Introduction Lung cancer is the leading cause of cancer-related death worldwide, with early detection critical for curative treatment. Low-dose computed tomography (LDCT) can detect lung cancer at earlier stages, but its implementation in the Nordic countries remains limited. This study surveys invasive respiratory physicians in Sweden, Finland, Norway, and Denmark to explore their views on LDCT screening. Methods A web-based survey was conducted among invasive respiratory physicians in Denmark, Norway, Sweden, and Finland to assess opinions on lung cancer screening. Responses were analysed using descriptive statistics and the Kruskal-Wallis test. Results A total of 125 respondents from 54 Nordic hospitals completed the survey. The majority reported no prior experience with LDCT screening. Most physicians were familiar with LDCT and recognized its potential to improve early detection, though opinions on national implementation were mixed. Key barriers identified included financial constraints, lack of trained personnel, and limited access to CT scanners. Significant differences were observed by country, hospital type, and years of clinical experience (p < 0.05). Conclusion Nordic respiratory physicians acknowledge the benefits of LDCT screening for early lung cancer detection but highlight substantial implementation challenges, particularly related to resources and personnel. Addressing these barriers, standardizing protocols, and exploring supportive measures such as risk-scores and AI-assisted imaging will be essential for successful adoption of national screening programs across the Nordic region.

Background:Lung cancer is a heterogeneous disease with unpredictable trajectories. Risk stratification in lung cancer remains imprecise within tumor-node-metastasis (TNM) stages. Objectives:This work aims to evaluate whether methylated circulating tumor DNA (ctDNA) can improve prognostication at the time of diagnosis. Methods:We enrolled 213 participants with recently diagnosed lung cancer, of whom 100 underwent curative treatment and 113 underwent palliative treatment. All blood samples were collected prior to lung cancer diagnosis and analyzed using multiplex methylation-specific digital droplet polymerase chain reaction targeting five methylated ctDNA markers. ctDNA output was interpreted in two models: a three-tiered (negative/Low-level/High-level ctDNA) and a binary (negative/positive). Results:We observed significantly increased overall survival (OS) among all participants with negative or low-level ctDNA results compared with those with high-level ctDNA. The adjusted hazard ratio (HR) for OS was higher when comparing high-level ctDNA to negative results (HR = 1.96, 95% confidence interval (CI): 1.09-3.51; p = 0.024). In the palliative treatment subgroup, HR for progression-free survival was higher comparing high-level ctDNA to negative results (adjusted HR = 2.32, 95% CI: 1.10-4.92; p = 0.028). In the curative treatment subgroup, the association between ctDNA levels and recurrence-free survival was not statistically significant (adjusted HR = 1.81, 95% CI: 0.73-4.48; p = 0.200). Conclusion:Detection of, and risk stratification based on, levels of methylated ctDNA at diagnosis appears to provide valuable prognostic information in lung cancer, both in early and late stages of the disease. Such information may have implications for the choice of follow-up regimens and treatment strategies. Design:Retrospective observational cohort study using prospectively collected blood samples.

Depression is common among patients with cancer, but its occurrence may vary across cancer types with differing prognoses and symptom burdens. This nationwide study examined the long-term development of depression among patients with lung, colon, breast, and prostate cancer. Using Danish health registries (1998–2022), we identified all individuals with a first diagnosis of lung, colon, breast, or prostate cancer. Depression was assessed through hospital-based diagnoses or antidepressant prescriptions (≥ 2 dispensations within two years after diagnosis). Logistic regression models estimated odds ratios (ORs) for antidepressant initiation among cancer types, adjusted for age, marital status, municipality, educational attainment, and comorbidity (Quan adaptation of the Charlson Comorbidity Index). The study included more than 280,000 patients with cancer. Antidepressant use before diagnosis was more frequent among lung cancer compared with colon, breast, and prostate cancer. Following diagnosis, 1-year antidepressant use reached 16.8

