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

A Multimodal Liquid Biopsy-Based Assay as a Pre-Screening Test Before Low Dose CT Thorax (LDCT) to Streamline Lung Cancer Screening in High-Risk Individuals

This study evaluates the feasibility and cost-effectiveness of using a blood-based liquid biopsy assay as a pre-screening tool before low-dose CT (LDCT) for lung cancer screening. By identifying individuals unlikely to have lung cancer, this approach aims to reduce unnecessary LDCT scans, radiation exposure, and healthcare costs, while improving early detection, particularly among high-risk individuals including never-smokers with a family history of lung cancer.

Study Overview

• Status: Recruiting
• Conditions: Lung Neoplasms; Lung Cancer; Cancer Screening; Early Lung Cancer Detection; High-Risk Populations
• Intervention / Treatment: Diagnostic test: Liquid Biopsy (SPOT-MAS Assay); Diagnostic test: Exosome-Based Liquid Biopsy Assay; Diagnostic test: Low-Dose CT Thorax (LDCT)

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 140
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Singapore
  • Singapore, Singapore, 119228
    • Recruiting
    • National University Hospital Singapore
    • Sub-Investigator: Kenneth Sooi
    • Sub-Investigator: Ross Soo
    • Contact: Soo-Chin Lee, MMed; Phone Number: +6569082222; Email: soo_chin_lee@nuhs.edu.sg
    • Principal Investigator: Soo-Chin Lee
    • Principal Investigator: Kang Hoe Lee
    • Sub-Investigator: Mamta Ruparel
    • Sub-Investigator: Adrian Kee
    • Sub-Investigator: See Kay Choong
    • Sub-Investigator: Yiqing Huang
    • Sub-Investigator: Jeffrey Shuen Kai Ng

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria

High-Risk Individuals (n = 100)

• No prior history of lung cancer

• Meets one of the following high-risk definitions:

  • Current or former smoker (quit within the past 15 years), aged 55-74 years, with a smoking history of ≥30 pack-years; OR
  • Never-smoker aged 55-75 years with a first-degree family history of lung cancer
• Able and willing to provide written informed consent

Early-Stage Lung Cancer Patients (n = 20)

• Aged ≥21 years
• Histologically or clinically confirmed stage I-II lung cancer
• Treatment-naïve (no prior surgery, chemotherapy, radiotherapy, or immunotherapy for lung cancer)
• Able and willing to provide written informed consent

Advanced-Stage Lung Cancer Patients (n = 20)

• Aged ≥21 years
• Histologically or clinically confirmed stage III-IV lung cancer
• Treatment-naïve (no prior systemic or local therapy for lung cancer)
• Able and willing to provide written informed consent

Exclusion Criteria

Applicable to All Participants

• Pregnant or breastfeeding women
• Inability or unwillingness to comply with study procedures

High-Risk Individuals Only

• Known allergy or contraindication to CT contrast agents
• Prior low-dose CT (LDCT), CT thorax, or PET-CT performed within 12 months prior to enrollment

Lung Cancer Cohorts Only

• Receipt of any prior cancer-directed treatment for lung cancer

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Screening
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: High-Risk Individuals Without Known Lung Cancer; High-risk individuals without a prior diagnosis of lung cancer undergo blood-based liquid biopsy testing followed by low-dose CT (LDCT) thorax screening as per the study protocol. Participants with positive liquid biopsy results and negative LDCT findings will be offered a study-funded CT-PET scan for further evaluation.	Diagnostic test: Liquid Biopsy (SPOT-MAS Assay); Blood-based genome-wide DNA methylation assay performed on plasma samples to detect tumor-associated methylation patterns suggestive of lung cancer.; Diagnostic test: Exosome-Based Liquid Biopsy Assay; Blood-based assay analyzing exosome-associated biomarkers to support early detection of lung cancer.; Diagnostic test: Low-Dose CT Thorax (LDCT); Low-dose computed tomography of the thorax performed for lung cancer screening
Experimental: Early-Stage Lung Cancer Patients (Stage I-II); Participants with histologically confirmed early-stage lung cancer (Stage I-II) undergo blood collection for liquid biopsy testing to evaluate assay performance in early disease.	Diagnostic test: Liquid Biopsy (SPOT-MAS Assay); Blood-based genome-wide DNA methylation assay performed on plasma samples to detect tumor-associated methylation patterns suggestive of lung cancer.; Diagnostic test: Exosome-Based Liquid Biopsy Assay; Blood-based assay analyzing exosome-associated biomarkers to support early detection of lung cancer.
Experimental: Advanced-Stage Lung Cancer Patients (Stage III-IV); Participants with histologically confirmed advanced-stage lung cancer (Stage III-IV) undergo blood collection for liquid biopsy testing to evaluate assay performance in advanced disease.	Diagnostic test: Liquid Biopsy (SPOT-MAS Assay); Blood-based genome-wide DNA methylation assay performed on plasma samples to detect tumor-associated methylation patterns suggestive of lung cancer.; Diagnostic test: Exosome-Based Liquid Biopsy Assay; Blood-based assay analyzing exosome-associated biomarkers to support early detection of lung cancer.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Negative Predictive Value of Liquid Biopsy Pre-Screening	Description: Negative predictive value of the liquid biopsy assay (SPOT-MAS), defined as the proportion of participants with a negative liquid biopsy result who have no lung cancer detected by low-dose computed tomography (LDCT) and clinical follow-up. Unit of Measure: Proportion (%)	12 months
Reduction in Unnecessary LDCT Screening	Proportion of high-risk participants who receive a negative liquid biopsy (SPOTMAS) result, representing individuals who may be eligible to defer LDCT screening under a liquid biopsy-guided pre-screening strategy. Unit of Measure: Proportion (%)	12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Diagnostic Accuracy of Liquid Biopsy Assays	Sensitivity, specificity and positive predictive value of liquid biopsy assays (SPOT-MAS and exosome-based assays) compared with LDCT and clinical follow-up. Unit of Measure: Proportion (%)	12 months
Cost-Effectiveness of Liquid Biopsy Pre-Screening	Comparative cost analysis (Mean total screening-related cost) of liquid biopsy-guided screening versus LDCT-only screening. Unit of Measure: Cost (USD per participant)	12 months

Collaborators and Investigators

• Sponsor: National University Hospital, Singapore
• Collaborators: Gene Solutions

Study record dates

Study Major Dates

• Study Start (Actual): November 1, 2024
• Primary Completion (Estimated): December 31, 2027
• Study Completion (Estimated): December 31, 2028

Study Registration Dates

• First Submitted: January 6, 2026
• First Submitted That Met QC Criteria: January 13, 2026
• First Posted (Actual): January 22, 2026

Study Record Updates

• Last Update Posted (Actual): January 22, 2026
• Last Update Submitted That Met QC Criteria: January 13, 2026
• Last Verified: January 1, 2026

More Information

Terms related to this study

• Keywords: Liquid biopsy; DNA methylation; Lung cancer screening; Exosomes; LDCT; Low-dose CT; Early cancer detection; Blood-based screening; High-risk individuals; Never-smokers; Multimodal assay
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Respiratory Tract Diseases; Lung Diseases; Respiratory Tract Neoplasms; Thoracic Neoplasms; Lung Neoplasms; Investigative Techniques; Specimen Handling; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Cytological Techniques; Biopsy; Cytodiagnosis; Liquid Biopsy
• Other Study ID Numbers: 2024-3143

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No