A BREATH TEST FOR LUNG CANCER

背景：原发性肺癌是美国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，挥发性有机化合物（VOCs）呼气试验对原发性肺癌具有敏感性和特异性。第三项多中心研究在胸部螺旋CT阴性的无癌对照和组织确诊的原发性肺癌患者中证实了这些发现。在一项451名受试者的研究中，肺癌VOC生物标志物的两分钟呼吸试验结合数据的模糊逻辑分析预测了所有TNM阶段的疾病，灵敏度为84.6%，特异性为80.0%，受试者工作特征（ROC）曲线下面积（AUC）为0.88。预测准确性不受原发性肺癌TNM分期、年龄、性别或吸烟的影响。呼吸试验的生物学基础：原发性肺癌的呼吸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出。在肺癌患者中，这些挥发性有机化合物可能会加速分解代谢，因此它们在呼吸中含量的改变提供了疾病的生物标志物。烷烃及其代谢物被烟草烟雾中多环芳烃诱导的高危细胞色素P450表型（如CYP1A1、CYP1A2和CYP2E1）快速代谢。这也许可以解释为什么呼吸试验在早期（TNM期I）疾病中异常，因为在肿瘤发生之前，高危细胞色素P450表型的诱导。研究原因：临床研究结果需要在额外的临床研究中得到证实，以便食品和药物管理局（FDA）批准呼气测试上市前的批准。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和预测算法。将对400名匿名受试者进行呼吸测试，以比较无癌对照（胸部螺旋CT阴性）和组织确诊的原发性肺癌患者。这将是一项盲法研究：呼吸样本将在两个独立的实验室进行分析，对诊断不知情，数据和安全监测委员会将核对呼吸测试的预测结果与临床诊断，以确定测试的准确性。长期目标：a.科学性：验证之前的临床发现。b.商业化：获得FDA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，呼吸试验可为肺癌的原发性检测提供一种安全、无创的辅助检测方法。其高阴性预测值（NPV）（约99%）可可靠地排除无癌正常人的肺癌。肺癌生物标志物的呼吸测试可以提供一种有价值的新测试，其本质上是安全的，非侵入性的和合理的。呼吸测试可能会降低肺癌早期检测的成本，并减少胸部螺旋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因该疾病而丧生的人数。我们将对肺癌生物标志物呼气测试进行验证研究，以获得美国食品和药物管理局的上市前批准。这种呼吸测试本质上是安全的、非侵入性的和合理的；它可以降低肺癌早期检测的成本，减少胸部螺旋CT辐射患者的数量。早期、安全和具有成本效益的肺癌检测可能会减少因该疾病而丧生的人数。

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.