Peri-Operative Plasma Cell-Free DNA Dynamics and Clinical Outcomes After Curative-Intent Surgery for Resectable Non-Small Cell Lung Cancer: A Prospective Pilot Cohort Including Pulmonary Venous Sampling

Background/Objectives: Total cell-free DNA (cfDNA) is not tumour-specific and may be affected by peri-operative injury and inflammation. We evaluated peri-operative plasma cfDNA dynamics and explored associations with recurrence and mortality in resectable non-small cell lung cancer (NSCLC). Methods: This prospective pilot cohort included 35 patients undergoing lobectomy with systematic nodal dissection and 30 healthy controls. Samples were collected pre-operatively, from the tumour-draining pulmonary vein before major manipulation, peripherally after resection, and on postoperative day 14. Analyses included group comparisons, receiver operating characteristic analysis, logistic regression and Cox regression. Results: Pre-operative cfDNA was higher in patients than controls (mean 1.96 versus 1.08 ng/µL; p = 0.002). Discrimination was modest (AUC 0.67, 95% CI 0.54–0.80), with sensitivity 49% and specificity 93% at an internally selected cut-off. cfDNA differed across timepoints (overall p = 0.008), with higher intra-operative and post-resection values than pre-operative values. Among 34 patients with complete three-year outcomes, 12 recurred and 13 died. Pre-operative cfDNA was associated with recurrence in multivariable logistic regression (adjusted OR 2.47, 95% CI 1.07–5.67; p = 0.034). Day-14 cfDNA was higher among patients who died (5.35 versus 2.17 ng/µL; p = 0.008). Conclusions: Total cfDNA showed modest diagnostic discrimination and exploratory outcome associations. Small sample size, potential model overfitting and incomplete analytical documentation limit interpretation. These hypothesis-generating findings require independent validation with standardised methods, peri-operative covariates and tumour-informed circulating tumour DNA assays.