Real-world clinical impact and prognostic utility of circulating tumor DNA in stage I–IV non–small cell lung cancer.

Abstract

e20091 Background: Circulating tumor DNA (ctDNA) is an established and widely used biomarker for detection of minimal residual disease (MRD) in non-small cell lung cancer (NSCLC). However, real-world data regarding its utilization, longitudinal interpretation, and impact on clinical management remains limited. Methods: We retrospectively analyzed 82 NSCLC patients undergoing serial ctDNA testing (≥3 tests). Clinical variables were compared by ctDNA status and stage using nonparametric tests. ctDNA trends were categorized as rising, stable positive, transient positive, or negative. Diagnostic performance for progression was assessed using sensitivity, specificity, PPV, and NPV with 95% CI. PFS and OS were estimated by Kaplan–Meier methods and compared using log-rank tests. Analyses were performed in R (v4.4.2). Results: The median age was 72 years and was predominantly male (54.9%), with adenocarcinoma histology (79.3%) and a non-acinar pattern (65.9%). ctDNA testing intensity differed by stage (p = 0.0309), with the highest median of 12.5 test per patient in stage III. In progressors, ctDNA-positive patients received more treatments (median 5 vs 3; p = 0.0205) and underwent more biopsies (median 2 vs 1; p = 4.63 × 10⁻⁵) than ctDNA-negative patients. The median lead time from ctDNA positivity to imaging-confirmed progression was 187 days (123.2–239.8). For detection of disease progression, ctDNA had a sensitivity of 0.58 (95% CI, 0.42–0.73), specificity of 0.89 (95% CI, 0.77–0.95), PPV of 0.81 (95% CI, 0.62–0.91), and NPV of 0.73 (95% CI, 0.60–0.83), with stage-specific performance reported in Table 1. Mutant Tumor Molecules per mL (MTM/ml) differed between true-positive (21.02 [2.43–123.89] and false positive cases 0.07 [0.06–0.07]; p = 0.001). For non rising and rising ctDNA, PFS at 24 and 48 months was 79.9% vs 20.0% and 68.0% vs 10.0% (log-rank p < 0.0001), while OS at 24 and 48 months was 96.6% vs 38.9% and 77.9% vs 25.9% (log-rank p < 0.0001), respectively. Conclusions: ctDNA provides stage-dependent diagnostic utility, with greater sensitivity and PPV in advanced disease and stronger NPV in early-stage disease. Low-level ctDNA positivity was more often associated with false-positive results, while rising ctDNA patterns were strongly associated with worse PFS and OS. ctDNA results impacts clinical management in regards biopsies and escalation of treatment. These findings support longitudinal ctDNA monitoring as a complementary diagnostic and therapeutic tool in NSCLC. Stage-stratified diagnostic performance of ctDNA. Stage Sensitivity Specificity PPV NPV I 0.50 (0.22–0.78) 0.88 (0.71–0.96) 0.57 (0.25–0.84) 0.85 (0.68–0.94) II 0.20 (0.04–0.62) 0.92 (0.65–0.99) 0.50 (0.09–0.91) 0.73 (0.48–0.89) III 0.64 (0.39–0.84) 0.75 (0.30–0.95) 0.90 (0.60–0.98) 0.38 (0.14–0.69) IV 0.78 (0.45–0.94) 1.00 (0.51–1.00) 1.00 (0.65–1.00) 0.67 (0.30–0.90)