Abstract Background Early detection of lung cancer (LC) remains a critical unmet need, as most cases are diagnosed after disease progression. While computed tomography lung screening (CTLS) reduces LC mortality, its impact is limited by low uptake. In the National Lung Screening Trial, the mortality benefit was driven by early detection of lung adenocarcinoma (LUAD), which also represents the predominant subtype in those who never smoked. Circulating extracellular vesicles and particles (EVPs) offer a promising analyte class for cancer detection, carrying molecular cargo reflective of their cellular origin. We developed an EVP-based liquid biopsy assay that quantifies multiple tumor-associated biomarkers co-localized on individual EVPs. We focused on the early detection of LUAD where survival gains are most achievable. Methods The LC Test, consisting of a predefined biomarker panel, classifier, and cutoff, was locked following a training study. A blinded case-control study was conducted using plasma samples from individuals enrolled in a routine LC screening program and from those enrolled in a lung cancer study in those who never smoked. The study included two arms: (1) High-risk participants with a history of tobacco use without evidence of lung cancer (n = 75; 37 Lung-RADS 1, 38 Lung-RADS and participants with LUAD (n = 20; median tumor diameter 1.8 cm), and (2) participants who never smoked without evidence of lung cancer (n = 74) and with LUAD (n = 26; median tumor diameter 2.3 cm). The design enabled evaluation of assay performance in detecting LC arising in both high and average risk individuals, with strong representation of early-stage disease (75.6% Stage I/II). Results At 90% specificity, the LC Test achieved 47.8% overall sensitivity for LUAD and 35.3% for Stage I/II disease in high-risk participants. In those who never smoked, overall sensitivity was 50%, including 31.3% for Stage I/II disease. Biomarker panel test score correlated with predicted tumor size at blood draw (R = 0.60; p = 0.0048) but not with smoking exposure (R = -0.30; p = 0.20). The smallest detected tumor measured 0.8 cm in diameter at imaging. Conclusions The LC Test enables sensitive and specific detection of LUAD in both high-risk individuals undergoing screening and those without a smoking history with incidentally detected disease. Performance was comparable between groups and approaches that of CTLS, supporting its potential as a minimally invasive complement or alternative to imaging-based screening. Further evaluation in larger clinical cohorts is warranted. This abstract is funded by: Mercy BioAnalytics, Inc
Hawkins et al. (2026) studied this question.