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BACKGROUND
The ability to undertake molecular analysis to inform on prognosis and predictors of response to therapy is limited by accessibility of tissue. Measurement of total circulating free DNA (cfDNA) or circulating tumor DNA (ctDNA) in peripheral blood may allow easier access to tumor material and help to predict clinical outcomes.

METHODS
A systematic review of electronic databases identified publications exploring the association between cfDNA or ctDNA and overall survival (OS) in solid tumors. Hazard ratios (HR) for OS were extracted from multivariable analyses and included in a meta-analysis. Pooled hazard ratios were computed and weighted using generic inverse-variance and random-effect modeling. For studies not reporting multivariable analyses, univariable odds ratios (OR) were estimated from Kaplan-Meier curves for OS at one and three years.

RESULTS
Thirty-nine studies comprising 4052 patients were included in the analysis. Detection of ctDNA was associated with a significantly worse OS in multivariable analyses (HR 2.70, 95% CI 2.02-3.61, p<0.001). Similar results were observed in the univariable analyses at 3 and one year (OR 4.83, 95% CI 3.20-7.28, p<0.001).There was also a statistically significant association between high total cfDNA and worse OS for studies reporting multivariable and univariate data at 3 years (HR 1.91, 95% CI 1.59-2.29, p<0.001; and OR 2.82, 95% CI 1.93-4.13, p<0.001, respectively).

CONCLUSIONS
High levels of total cfDNA and presence of ctDNA are associated with worse survival in solid tumors.

IMPACT
circulating DNA is associated with worse outcome in solid tumors.