Introduction: Low-dose computed tomography (LDCT) screening saves lives but is limited by high false-positive rates, necessitating noninvasive risk stratification. The prospective Bio-Multicentric Italian Lung Detection (BioMILD) trial was the first to validate the combination of a plasma microRNA test (MSC) with LDCT to personalize screening intervals. This study integrates a novel immune signature classifier (ISC), based on peripheral blood mononuclear cell profiling, to complement MSC, maximize information from a single blood draw, and further optimize the management of suspicious lung nodules. Methods: Plasma and peripheral blood mononuclear cell samples were prospectively collected from 304 heavy smokers enrolled in the BioMILD trial who presented with LDCT-detected suspicious nodules and a 7.5-year median follow-up. MSC and ISC tests were determined by real-time quantitative polymerase chain reaction. Grafting of patient-derived xenograft models, obtained from the same patients, was used as indicator of tumor aggressiveness. Results: ISC was associated with age (p = 0.0323) and Lung-RADS (p = 0.0008) and was significantly higher in patients with cancers diagnosed within 2 years (p = 0.0006). Higher ISC values also correlated with successful patient-derived xenograft engraftment (p = 0.0449). In terms of diagnostic performance, the combined ISC and MSC model achieved 96% sensitivity and 98% negative predictive value (NPV) (95% confidence interval: 0.93–0.99). It represented a significant enhancement than MSC alone (ΔNPV = +0.05; 95% confidence interval: 0.01–0.08) and resulted in a 37% reduction of false positives. Conclusion: Integration of immune and molecular markers significantly enhances LDCT screening accuracy. The higher NPV achieved by the combined model allows greater confidence in ruling out malignancy among LDCT-detected nodules, thereby reducing unnecessary follow-up examinations and invasive procedures.
Clinical Value of Combining Molecular and Immune Blood Tests to Safely Reduce False Positives in Low-Dose Computed Tomography Lung Cancer Screening / Zanghi, A., Moro, M., Fortunato, O., Segale, M., Sabia, F., Suatoni, P., Ledda, R.E., Rolli, L., Marchiano, A., Pastorino, U., Sozzi, G., Boeri, M.. - In: JOURNAL OF THORACIC ONCOLOGY. - ISSN 1556-0864. - 21:6(2026). [10.1016/j.jtho.2026.103614]
Clinical Value of Combining Molecular and Immune Blood Tests to Safely Reduce False Positives in Low-Dose Computed Tomography Lung Cancer Screening
Ledda R. E.;
2026-01-01
Abstract
Introduction: Low-dose computed tomography (LDCT) screening saves lives but is limited by high false-positive rates, necessitating noninvasive risk stratification. The prospective Bio-Multicentric Italian Lung Detection (BioMILD) trial was the first to validate the combination of a plasma microRNA test (MSC) with LDCT to personalize screening intervals. This study integrates a novel immune signature classifier (ISC), based on peripheral blood mononuclear cell profiling, to complement MSC, maximize information from a single blood draw, and further optimize the management of suspicious lung nodules. Methods: Plasma and peripheral blood mononuclear cell samples were prospectively collected from 304 heavy smokers enrolled in the BioMILD trial who presented with LDCT-detected suspicious nodules and a 7.5-year median follow-up. MSC and ISC tests were determined by real-time quantitative polymerase chain reaction. Grafting of patient-derived xenograft models, obtained from the same patients, was used as indicator of tumor aggressiveness. Results: ISC was associated with age (p = 0.0323) and Lung-RADS (p = 0.0008) and was significantly higher in patients with cancers diagnosed within 2 years (p = 0.0006). Higher ISC values also correlated with successful patient-derived xenograft engraftment (p = 0.0449). In terms of diagnostic performance, the combined ISC and MSC model achieved 96% sensitivity and 98% negative predictive value (NPV) (95% confidence interval: 0.93–0.99). It represented a significant enhancement than MSC alone (ΔNPV = +0.05; 95% confidence interval: 0.01–0.08) and resulted in a 37% reduction of false positives. Conclusion: Integration of immune and molecular markers significantly enhances LDCT screening accuracy. The higher NPV achieved by the combined model allows greater confidence in ruling out malignancy among LDCT-detected nodules, thereby reducing unnecessary follow-up examinations and invasive procedures.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
