title: Quantitative Analysis of Circulating Cell-Free DNA for Correlation with Lung Cancer Survival: A Systematic Review and Meta-Analysis.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Department of Pharmaceutical Sciences and Interdepartmental Research Center of Pharmacogenetics and Pharmacogenomics, University of Piemonte Orientale "A. Avogadro," Novara, Italy.
authors.forename: Sarah
authors.initials: S
authors.lastname: Cargnin
authors.affiliation: Department of Pharmaceutical Sciences and Interdepartmental Research Center of Pharmacogenetics and Pharmacogenomics, University of Piemonte Orientale "A. Avogadro," Novara, Italy.
authors.forename: Pier Luigi
authors.initials: PL
authors.lastname: Canonico
authors.affiliation: Department of Pharmaceutical Sciences and Interdepartmental Research Center of Pharmacogenetics and Pharmacogenomics, University of Piemonte Orientale "A. Avogadro," Novara, Italy.
authors.forename: Armando A
authors.initials: AA
authors.lastname: Genazzani
authors.affiliation: Department of Pharmaceutical Sciences and Interdepartmental Research Center of Pharmacogenetics and Pharmacogenomics, University of Piemonte Orientale "A. Avogadro," Novara, Italy. Electronic address: salvatore.terrazzino@uniupo.it.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Terrazzino
mesh_terms: D014408:Biomarkers, Tumor / Q000097:blood / Q000235:genetics*; D004273:DNA, Neoplasm / Q000097:blood* / Q000235:genetics*; D055088:Early Detection of Cancer; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000401:mortality* / Q000473:pathology / Q000628:therapy; D011379:Prognosis; D015996:Survival Rate
chemical_list: D014408:Biomarkers, Tumor; D004273:DNA, Neoplasm
keywords: Circulating cell-free DNA; Meta-analysis; NSCLC; Survival