Clinical Value of Combining Molecular and Immune Blood Tests to Safely Reduce False Positives in Low-Dose Computed...

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.

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.

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.

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.