INTRODUCTION:House dust mite (HDM) allergy significantly impacts quality of life. Allergen immunotherapy (AIT), specifically sublingual immunotherapy (SLIT), is an effective treatment for HDM allergy, but adherence to SLIT remains a challenge. This study aimed to evaluate the impact of adherence to SLIT on the use of allergy medications, including antihistamines, nasal corticosteroids, and inhaled corticosteroids (ICS) in a real-world setting. METHODS:We conducted a nationwide cohort study using data from Denmark's comprehensive registries. Patients who initiated HDM SLIT between 2015 and 2020 were included, with follow-up through 2022. Adherent patients, defined as those obtaining at least 80% of the prescribed Defined Daily Dose (DDD) of SLIT, were compared to non-adherent patients. Medication use was tracked for antihistamines, nasal corticosteroids, and ICS. Statistical analyses, including Probit and generalised linear models, assessed the likelihood of obtaining medications and the quantity dispensed, adjusted for age and sex. RESULTS:Of 950 patients, 456 (48%) were classified as adherent. Adherent patients showed significantly reduced usage of antihistamines (p < 0.001) and nasal corticosteroids (p < 0.001) compared to non-adherent patients. No significant differences were found in ICS use or dosage. Additionally, adherent patients were more likely to have higher education levels and be married or cohabiting. CONCLUSION:Adherence to SLIT for HDM allergy is associated with reduced use of antihistamines and nasal corticosteroids. These findings emphasise the importance of SLIT adherence in managing HDM allergy and suggest that improving adherence could further reduce medication usage, improving patient outcomes in real-world settings.

We assessed the feasibility of a multi-reader, multi-case (MRMC) observer-performance design to evaluate the simulated decision impact of a radiomics-based computer-assisted diagnostic tool (CADx) and a methylated circulating tumour DNA (ctDNA) assay in lung cancer work-up. Patients referred to a Danish fast-track lung cancer clinic were enrolled. Baseline chest CT scans were analysed with the CADx RevealAI-Lung and plasma with a five-target methylated ctDNA assay. Virtual cases were presented in four information sets: standard of care (SoC), SoC plus ctDNA, SoC plus CADx, and SoC plus both tests. Four pulmonologists independently triaged each case. Diagnostic performance was evaluated using ROC analyses, and triage patterns were compared across information sets. The cohort comprised 239 participants, including 104 lung cancer cases and 135 cancer-free subjects, resulting in 956 unique cases. Both the CADx result and ctDNA positivity were associated with lung cancer. Discrimination was high and similar across information sets (AUC 0.84 to 0.86), with no significant differences. Additional information produced modest, non-significant shifts, mainly among cancer-free subjects, with the combined set tending towards fewer nodule follow-up allocations and more discharges. These findings show that the MRMC framework was feasible in a practice-proximate setting and the trends merit further evaluation in larger cohorts and earlier diagnostic settings.

INTRODUCTION:Patients who have undergone curative surgery for non-small cell lung cancer (NSCLC) often experience long-term reduced quality of life (QoL), high symptom burden, risk of physical deconditioning and comorbidity. Current Danish rehabilitation offers are heterogeneous and not specifically tailored to the disease-specific needs and no long-term targeted support is currently available. Previously, singing-delivered as a structured training modality-has conferred both physiological and psychological improvements in chronic obstructive pulmonary disease, which may likely be transferable to NSCLC, as the two conditions share overlapping symptoms and characteristics. We aim to explore whether a singing-based intervention improves physical function, QoL and symptom burden 6-18 months postsurgery in NSCLC. Moreover, we aim to explore the underpinning physiological mechanisms of singing. METHODS AND ANALYSIS:We will conduct a multicentre randomised controlled trial, comparing 10 weeks' online-delivered structured singing training to usual care. Trial outcomes include primary outcome, physical capacity (measure: Six-Minute Walking Test), and secondary outcomes, QoL and symptoms (measures: St. George's Respiratory Questionnaire (SGRQ); the European Organisation for Research and Treatment of Cancer Questionnaire (QLQ-C30; QLQ-LC13); Hospital Anxiety and Depression Scale (HADS) and airway physiology (measure: forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC)). Explorative outcomes include aerobic fitness/maximal oxygen uptake (VO2-max); exercise-induced adaptations; respiratory muscle strength and control; inflammatory biomarkers. ANALYSIS:Descriptive statistics, stratified analyses, regression models and association and independence between objective and subjective outcomes. ETHICS AND DISSEMINATION:The trial was approved by the Committee on Health Research Ethics (SJ-1027) and the Danish Act on Processing of Personal Data (p-2024-19634). Results will be reported in peer-reviewed scientific journals. TRIAL REGISTRATION NUMBER:NCT07460999.

