Diagnostic performance of circulating cell-free DNA as a minimally invasive biomarker for breast cancer: a systematic review and meta-analysis of methylation, quantitative, and integrity markers.

INTRODUCTION

We evaluated the diagnostic accuracy of circulating cell-free DNA (cfDNA) and circulating tumor DNA (ctDNA) compared to tissue biopsy in breast cancer across three assay modalities.

METHODS

We searched PubMed, Scopus, and Cochrane for studies published from January 2014 to March 2026. Bivariate random effects models pool sensitivity, specificity, and area under the curve (AUC). Registered under (CRD420261333264).

RESULTS

Eighteen studies with 4,743 participants were included. Quantitative assays achieved the highest sensitivity of 0.930 (95% CI: 0.603-0.991), specificity of 0.899 (95% CI: 0.802-0.951), and AUC of 0.928. Methylation assays showed a sensitivity of 0.752 (95% CI: 0.595-0.862), specificity of 0.841 (95% CI: 0.737-0.908), and AUC of 0.862. Integrity assays yielded a sensitivity of 0.863 (95% CI: 0.682-0.948), specificity of 0.874 (95% CI: 0.781-0.931), and AUC of 0.927. Substantial statistical heterogeneity (I2) occurred across all subgroups. Overall certainty was low, due to case-control designs and inconsistency.

CONCLUSION

While cfDNA cannot replace tissue biopsies, current pooled estimates demonstrate high specificity, suggesting promising potential as an adjunctive diagnostic tool. Quantitative assays show the greatest potential for optimizing patient triage. However, the overall low certainty of evidence highlights an urgent need for standardized prospective studies.