Postoperative circulating cell-free DNA (cfDNA) dynamics as an early indicator of molecular residual disease in lung cancer: preliminary results and correlation with TNM status, adjuvant therapy, and clinical outcome
Authors/Creators
- 1. Department of Medical Genetics, Medical University of Plovdiv, Plovdiv, Bulgaria
- 2. Department of Special Surgery, Medical University of Plovdiv, Plovdiv, Bulgaria
Description
Background: Recurrence after curative-intent surgery remains a major clinical challenge in non-small cell lung cancer (NSCLC). Conventional radiologic follow-up detects relapse only once macroscopic disease becomes evident, missing the minimal residual disease (MRD) window. Circulating tumor DNA (ctDNA), a tumor-derived fraction of total circulating cell-free DNA (cfDNA), has emerged as a sensitive biomarker for early MRD detection. This pilot study evaluates postoperative cfDNA dynamics as an accessible surrogate for MRD monitoring.
Methods: Twelve patients with histologically confirmed NSCLC undergoing curative-intent resection were prospectively monitored at four time points: preoperatively (T0), postoperative day 10 (T1), 1 month (T2), and 3 months (T3). Blood samples were collected in Streck Cell-Free DNA BCT® tubes and processed using a double-centrifugation protocol. cfDNA was extracted using the Maelstrom Switch 8 automated system and quantified fluorometrically. Longitudinal cfDNA trends were correlated with TNM stage, adjuvant therapy, and survival outcome. Welch's t-tests, ANOVA, and simple linear regression assessed associations between cfDNA levels and mortality.
Results: Most patients (10/12; 83.3%) demonstrated a steady postoperative decline in cfDNA, consistent with molecular clearance. Two patients (16.7%) exhibited persistent or rising cfDNA and were the only patients who died during follow-up. At T3, cfDNA levels were significantly higher in deceased vs. surviving patients (0.2821 vs. 0.2325 ng/µL, p = 0.029). Linear regression revealed a negative association between cfDNA at T3 and survival probability (β = –3.62, R2 = 0.18). Early postoperative cfDNA (T1–T2) lacked prognostic value.
Conclusion: Persistently elevated cfDNA levels at 3 months post-surgery were observed in patients with unfavorable outcomes; however, variability between individual trajectories was also present. These findings suggest that postoperative cfDNA dynamics may reflect underlying biological processes related to minimal residual disease, but given the small cohort size, they should be interpreted as hypothesis-generating. Larger prospective studies integrating mutation-specific ctDNA assays and time-to-event analyses are required to validate the potential clinical utility of cfDNA-based postoperative monitoring.
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