A BREATH TEST FOR LUNG CANCER

描述(申请人提供)：背景：在美国，肺癌是癌症死亡的主要原因。一种检测早期疾病的测试可能会减少死亡人数。在两项多中心临床研究中，呼气试验对原发性肺癌具有敏感性和特异性。第三项多中心研究证实了在非癌症对照组中的这些发现，即胸部螺旋CT阴性，以及组织确认的原发性肺癌患者。在对451名受试者的研究中，肺癌VOC生物标志物的两分钟呼气试验结合数据的模糊逻辑分析预测所有TNM分期的敏感性为84.6%，特异性为80.0%，受试者工作特征(ROC)曲线的曲线下面积(AUC)为0.88。预测准确性不受原发肺癌的TNM分期、年龄、性别或吸烟的影响。呼气试验的生物学基础：原发性肺癌的呼气标志物似乎来自其他组织，而不是肿瘤本身。氧化应激的挥发性产物在身体的所有组织中产生，并以烷烃和甲基化烷烃的形式在呼吸中排泄。在肺癌患者中，这些VOCs可能会经历加速的分解代谢，因此它们在呼吸中变化的丰度提供了疾病的生物标志物。在烟草烟雾中多环芳烃诱导的高危细胞色素P450表型(例如，CYP1A1、CYP1A2和CYP2E1)可以快速代谢烷烃及其代谢物。这可能解释了呼气试验在早期(TNM I期)疾病中异常的原因，因为高危细胞色素P450表型的诱导先于肿瘤的发生。研究理由：临床结果需要在一项额外的临床研究中得到确认，以便食品和药物管理局(FDA)在上市前批准呼气测试。实验计划：我们将进行一项横断面多中心研究，以验证先前开发的方法学和预测算法。将对400名匿名受试者进行呼气测试，以比较无癌症对照(胸部螺旋CT阴性)和组织确认的原发性肺癌患者。这将是一项盲目研究：呼吸样本将在两个对诊断盲目的独立实验室进行分析，数据和安全监测委员会将把呼吸测试的预测与临床诊断进行核对，以确定测试的准确性。长期目标：a.科学：验证先前的临床发现。B.商业：获得FDA对该试验的上市前批准(PMA)，以便将其推向市场。研究意义：在临床实践中，呼气试验可以为肺癌的初步检测提供一种安全、非侵入性的辅助试验。其高的阴性预测值(NPV)(&gt；99%)可以可靠地排除无癌正常人中的肺癌。呼气试验对肺癌的生物标志物可能提供一种有价值的新的检测方法，它本质上是安全的、非侵入性的和合理的。呼气测试可能会降低早期发现肺癌的成本，并减少暴露于胸部螺旋CT辐射的患者数量。早期、安全和具有成本效益的肺癌检测可能会减少死于这种疾病的人数。我们将对呼气试验进行肺癌生物标志物的验证研究，以获得食品和药物管理局的上市前批准。这种呼气试验本质上是安全、无创、合理的；它可以降低肺癌早期发现的成本，并减少接受胸部螺旋CT辐射的患者数量。早期、安全和具有成本效益的肺癌检测可能会减少死于这种疾病的人数。

DESCRIPTION (provided by applicant): Background: Primary carcinoma of the lung is the leading cause of cancer death in the United States. A test that detects early-stage disease could potentially reduce the number of deaths. A breath test for volatile organic compounds (VOCs) was sensitive and specific for primary lung cancer in two multicenter clinical studies. A third multicenter study confirmed these findings in cancer-free controls with a negative spiral CT of chest and patients with tissue-confirmed primary lung cancer. In a study of 451 subjects, a two-minute breath test for VOC biomarkers of lung cancer combined with fuzzy logic analysis of data predicted all TNM stages of disease with 84.6% sensitivity, 80.0% specificity and 0.88 area under curve (AUC) of the receiver operating characteristic (ROC) curve. Predictive accuracy was not affected by TNM stage of primary lung cancer, age, sex, or tobacco smoking. Biological basis of the breath test: Breath markers of primary lung cancer appear to emanate from other tissues, not from the tumor itself. Volatile products of oxidative stress are generated in all tissues of the body and excreted in the breath as alkanes and methylated alkanes. In patients with lung cancer, these VOCs may undergo accelerated catabolism, so that their altered abundance in breath provides a biomarker of disease. Alkanes and their metabolites are metabolized rapidly by high risk cytochrome P450 phenotypes (e.g., CYP1A1, CYP1A2 and CYP2E1) whose activity is induced by polycyclic aromatic hydrocarbons in tobacco smoke. This may explain why the breath test was abnormal in early (TNM stage I) disease, because induction of high risk cytochrome P450 phenotypes precedes the onset of neoplasia. Reason for the research: The clinical findings require confirmation in an additional clinical study in order for the Food & Drug Administration (FDA) to award the breath test pre-marketing approval. Experimental plans: We will perform a cross-sectional multicenter study to validate the methodology and the predictive algorithm that were previously developed. Breath tests will be performed in 400 anonymized subjects in order to compare cancer-free controls (with a negative spiral CT of chest) to patients with tissue-confirmed primary lung cancer. This will be a blinded study: breath samples will be analyzed at two independent laboratories blinded to the diagnosis, and a Data and Safety Monitoring Board will collate the predictions of the breath tests with the clinical diagnoses in order to determine the accuracy of the test. Long term aims: a. Scientific: To validate the previous clinical findings. b. Commercial: To obtain FDA pre-marketing approval (PMA) of the test in order to market it. Importance of the research: In clinical practice, the breath test could provide a safe and non-invasive ancillary test for primary detection of lung cancer. Its high negative predictive value (NPV) (>99%) could dependably exclude lung cancer in cancer-free normals. The breath test for biomarkers of lung cancer could provide a valuable new test that is inherently safe, non- invasive, and rational. Breath testing could potentially reduce the costs of early detection of lung cancer, and reduce the number of patients exposed to radiation from spiral CT of chest. Early, safe and cost-effective detection of lung cancer could potentially reduce the number of lives lost to the disease. We will perform a validation study of the breath test for biomarkers of lung cancer in order to obtain pre-marketing approval from the Food & Drug Administration. This breath test is inherently safe, non-invasive, and rational; it could reduce the costs of early detection of lung cancer, and reduce the number of patients exposed to radiation from spiral CT of chest. Early, safe and cost-effective detection of lung cancer could potentially reduce the number of lives lost to the disease.