Diagnostic properties of a novel ctDNA assay for lung cancer detection.

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.