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Circular tumor DNA (ctDNA) positivity is associated with poorer survival and higher recurrence rates among patients with non–small cell lung cancer (NSCLC), but early detection may allow for timely intervention and improved outcomes, according to a study published in Translational Lung Cancer Research.¹

Evidence Gaps on the Prognostic Utility of ctDNA in NSCLC

Despite treatment advances, many patients with stage I to III NCSLC still experience disease progression, resulting in poor prognosis and low 5-year survival rates. Imaging is commonly used to assess treatment response and monitor postoperative recurrence. The results, however, do not always align with pathological findings from invasive procedures such as surgical resection or biopsy. This highlights the need for accurate, non-invasive biomarkers that can predict prognosis, guide timely treatment decisions, and reduce recurrence risk.

In recent years, ctDNA sequencing has emerged as a promising non-invasive method for detecting minimal residual disease. These DNA fragments originate from tumor cells and carry tumor-specific genetic information, with the potential to be used in early diagnosis, prognostic stratification, disease monitoring, and treatment response assessment across cancer types.²

The researchers noted that ctDNA testing is highly sensitive, less repetitive, and more cost-effective than traditional approaches.¹ Despite this, prior studies evaluating the early detection and prognostic utility of ctDNA in NSCLC often focused on specific disease stages or individual outcomes. To better understand the broader role of ctDNA in NSCLC treatment, the investigators conducted a comprehensive systematic review and meta-analysis of global research examining ctDNA detection at multiple time points and its association with various prognostic outcomes.

Specifically, they searched multiple databases for studies published between January 2016 and May 2022, with updates monitored through June 2024. Eligible studies compared patients with ctDNA positivity vs negativity and reported associated survival outcomes. The researchers then pooled HRs or risk ratios (RRs) for relapse-free survival (RFS), overall survival (OS), and recurrence risk using random-effects models.

CtDNA Positivity Predicts Worse Survival, Higher Recurrence Risk in NSCLC

The literature search identified 52 eligible studies, including 50 original research articles, 1 conference abstract, and 1 research letter. The studies were published between 2016 and 2024 and were conducted across several countries, most commonly China and the US. Most focused on stage II and III NSCLC, with sample sizes ranging from 12 to 330 patients. Across studies, ctDNA was collected at multiple time points, including baseline, post-surgery, post-treatment, and during surveillance, using varied definitions of positivity.

Baseline ctDNA was associated with poorer RFS in the overall NSCLC population (HR, 2.23; 95% CI, 1.82-2.75; I² = 49%). Among patients with resectable NSCLC, positive ctDNA detected immediately after surgery was strongly linked to worse RFS (HR, 5.64; 95% CI, 3.88-8.19; I² = 36%). Following treatment completion, patients with positive ctDNA were at a significantly higher risk of recurrence in both resectable (HR, 5.82; 95% CI, 3.12-10.87; I² = 53%) and unresectable (HR, 2.72; 95% CI, 1.99-3.72; I² = 39%) NSCLC, with elevated risk persisting during long-term surveillance.

CtDNA positivity was also consistently associated with poorer OS throughout the course of treatment. At baseline, positive ctDNA predicted worse OS in both resectable (HR, 4.15; 95% CI, 2.45-7.02) and unresectable (HR, 1.74; 95% CI, 1.49-2.03) NSCLC. This persisted post-treatment, as patients with positive ctDNA and resectable disease had significantly worse OS following surgery (HR, 4.17; 95% CI, 2.22-7.84; I² = 12%), while those with positive ctDNA and unresectable disease experienced poorer OS after completing treatment (HR, 3.38; 95% CI, 1.97-5.80; I² = 57%). Studies also reported that this association remained statistically significant during the surveillance period.

Lastly, ctDNA positivity was associated with an increased risk of recurrence across NSCLC subtypes. Patients with positive ctDNA had a higher recurrence risk at baseline (RR, 1.67; 95% CI, 1.27-2.20; I² = 64%), after treatment completion (RR, 3.13; 95% CI, 2.09-4.67; I² = 52%), and during long-term surveillance (RR, 5.42; 95% CI, 3.20-9.18; I² = 81%). Among studies enrolling at least 10 patients, the median interval between ctDNA detection and radiographic or clinical recurrence was 2.93 months (range, 1.70-12.60).

Realizing ctDNA’s Potential Through Further Research

The researchers acknowledged several limitations, including significant heterogeneity across studies. Many included studies were also small and retrospective, which may limit the robustness of these findings. Still, they expressed confidence in their research and used it to identify areas for future investigation.

“These findings underscore the potential of ctDNA-based liquid biopsy to refine risk stratification, guide individualized treatment decisions, and ultimately improve clinical outcomes in NSCLC,” the authors concluded. “Prospective trials with standardized methodologies are warranted to further substantiate these clinical benefits.”

References

1. Chen X, Zhang M, Zhou Q, et al. Circulating tumor DNA as prognostic markers of non-small cell lung cancer (NSCLC): a systematic review and meta-analysis. Transl Lung Cancer Res. 2025;14(12):5491-5508. doi:10.21037/tlcr-2025-900
2. Schmid S, Jochum W, Padberg B, et al. How to read a next-generation sequencing report-what oncologists need to know. ESMO Open. 2022;7(5):100570. doi:10.1016/j.esmoop.2022.100570