Circulating Tumor DNA Mutations and Methylation Status as Biomarkers for Early Detection of Lung Cancer in Patients With Suspicious Lung Nodules

May 22, 2026 updated by: Dr. David Chi-leung Lam, The University of Hong Kong

Lung Cancer is common in Asia and is different from lung cancer from Western countries in terms of lung cancer epidemiology and management. Lung cancer can be detected early but most early stage lung cancer appear as lung nodules with suspicious features on imaging. Workup and surveillance for subjects with suspicious lung nodule is a clinical problem. There is no consensus and clinical practice usually varies with local epidemiology of lung diseases namely the local clinical characteristics especially with lung cancer and pulmonary tuberculosis. The clinical challenge is to address whether pulmonary nodules identified on CT screening carry short- and long-term risk for lung cancer.

The main objective of this study is to test the improvement of efficiency of diagnostic evaluation with clinical parameters and ctDNA mutation/methylation profiling for artificial intelligence modeling of for early detection of lung cancer in subjects with suspicious lung nodules.

The hypothesis is that ctDNA mutation and methylation will enhance early detection of lung cancer in patients with suspicious lung nodules.

This is a longitudinal cohort study. A total of 200 subjects (100 from Hong Kong and 100 from Vietnam) with suspicious lung nodules on CT Thorax will be recruited. Blood samples will be collected at recruitment and subsequent 6 months follow up. ctDNA mutations and methylation with SPOTMAS Lung assays would be performed at baseline and at 6 months follow up. The CT scan where the suspicious lung nodules were identified, will be used as baseline scan for recruitment. Recruited subjects will be arranged with a non-contrast LDCT scans at 6 months follow up.

The primary outcome measure of the study is the detection of ctDNA mutation and methylation in correlation with diagnosis of lung cancer or persistence of suspicious lung nodules. The secondary outcome measures of the study are the Sensitivity and specificity of clinical biomarkers in correctly identifying malignant lung nodule, i.e. lung cancer.

Study Overview

Status

Not yet recruiting

Conditions

Intervention / Treatment

Detailed Description

In Asia, the incidence and mortality of lung cancer are both high . The clinical demographics of lung cancer patients in Asia are different when compared with western countries. Both in Hong Kong and in Vietnam, there is a prominence of female non-smokers with lung cancer in Hong Kong, with a male: female ratio of 1.5:1. The biology of lung cancers arising from non-smokers are believed to be different from lung cancers from smokers. This is well reflected in the heterogeneity of lung cancer cell types and also their respective mutation profiles. For instance, there are more female non-smokers with lung cancer with the cell types of being adenocarcinomas, with about half in proportion of them carrying EGFR mutations; whereas in male smokers with lung cancer there are usually additional possibility of have squamous cell carcinomas, and the chance of the tumors carrying EGFR mutations is lower compared with non-smokers. Thus, different clinical biomakers should be used for early detection of lung cancer in smokers and non-smokers.

There is an urgent need to develop strategy for early detection of lung cancer in non-smokers who have no obvious risk factors like smokers. Blood-based biomarkers has the potential utility for identifying subjects with lung nodules showing high risk features for these lung nodules being malignant or becoming malignant, with whom additional workup for early diagnosis of lung cancer is indicated.

What are lung nodules with suspicious features of malignancy? Lung nodules are primarily defined by size of 3 cm or less. They may come in variable numbers or in different lung areas. The radiological appearance could be completely solid nodule (CSN), heterogeneous part-solid/part-ground glass nodules (hGGN) or pure ground glass nodules (pGGN). hGGN and pGGN have been shown to be more likely to be malignant compared to CSN. The presence of calcification, or simply radiological reporting to be granuloma, or fat density inside the nodule is known to indicate benign nature. Lung nodules with irregular or spiculated border are likely malignant whereas smooth border and roundish appearance usually indicates benign lesion. Thus, there is always an element of likelihood or probability of malignancy based on radiological appearance, but it is not possible to tell with full confidence, from imaging features, that a lung nodule is malignant or not.

With the often relatively small size and deep-seated location of lung nodules shown only on CT scan, invasive investigations for a lung nodule with tissue biopsy to confirm malignancy are associated with high morbidity. Non-invasive diagnostic biomarkers have become unique chance of improvement of risk management for subjects at risk. The challenges related to sorting out a large majority of benign nodules from malignant ones and among those a majority of aggressive from indolent cancers. The key questions in determining individual probabilities of diseases, given their history, findings on CT, and biomarkers of risk, remain most challenging. Appropriate risk assessment in reducing the false positives associated with current low-dose computed tomography practices and identification of individuals who need therapy and at what time during tumor surveillance could reduce costs and morbidities associated with unnecessary interventions.

Different blood-based biomarkers have been used alone or in combination in clinical practice. The most well-known one is Carcinoembryonic antigen (CEA). However, it is sensitive but not specific enough (raised level not limited to lung cancer but equally prevalent in colorectal tumor, and also inflammatory conditions). Newer biomarkers are urgently needed to enhance diagnosis of indeterminate or suspicious lung nodule.

Recently, the development of a multimodal assay called SPOTMAS Lung assay that simultaneously profile methylomics, fragmentomics, DNA copy number and end motifs in a single workflow of targeted and shallow genome-wide sequencing of cell free DNA with the aim of early detection of lung cancer. This assay has shown good diagnostic performance of overall sensitivity of 94% for detection of lung cancer.

