The clinical potential of circulating-free DNA (cfDNA) for real-time longitudinally monitoring clinical outcomes in a real-world first-line non-small cell lung cancer (NSCLC) prospective study

In this real-word study, we prospectively evaluated longitudinal plasma samples to investigate the potential of cfDNA kinetics as early marker of therapeutic efficacy and predictor of prolonged survival in advanced NSCLC patients undergoing standard first-line treatments. This is a single-center, prospective, cohort study including treatment-naive advanced NSCLC patients who received standard first-line treatments. Between February, 2020 and March, 2022, 72 patients with advanced NSCLC were consecutively recruited. For the cfDNA kinetic analysis, consecutive paired blood collection was performed at baseline, at 4 weeks after the first drug administration or at the radiological response assessment within 12 weeks of the serial follow-up. We used X-tile analysis to determine the optimal cfDNA cut-off value for survival prediction, randomizing two-thirds and one-third of patients as training and validation sets, respectively, according to PFS and OS. The median age was 50, with the majority of patients being males (64%), smokers (74%), adenocarcinoma histology (75%) and an ECOG PS 0-1 (92%). A baseline cfDNA cut-off value of 0.62 ng/ml for PFS and 0.61 ng/mL for OS seemed to discriminate patients' prognosis. In the oncogene-addicted disease we observed a cfDNA cut-off value of 0.62 ng/mL for PFS and 0.54 ng/mL for OS among patients receiving TKI. In the IO subgroup patients presenting with baseline cfDNA level higher than 0.65 and 0.68 ng/mL seemed to experience poorer PFS and OS, when compared to patients with lower cfDNA concentrations. Patients with baseline cfDNA levels higher than 0.53 ng/ml and 1.26 ng/ml showed a shorter PFS (median PFS= 5.6 mo; 95% CI: 4.0-7.3 mo) and OS (median OS= 10.4 months; 95% CI: 6.5-14.2 months) than those with lower cfDNA concentrations (median PFS = 15.8 months; 95% CI: 10.8-20.7 months; median OS = 28.9 months; 95% CI: 5.2-52.8 months). In the current study, among both the all-comers population and the specific treatment subgroups, patients with higher baseline cfDNA levels showed significantly shorter median survival than those with low cfDNA concentrations.