Curative surgery is the best treatment for patients with early-stage non-small cell lung cancer (NSCLC), but around 40

BACKGROUND:Surgical resection is essential in the treatment of early-stage non-small cell lung cancer (NSCLC), followed by rehabilitation with physical exercise training to improve physical capacity, quality of life (QoL) and symptom burden. In Denmark, rehabilitation is municipality-based and not disease-specific and without a maintenance model. We aimed to investigate QoL and symptoms 6-12 months after NSCLC surgery, hypothesising impaired QoL and symptom levels. Moreover, we explored rehabilitation attendance. METHODS:An observational, cross-sectional, survey-based study was conducted from March to June 2025 across two Danish regions in patients after surgery for stage I or II NSCLC and without adjuvant oncological treatment (preregistration: osf.io/vmpft). Each site contacted their own eligible patients via digital mail. Registry data from the Danish Lung Cancer Registry and electronic patient registries: socio-demographics, disease-specific characteristics and surgical procedure. Survey data: QoL and symptoms burden (measure: The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30; Reporting: Raw and transformed scores and dichotomised according to defined thresholds and cut-offs for clinical importance) and self-reported information about rehabilitation attendance. DATA ANALYSES:descriptive and stratified analyses. RESULTS:We identified 168 patients, 94 (56% of 168) were eligible and 67 (71% of 94) responded to the survey. No differences were found in baseline characteristics and overall mean time since surgery was 8.9±1.8 months. Current QoL and symptoms were clinically impaired (eg, physical functioning: 51%; dyspnoea: 70%). Around half (54%) reported having attended a rehabilitation programme and those having attended were more likely to have clinically impaired physical functioning and dyspnoea at present. CONCLUSIONS:QoL and symptoms were impaired 6-12 months after NSCLC surgery, and the current level did not seem to be related to having attended a postsurgical rehabilitation programme. Disease-specific challenges should be addressed in future rehabilitation and maintenance models.

Lung cancer remains the leading cause of cancer-related death worldwide, largely because of late-stage diagnosis. Although low-dose computed tomography screening can reduce mortality, it is limited by high false-positive rates, radiation exposure, and low adherence. Thus, there is an urgent need for precise, accessible, and noninvasive diagnostic alternatives. This study evaluated the diagnostic accuracy of a novel multiplexed digital droplet PCR (ddPCR) assay targeting hypermethylated circulating tumor DNA (ctDNA) markers (HOXA9, OTX1, MCIDAS, SP9, and TFAP2B) in plasma for lung cancer detection. A total of 249 patients referred for lung cancer diagnostics were prospectively enrolled, identifying 109 lung cancer cases and 140 cancer-free subjects. Participants were recruited and blood samples were drawn before any clinical outcomes were known. Plasma was analyzed using a multiplex ddPCR assay for methylated ctDNA. Diagnostic performance was assessed through receiver operating characteristic analysis and logistic regression models. The assay demonstrated an area under the receiver operating characteristic curve of 0.76. Sensitivity and specificity were 67.0% and 77.1%, respectively, at the sensitivity optimized cutoff. The assay performed better in late-stage lung cancers than early-stage cancers (73.1% versus 51.6% sensitivity). Incorporating clinical characteristics improved the diagnostic model (P < 0.001) for advanced-stage disease. Thus, the multiplex ddPCR ctDNA assay may serve as a relevant diagnostic tool, complementing existing low-dose computed tomography lung cancer screening.

OBJECTIVE:Depression is common among patients with lung cancer, but evidence from large, population-based studies is limited. This study examined antidepressant use and hospital-diagnosed depression before and after lung cancer diagnosis in Denmark. METHODS:We conducted a nationwide registry-based study including all patients diagnosed with lung cancer from 1998 to 2022 and a comparison cohort (1:4 ratio) matched on age, sex, municipality, and marital/cohabiting status. Data on hospital diagnoses and redeemed antidepressant prescriptions were obtained from Danish national registries. RESULTS:Among 73,930 patients with lung cancer and 293,892 matched comparison subjects, antidepressant use was already higher among lung cancer patients two years before diagnosis (12.7% vs. 9.9%) and increased markedly after diagnosis (23.7% vs. 11.9% 2 years post-diagnosis, p < 0.001). Among individuals without prior antidepressant use, 8.4% of patients with lung cancer initiated antidepressants within the first year and 13.7% within the second year, compared with 1.9% and 3.4% of controls (p < 0.001). Hospital-diagnosed depression occurred in 2.1% of lung cancer patients versus 0.8% of controls, with higher rates among females. CONCLUSIONS:Antidepressant use is prevalent before, and rises further after, a lung cancer diagnosis. The difference relative to the comparison cohort was most evident among individuals with no history of antidepressant use. These findings underscore the need for systematic psychosocial assessment and integrated mental health support throughout the lung cancer care pathway.