Previous studies have shown that a quarter of patients with incidental pulmonary nodules experienced clinically significant distress that may relate to the poor knowledge about cancer risk and evaluation. Health care professionals have important roles to alleviate patients' distress through a good understanding on patients' level of understanding and distress related to the lung nodules and social support system. At the same time, it is important for physicians to know the applicability of available newer biomarker panels in different clinical situation to guide their respective clinical decision in further investigations.

The aim of this project is to use the assay of circulating tumor DNA mutations and methylomics to detect early lung cancer among subjects with suspicious lung nodules on lung imaging. The Key questions in determining individual probabilities of lung cancer, given their clinical history, findings on CT scan, and ctDNA mutation and methylation status for risk of early lung cancer, will be addressed. Reducing the false positives associated with current low-dose computed tomography practices and identification of individuals who need therapy and at what time during tumor surveillance could reduce costs and morbidities associated with unnecessary interventions.

Data will be collected and analysed according to the list of primary and secondary outcomes.

The primary outcome measure of the study is - the detection of ctDNA mutation and methylation in correlation with diagnosis of lung cancer or persistence of suspicious lung nodule.

The secondary outcome measures of the study are - the Sensitivity and specificity of clinical biomarkers in correctly identifying malignant lung nodule, i.e. lung cancer. The area under the summary receiver operating characteristic curve (AUC) and diagnostic odds ratio (DOR) with the ctDNA assay.

Improvement of positive diagnostic likelihood ratio (DLR+) and negative diagnostic likelihood ratio (DLR-) of using the in diagnosing lung cancer.

Cost-effectiveness in adding a clinical biomarker panel in enhancing risk stratification of lung nodules and hence diagnosis of lung cancer, defined as the incremental cost per additional lung cancer diagnosed.

The result from this project will provide means to early detection of lung cancer by ctDNA and methylomics assay. The Key questions in determining individual probabilities of lung cancer, given their clinical history, findings on CT, and ctDNA mutation and methylation status for risk of early lung cancer, will be addressed. Reducing the false positives associated with current low-dose computed tomography practices and identification of individuals who need therapy and at what time during tumor surveillance could reduce costs and morbidities associated with unnecessary interventions. The impact of psychological stress associated with the diagnosis and surveillance of lung nodules could also be evaluated.

The information gained from this project will provide evidence-based practice guidance for diagnostic evaluation for lung nodules or lung cancer.

Study Type

Observational

Enrollment (Estimated)

200

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Hong Kong
    • Hong Kong
      • Hong Kong, Hong Kong, Hong Kong
        • University of Hong Kong Queen Mary Hospital
        • Contact:
          • David CL Lam, BSc,MBBS,PhD,FCCP,FACP,FRCP(E)
          • Phone Number: 85222555814
          • Email: dcllam@hku.hk
        • Principal Investigator:
          • David CL Lam, BSc,MBBS,PhD,FCCP,FACP,FRCP(E)
        • Sub-Investigator:
          • Lynn YW Shong

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Sampling Method

Non-Probability Sample

Study Population

People with suspicious lung nodules on CT Thorax

Description

Inclusion Criteria:

  1. Age 45 - 80 years;
  2. Suspicious lung nodules (> 0.5 - 30mm in longest diameter, non-calcified) found within the past six months, or if PET scan has been done before, the specific uptake value (SUV) should be more than 1

Exclusion Criteria:

  1. Age < 45 or > 80;
  2. Lung nodules of < 0.5 cm in longest diameter, or with calcification seen in imaging;
  3. Known lung cancer or lung metastasis before, or history of extra-pulmonary cancer;
  4. Active tuberculosis;
  5. Clinical unstable conditions including untreated ischemic heart disease or arrhythmia, uncontrolled airway disease;
  6. Unwillingness to undergo invasive investigation like bronchoscopy;
  7. Unable to provide informed written consent.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
ctDNA mutation and methylation will enhance early detection of lung cancer in patients with suspicious lung nodules.
Time Frame: 2 year study follow up and survillance
The detection of ctDNA mutation and methylation in correlation with diagnosis of lung cancer or persistence of suspicious lung nodule.
2 year study follow up and survillance

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Reducing the false positives associated with current LDCT practices and identification of individuals who need therapy and at what time during tumor surveillance could reduce costs and morbidities associated with unnecessary interventions.
Time Frame: 2 year study follow up and surveillance

The Sensitivity and specificity of clinical biomarkers in correctly identifying malignant lung nodule, i.e. lung cancer. The area under the summary receiver operating characteristic curve (AUC) and diagnostic odds ratio (DOR) with the ctDNA assay.

Improvement of positive diagnostic likelihood ratio (DLR+) and negative diagnostic likelihood ratio (DLR-) of using the in diagnosing lung cancer.

Cost-effectiveness in adding a clinical biomarker panel in enhancing risk stratification of lung nodules and hence diagnosis of lung cancer, defined as the incremental cost per additional lung cancer diagnosed.
2 year study follow up and surveillance

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

The University of Hong Kong

Collaborators

Bach Mai Hospital
Tam Anh TP. Ho Chi Minh General Hospital
Asian Pacific Society of Respirology

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Estimated)

June 1, 2026

Primary Completion (Estimated)

June 1, 2028

Study Completion (Estimated)

December 1, 2028

Study Registration Dates

First Submitted

May 22, 2026

First Submitted That Met QC Criteria

May 22, 2026

First Posted (Actual)

May 29, 2026

Study Record Updates

Last Update Posted (Actual)

May 29, 2026

Last Update Submitted That Met QC Criteria

May 22, 2026

Last Verified

October 1, 2025

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • HKU_UW_25_481

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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