Circulating tumor DNA as prognostic markers of non-small cell lung cancer (NSCLC): a systematic review and meta-analysis.

Background: Circulating tumor DNA (ctDNA) has recently garnered attention as a promising prognostic biomarker in cancer patients. This review aimed to evaluate the prognostic significance of ctDNA in patients with non-small cell lung cancer (NSCLC) at different treatment timepoints. Methods: A comprehensive search of PubMed, Web of Science, Embase, Cochrane Library, Scopus, ClinicalTrials.gov and World Health Organization International Clinical Trials Registry Platform (WHO-ICTRP) was performed covering the period from January 2016 to May 2022, with updates monitored until June 2024. Studies reporting ctDNA positivity versus negativity and associated survival outcomes were included. Hazard ratios (HRs) or risk ratios (RRs) were pooled using random-effects models for relapse-free survival (RFS), overall survival (OS), and recurrence risk. The risk of bias of observational studies was assessed by the Newcastle-Ottawa Scale (NOS). Results: Fifty-two studies were included. Total sample sizes of these studies ranged from 12 to 330 participants. Baseline ctDNA positivity was associated with worse RFS [HR =2.23, 95% confidence interval (CI): 1.82-2.75] in all NSCLCs. Among resectable NSCLC, postoperative ctDNA was strongly associated with inferior RFS (HR =5.64, 95% CI: 3.88-8.19) and OS (HR =4.17, 95% CI: 2.22-7.84). Similar trends were noted after full-course treatment for both resectable and unresectable patients. CtDNA detection often preceded radiographic or clinical recurrence, supporting its potential as an early indicator of relapse. Conclusions: CtDNA positivity serves as a robust prognostic marker of worse survival and higher recurrence in NSCLC patients throughout the treatment cycle. Early ctDNA detection may facilitate timely therapeutic interventions and improve patient outcomes.