Lung cancer remains the leading cause of cancer-related deaths globally, with low-dose computed tomography (LDCT) screening widely implemented in several countries. However, current screening eligibility, based largely on the National Lung Cancer Screening Trial and NELSON trial outcomes, does not account for socioeconomic risk factors such as education and employment status, which may impact lung cancer incidence and outcomes. This study used data from the Danish National Patient Register to examine educational attainment and employment status among 109,940 lung cancer patients diagnosed between 1994 and 2018, compared to a randomly selected matched general population cohort. Patients were less likely to hold higher education degrees and more likely to be on disability pension compared to controls, underscoring a significant socioeconomic disparity. Lung cancer patients frequently had only primary school education, with this educational gap widening over time. Employment disparities were also noted, with lung cancer patients twice as likely to be on disability benefits. These findings suggest that socioeconomic vulnerabilities, including educational level and employment, may exacerbate lung cancer risk, possibly linked to higher smoking prevalence and occupational carcinogen exposure in lower socioeconomic groups. Targeted public health initiatives focusing on smoking cessation and LDCT access for socioeconomically disadvantaged individuals are crucial for addressing these disparities and improving lung cancer outcomes. National wealth alone appears insufficient in bridging these socioeconomic gaps, emphasizing the need for strategic, targeted interventions in lung cancer prevention and early detection.

Recurrent pleural effusions and ascites significantly impair quality of life, particularly in patients with advanced malignant and non-malignant disease. Traditional management often relies on repeated hospital-based procedures, which provide temporary symptom relief but place a considerable burden on patients and healthcare systems. This retrospective cohort study evaluates the safety, effectiveness, and clinical outcomes of indwelling pleural and peritoneal catheters (IPCs and IPeCs) in 63 patients treated at Lillebaelt Hospital Vejle between October 2019 and October 2024. A total of 30 patients received IPCs and 33 received IPeCs. Most had malignant effusions or ascites, but a notable proportion had non-malignant causes such as heart failure, liver cirrhosis, or renal disease. Following catheter placement, median survival was 45 days for IPC patients and 34 days for IPeC patients. Infection rates were low: 17% of IPC patients developed superficial skin infections, all treated successfully with oral antibiotics, and 6% of IPeC patients developed peritonitis, with one case potentially unrelated to the catheter. Importantly, 70% of IPC and 76% of IPeC patients had no hospital visits due to catheter-related complications, supporting the safety and outpatient feasibility of these devices. Additionally, a substantial proportion of patients-23% (IPC) and 30% (IPeC) - were able to remain in their own homes, potentially with support from home care services, rather than requiring institutionalization. These findings underline the benefit of early catheter placement in supporting patient autonomy and symptom control. Our results confirm that IPCs and IPeCs are safe and effective for managing both malignant and non-malignant effusions, with low complication rates and high patient benefit. Our findings support broader use of these catheters in palliative care. Earlier consideration of catheter placement may further improve outcomes and quality of life.

BackgroundSmoking cessation at or around the time of lung cancer diagnosis is associated with improved treatment outcomes, enhanced quality of life and increased survival. However, many patients continue smoking post-diagnosis.AimThis study evaluated the effectiveness of a national initiative in Denmark that integrated smoking cessation support into the diagnostic workup for lung cancer within a pragmatic, multicenter, cluster-randomised controlled trial.MethodsNine Danish hospitals were cluster-randomised to either the intervention group (integrated cessation support) or the control group (usual care). The intervention was implemented in five hospitals. Eighty-six patients (intervention = 39; control = 47) who were active smokers at referral completed questionnaires assessing smoking cessation initiation, motivation, quality of life and psychosocial consequences of diagnostic workup at baseline and 6-weeks follow-up. Logistic and multiple regression analyses were conducted. Additionally, 140 healthcare professionals completed a survey on cessation support practices pre-intervention, and 54 completed it post-intervention. Descriptive analyses were used to assess changes in clinical practice.ResultsThere were no statistically significant differences in smoking cessation initiation between the intervention and control groups (OR = 0.81 [0.41, 1.58], p = 0.53; adjusted OR = 0.79 [0.35, 1.79], p = 0.57). Among healthcare professionals in the intervention group, a larger proportion reported they “almost always” provided cessation after the implementation (35.1%) than before (18.3%). But the proportion who responded that they “almost never” provide support was also considerably larger after the implementation (13.5%) than before (3.2%). In the control group, proportions tended to shift more generally towards providing more support over time, and a considerably larger proportion reported to refer patients to external smoking cessation support at the follow-up measurement.ConclusionThe study was inconclusive, showing no significant effect of smoking cessation support during lung cancer diagnostic workup on patients' cessation initiation, possibly influenced by selection bias and varying intervention fidelity at study sites.

