Quantitative Analysis of Circulating Cell-Free DNA for Correlation with Lung Cancer Survival: A Systematic Review and Meta-Analysis

Introduction: Despite the growing interest in circulating cell-free DNA (cfDNA), no conclusive evidence exists on the value of quantitative analysis of cfDNA for the prediction of lung cancer survival. We performed a systematic review and meta-analysis of primary studies to estimate the impact of higher baseline cfDNA levels on survival outcomes of patients with lung cancer.

Methods: A comprehensive search was performed using the PubMed, Web of Knowledge, and Cochrane databases up to March 2016. The methodologic quality of identified studies was assessed by the Newcastle-Ottawa scale. Potential sources of heterogeneity were investigated via subgroup and sensitivity analyses, while publication bias was evaluated by funnel plot and Egger's test.

Results: Among the 17 studies identified, 16 studies (n = 1723 patients) and 5 studies (n = 640) were included in the meta-analysis of overall survival (OS) and progression-free survival (PFS), respectively. Despite the fact that the association with PFS did not reach statistical significance (hazard ratio 1.12% [95% confidence interval 0.91-1.37), the pooled analysis for OS showed evidence of an increased risk of death in patients with higher baseline cfDNA levels (hazard ratio 1.76 [95% confidence interval 1.38-2.25]; p < 0.001). Further subgroup and sensitivity analyses confirmed this relationship, although significant between-study heterogeneity was still detected in most comparisons. The Egger's test revealed no statistical evidence of publication bias in the results.

Conclusion: Our findings support the clinical validity of quantitative analysis of cfDNA for the prediction of lung cancer survival. Nevertheless, the establishment of a robust standardized method for determination of optimal cutoff thresholds is required to define the clinical relevance of cfDNA quantification for lung cancer management.