Breath analysis of volatile organic compounds with mid-infrared laser spectroscopy in a cohort of lung cancer patients and control subjects.

8029 Background: Exhaled volatile organic compounds (VOCs) represent potential non-invasive biomarkers for lung cancer detection. This study assessed a mid-infrared cavity ring-down spectroscopy (CRDS) platform for measuring key breath VOCs in a large clinical cohort including lung cancer patients across stages/histologies, carcinoma in situ, and non-cancer controls. Methods: This prospective single-center validation study enrolled 1,041 participants: approximately 500 with pathologically confirmed lung cancer (various stages and histologies), 25 with carcinoma in situ, healthy controls, patients with benign pulmonary diseases, and those with low- and high-risk pulmonary nodules. Breath samples were collected under standardized fasting and mouth-rinsing conditions and analyzed using a self-developed mid-infrared CRDS system targeting isoprene, acetone, and formaldehyde (detection limit 85% power at α = 0.05. Group comparisons used independent t-tests or Mann-Whitney U tests with Bonferroni correction for multiple testing. Predictive modeling employed logistic regression and machine learning (random forest and XGBoost) with 5-fold cross-validation; feature importance and SHAP values were assessed. Performance metrics included AUC, sensitivity, specificity, and 95% confidence intervals (CI). Results: Isoprene exhibited the most consistent group differences across comparisons (P < 0.001 in lung cancer vs healthy and carcinoma in situ vs healthy). Random forest and XGBoost models yielded AUC of 0.94 (95% CI, 0.92-0.96) for lung cancer vs healthy controls and 0.97 (95% CI, 0.95-0.99) for carcinoma in situ vs healthy controls. At optimal thresholds, sensitivity and specificity reached 90-96% and 92-95%, respectively, in primary analyses. Subgroup performance remained robust in non-smokers and stage I patients. Decision curve analysis demonstrated net clinical benefit across 1-20% risk thresholds compared with low-dose CT screening strategies. Acetone and formaldehyde provided supplementary contributions in pathological subtype and benign disease distinctions. Conclusions: Mid-infrared CRDS-based breath VOC analysis shows feasible diagnostic performance for lung cancer detection, including strong results in carcinoma in situ and early-stage disease, in this large cohort. Multi-center prospective validation is needed to confirm clinical utility and integration into screening strategies.