8033 Background: Lung cancer (LC) is the leading cause of cancer-related mortality, primarily due to late-stage diagnoses. Low-dose computed tomography (LDCT) screening lowers mortality rates by detecting LC at earlier stages, but the program is limited by high costs, capacity constraints, and low compliance. We describe the early-phase development of a test based on the APTASHAPE technology, designed as a cost-effective, scalable tool to pre-qualify individuals for LDCT screening. This technique uses RNA aptamers to analyze protein composition in lung cancer patients, identifying cancer-specific protein fingerprints across all stages. Variations in aptamer ratios reflect plasma protein composition, profiled through next-generation sequencing and machine learning. Methods: A discovery cohort of 24 LC patients (stage I+II, n=12; stage III+IV, n=12) and 24 individuals initially referred on suspicion of LC but ultimately diagnosed as non-cancer cases were analyzed. Additionally, a test cohort of 48 LC patients (stage I+II, n=24; stage III+IV, n=24) and 48 non-LC cases were analyzed. In four rounds of Systematic Evolution of Ligands by EXponential Enrichment (SELEX), a library of 10 15 2’-fluoro-protected RNA aptamers was incubated with a pool of plasma prepared from the LC patients in the discovery cohort to facilitate binding to the plasma proteins. Non-binders were removed, and bound aptamers were amplified by PCR. Following SELEX, linear regression identified the aptamers capturing LC-specific protein signatures. The selected aptamers were then applied to the test cohort and their ability to differentiate between LC and non-LC cases was evaluated using principal component analysis and receiver operating characteristic (ROC) curve. Results: In the discovery cohort, statistical analysis identified 13 aptamers whose binding to plasma proteins formed a cancer-specific fingerprint, able to discriminate participants with lung cancer from those without. We used this profile to predict LC in the test cohort and obtained an area under the curve (AUC) of 0.74 (95% confidence interval (CI) 0.62-0.87). Importantly, the discriminatory ability was equally effective for stage I+II and stage III+IV (AUC=0.71 (95% CI 0.58-0.84) and AUC=0.74 (95% CI 0.61-0.86), respectively). Conclusions: We present a proof-of-concept for a promising, cost-effective, and scalable technique for pre-qualifying individuals for LDCT screening. While still in the earliest stage of development, we anticipate that expanding the study population will improve the machine learning algorithm and markedly increase the AUC value. Importantly, this approach holds significant promise in detecting early-stage lung cancer -an area where blood-based technologies usually face substantial limitations. Ongoing optimizations aim to enhance its performance.

BACKGROUND:Lung cancer remains the leading cause of cancer-related deaths globally, with gradual improvements in patient survival attributed to early detection through low-dose computed tomography screening and advances in oncological therapies. Despite these advancements, the management of comorbidities, particularly cardiovascular disease and chronic obstructive pulmonary disease, is critical due to their shared causal link with lung cancer - smoking. This study explores the prevalence of comorbidities among lung cancer patients in Denmark over four decades, using comprehensive national registry data. METHODS:By examining the Danish National Patient Register and Danish Cancer Registry, we identified all Danish lung cancer cases diagnosed from 1980 to 2018, analyzing comorbidities and causes of death. A comparison cohort matched by age, sex, municipality, and marital status was also established. FINDINGS:The findings reveal a significant increase in comorbidities among lung cancer patients over time, while this increase was less significant in the comparison cohort. Almost half of lung cancer patients had at least one comorbidity in the most recent period, 2008-2018. Cardiovascular disease, chronic obstructive pulmonary disease, diabetes, stroke, and peripheral atherosclerosis were the most prevalent comorbidities. Among patients diagnosed with lung cancer, it was the cause of death in 84 % of cases. The study also highlights a notable decrease in deaths from ischemic heart disease, with an increase in dementia-related deaths, suggesting an increasing burden of neurodegenerative diseases in aging populations. INTERPRETATION:This longitudinal analysis highlights that as the burden of comorbidities increases, comprehensive management strategies become increasingly crucial. These strategies could include less invasive diagnostic approaches, such as endobronchial evaluation, as well as treatment options like segmental resection and stereotactic body radiation. Addressing comorbidities alongside cancer treatment may improve patient outcomes and overall quality of life in aging populations.

