Prognostic significance of circulating tumor DNA in early breast cancer: a systematic review and meta-analysis.

BACKGROUND

Circulating tumor DNA (ctDNA) has emerged as a promising noninvasive biomarker for monitoring minimal residual disease (MRD) and predicting recurrence in early-stage breast cancer (EBC). Despite growing interest, the prognostic impact of ctDNA detection in this setting remains to be fully elucidated.

METHODS

A systematic review and meta-analysis were conducted on prospective studies assessing the association between ctDNA positivity and outcomes in early or locally advanced non-metastatic breast cancer. Databases including PubMed and the Cochrane Library were systematically searched. Studies were included if they reported hazard ratios (HRs) for disease-free survival (DFS) and/or overall survival (OS) according to ctDNA status. Pooled HRs were calculated using random-effects models; heterogeneity was evaluated with the I2 statistic.

RESULTS

Eighteen studies comprising 1670 patients were included. ctDNA positivity was significantly associated with shorter DFS (pooled HR 6.92, 95% CI 3.64-13.13; p < 0.0001; I2 = 79.7%). This association held across subtypes and timepoints, including post-surgical and longitudinal assessments. In the neoadjuvant setting, ctDNA positivity was associated with increased recurrence risk (HR 6.06, 95% CI 2.85-12.87; p < 0.0001), while in the adjuvant setting, it was an even stronger predictor of relapse (HR 14.76, 95% CI 1.11-197.02; p = 0.042). In a combined early-stage setting, ctDNA positivity correlated with significantly worse DFS (HR 6.55, 95% CI 1.41-30.39; p = 0.017). A non-significant trend was observed for worse OS (HR 3.91, 95% CI 0.78-19.72; p = 0.098).

CONCLUSIONS

ctDNA positivity is a robust prognostic biomarker for recurrence in early breast cancer. Its integration into post-treatment surveillance and interventional trials may enable risk-adapted strategies and early therapeutic intervention.