放射检测之前发现癌症和预测非小细胞肺癌发病的结果。与公共卫生的相关性。肺癌的血液检测可以提高早期发现的能力和成本效益，作为降低这种疾病死亡率的可行策略。

DESCRIPTION (provided by applicant): The use of only age and smoking history as selection criteria in population-based CT screening trials has afforded a low yield of cancer detection at significant cost. Moreover, the routine identification of indeterminate pulmonary nodules during CT screening often requires additional workup, magnifying the cost and adding potential morbidity from related interventional diagnostic procedures. We have developed a blood test for NSCLC that may address these limitations when integrated into the early detection paradigm. Specifically, we exploited the expansive autoantibody repertoire of lung cancer patients to develop a multi-marker assay that compensates for NSCLC heterogeneity. Capture proteins were selected from cDNA tumor libraries using antibodies in patient plasma and in turn used to measure tumor-associated antibodies as markers of disease. Fluorescent microarray was adapted as a platform to accommodate a multiple marker approach. Individual markers were ranked by statistical differences between case and control samples, and Receiver Operating Characteristic (ROC) was used to statistically define an optimal combination of those markers with high discriminatory value. Classifiers for a combined marker set were then built on known case and control samples and used to predict disease in available samples. Performance results indicate excellent potential for clinical utility. Having successfully completed the biomarker discovery phase of this project, the current proposal has three primary objectives: 1) To evaluate assay performance for established lung cancer diagnosed in an expanded clinical population 2) to define a role for this assay in management of radiographically identified indeterminate pulmonary nodules independent of a screening study, and 3) to confirm results that indicate this marker set may detect cancer and predict the onset of NSCLC prior to radiographic detection in a screened population. Relevance to Public Health. A blood test for lung cancer could improve the capability and cost- effectiveness of early detection as a viable strategy for reducing mortality from this disease.