Allergic rhinitis (AR), which is prevalent among children and adolescents, often impairs quality of life and coexists with asthma. Allergen immunotherapy (AIT), particularly sublingual immunotherapy (SLIT), is recommended for individuals with insufficient response to standard treatments. While adherence is critical to AIT effectiveness, its impact on the use of allergy medications remains unclear. This study aimed to investigate the association between adherence to SLIT for grass pollen and use of prescription allergy medications. A nationwide cohort study was conducted using Danish health registries. Children and adolescents initiating SLIT from 2007–2022 were classified as adherent (≥ 80

BACKGROUND:Early detection of lung cancer (LC) is crucial for curative treatment, but current screening methods face challenges due to high costs and poor adherence. Artificial intelligence tools, such as the LungFlag model, uses routine clinical data for innovative risk stratification. This study validates LungFlag in Danish high-risk populations to assess its potential in LC screening. METHODS:This retrospective study included data from 2 populations in Southern Denmark (2013-2021): (A) LC fast-track clinic patients (∼25% LC incidence) and (B) outpatients followed with chronic obstructive pulmonary disease (COPD) (∼6% LC incidence). Data included laboratory results, comorbidities, body mass index (BMI), and smoking history from up to 3 years prior to the index date. LungFlag's performance was compared to the PLCOm2012 model. Model interpretation was conducted using Shapley additive explanation (SHAP) values, and risk stratification was analyzed by age. RESULTS:In Population A, 5271 LC cases were identified from 18,600 patients, with a stable LC incidence of 28%. In Population B, LC incidence varied by index-date approach: 6.6% using the diagnosis date and 2.1% using the first visit approach. LungFlag outperformed PLCOm2012 in Population A (AUC: 0.63 vs. 0.60) and showed slightly higher sensitivity in Population B, though differences were minor. Key predictors included smoking, age, and COPD. High-risk individuals identified by LungFlag were generally younger compared to using PLCOm2012. CONCLUSION:LungFlag demonstrates promise as a decision-support tool in detecting LC, particularly for COPD patients, who lack systematized screening. However, prospective real-world studies are needed to confirm its effectiveness and clinical value.

8034 Background: Lung cancer is a devastating disease, characterized by high mortality rates and limited treatment options once it progresses to advanced stages. Early detection is critical for improving survival outcomes, as curative treatments are only possible in the early stages of the disease. Developing a blood test for lung cancer detection would provide a minimally invasive, highly valuable tool for early diagnosis and could significantly enhance screening efforts. A novel digital droplet polymerase chain reaction multiplex assay was evaluated for its diagnostic accuracy in detecting hypermethylated circulating tumor DNA (ctDNA) in lung cancer in a high-risk population. Methods: The study enrolled 249 patients undergoing diagnostic evaluation for suspected lung cancer. Blood samples for ctDNA analysis were collected during the first hospital visit. Lung cancer diagnoses were subsequently determined through clinical workup and assessment by a multidisciplinary team (MDT). If the initial MDT assessment refuted the suspicion of lung cancer, participants were followed for at least 12 months to ensure they did not develop lung cancer in the follow up period. The assay targeted hypermethylated CpG-islands in five genes: HOXA9, OTX1, MCIDAS, TFAP1B , and SP9 . ROC-analyses were performed for the five ctDNA markers alone and in combination. Results: The assay, using the combined model of the five markers, showed a sensitivity of 67% (95% Confidence Interval [CI]: 57–76) and a specificity of 77% (95% CI: 69–8) to discriminate cases from cancer-free controls. Positive and negative predictive values were 70% (95% CI: 60–78) and 75% (95% CI: 67–82), respectively. Sensitivity increased to 73% (95% CI: 62–83) in subgroup analysis of stages III and IV lung cancer and cancer-free controls. Notably, the assay successfully detected all 9 cases of small cell lung carcinoma (SCLC) within the cohort. Additional analysis revealed an association in stage IV participants between ctDNA and higher tumor burden, potentially explaining the improved assay performance in these advanced stages. Conversely, amongst the seven false negative stage IV cases, they all had lower tumor burden and were diagnosed with adenocarcinomas. Conclusions: The presence of aberrantly methylated ctDNA is a potential diagnostic biomarker for lung cancer. Further optimization of the multiplex assay might improve its overall performance making it a relevant tool for early detection of lung cancer. Importantly, this study was performed in a high-risk cohort, with a lung cancer prevalence of 43%, and hence, the assay would potentially perform better in a screening population.