Liquid Biopsy-Based Pre-Screening to Streamline LDCT Lung Cancer Screening in High-Risk Individuals

Lung cancer remains the leading cause of cancer-related mortality worldwide, largely due to late-stage diagnosis. Low-dose computed tomography (LDCT) has been shown to reduce lung cancer mortality in high-risk populations; however, its population-level implementation is limited by high false-positive rates, radiation exposure, cost, and poor uptake. These challenges are particularly relevant in Asian populations, where a substantial proportion of lung cancer occurs among never-smokers, for whom optimal screening strategies remain unclear.

Recent advances in liquid biopsy technologies have enabled the detection of circulating tumor-derived signals, including DNA methylation patterns and extracellular vesicle-associated biomarkers, offering a minimally invasive approach for early cancer detection. Multimodal liquid biopsy assays may serve as an effective pre-screening tool to identify individuals who are unlikely to have lung cancer and who may not require immediate LDCT screening.

This prospective, interventional study aims to evaluate the feasibility, diagnostic performance, and potential cost-effectiveness of a multimodal liquid biopsy-based assay as a pre-screening strategy prior to LDCT for lung cancer screening in high-risk individuals. The study includes three cohorts: (1) Healthy but high-risk individuals, without a prior diagnosis of lung cancer, (2) patients with early-stage lung cancer (Stage I-II), and (3) patients with advanced-stage lung cancer (Stage III-IV).

Healthy, but high-risk individuals will undergo blood collection for two liquid biopsy assays: a genome-wide DNA methylation-based assay (SPOT-MAS) and an exosome-based biomarker assay. All healthy individuals will subsequently undergo LDCT thorax screening. In cases where the SPOT-MAS result is positive but LDCT findings are negative, participants will be offered a study-funded CT-PET scan, within 3 months of blood collection to further evaluate the presence of malignancy. If CT-PET is negative, participants will be referred for further follow-up tests, e.g., Oesophago-Gastro-Duodenoscopy (OGD) / colonoscopy/ mammogram (funded by the study) or no further tests, at physician's discretion. Healthy, high-risk volunteers with positive LDCT results will be referred to a respiratory physician for further evaluation as per routine clinical pathway (not funded by the study). Healthy, high-risk individials who are negative on both tests will have no further study-mandated visits. In rare cases where the SPOT-MAS result is inconclusive, a second blood sample (10 mL) will be collected after 1month but within 6 months after the first blood draw.

Early- and advanced-stage lung cancer patients will undergo blood collection for liquid biopsy testing only, to assess assay performance across different disease stages.

The primary outcomes include the negative predictive value of the liquid biopsy assays and the proportion of high-risk individuals who could potentially be spared LDCT screening based on negative liquid biopsy results. Secondary outcomes include the sensitivity, specificity, and predictive values of the assays compared with imaging and clinical diagnosis, as well as exploratory analyses of the cost-effectiveness of a liquid biopsy-guided screening strategy.

By evaluating a blood-based pre-screening approach integrated with imaging, this study aims to inform more efficient and personalized lung cancer screening strategies that may reduce unnecessary imaging, radiation exposure, and healthcare costs, while maintaining early detection performance in high-risk populations.