Abstract A36: Breath Biomarkers in the Post NLST-era for the Discrimination between Malignant from Benign Pulmonary Nodules
Authors: Peled Nir , Hirsch Fred R. , Haick Hossam , Hakim Meggie , Tisch Ulrike , Bunn Paul A. , Miller York E. , Kennedy Timothy C. , Mattei Jane , Mitchell John D. , Weyant Michael J. 
Published: March 2013

Abstract
Background: The recent National Lung Cancer Screening Trial (NLST) has proven that screening for lung cancer by low dose CT (LDCT) scans reduces the related mortality rate by 20%. However, in this program, the false positive rate was extremely high: 96% out of the 24% positive CT findings were non-cancerous. A high rate of false positives leads to unnecessary invasive procedures, which are both costly and associated with significant morbidity and mortality. It is now widely anticipated that LDCT screening programs will be launched in many countries in the near future. This will lead to a dramatically increased detection of small solitary pulmonary nodules (SPNs) for invasive investigation. Consequently, additional non-invasive biomarker approach to distinguish between benign and cancerous conditions is necessary. For that purpose, we evaluated in this study the role of exhale breath analysis as a potential non-invasive biomarker to discriminate between benign and malignant SPNs in the post NLST-era.
Objectives: Developing a signature of volatile organic compounds (VOCs) in the exhaled breath that aids to distinguishes between benign and cancerous SPNs, and therefore also aids in 1) Early detection of lung cancer, 2) Improves the specificity of the NLST screening protocol in high risk cohorts, 3) helps prevent unnecessary invasive procedures, 4) results in the early treatment of lung cancer, and 5) Improves the costeffectiveness of the NLST screening program. Specifically, in this study we report the VOCs signature that discriminates benign from malignant SPNs, between NSCLC and SCLC and between early and advanced NSCLC.
Methods: Cross-sectional comparative survey from 74 patients with solitary pulmonary nodules (SPNs) attending the University of Colorado Cancer Center or Denver Veterans Affairs Medical Center; USA. Breath samples were taken and the VOC profiles for malignant and benign lung nodules were determined by gas-chromatography/mass-spectrometry (GCMS), and the corresponding collective VOCs patterns were identified by a nanomaterialbased array of sensors.
Results: Among the 74 high risk patients with SPNs on their LDCTs, 53 were malignant and 21 were benign. Age, smoking history, co-morbidity and medications were similar in both groups. Nodule sizes were 2.7±1.7 cm vs. 1.9±1.1 cm accordingly (NS). Within the malignant group, 47 were NSCLC and 6 were SCLC. Thirty had early disease (stage I-II/limited) and 23 had advanced disease (stage III-IV/extensive).
GC-MS analysis identified two VOCs in the exhaled breath of nodule positive patients that showed statistically significant differences in concentration for benign and malignant lung nodules (N=11, 28 respectively; Benzene, 1-methyl-4-(1-methylethyl) and 1-Octene). The sensor array could distinguish between the corresponding collective VOCs patterns with an accuracy of 89.4%. Among the malignant SPNs we could further distinguish between SCLC and NSCLC (accuracy 93.9%) and between early and advanced disease (89.7%).
Conclusions: An array of nanomaterial-based sensors could discriminate significantly between benign and malignant SPNs in a high-risk cohort with positive LDCTs based on lung cancer related VOCs profiles. Further, it was able to discriminate between NSCLC and SCLC, as well as between early and advanced disease. These results could promote the development of a non-invasive, fast and potentially cost-effective diagnostic tool for the management of nodule-positive patients that could help to eliminate risky invasive procedures in patients with benign nodules in the post NLST-era.