Prognostic value of circulating tumor DNA mutation panels to predict early recurrence and survival outcomes in early-stage breast cancer: a systematic review and meta-analysis

Early-stage breast cancer (BC) shows heterogeneous recurrence risk. Circulating tumor DNA (ctDNA) is promising non-invasive biomarker for minimal residual disease and recurrence prediction, though prognostic performance varies by assay and context.
Eligible studies on ctDNA-based recurrence and survival were identified through comprehensive searches, quality assessed, and analyzed using random-effects meta-analysis to estimate pooled hazard ratios for clinical outcomes. Heterogeneity (I2, τ2, Cochran’s Q), subgroup (detection method or assay type), and sensitivity analyses were performed to examine the consistency and robustness of results.
For recurrence-free survival endpoints, the pooled HR was 3.28 [95% CI: 1.81; 5.93], indicating a high risk of recurrence-related events among ctDNA-positive patients, though substantial heterogeneity was observed (I2 = 93.3%). Pooled effect sized for overall survival (8.92 HR [0.45; 177.87], I2 = 74.7%) and recurrence/relapse (5.21 [0.98; 27.69], I2 = 84.4%) indicating substantial heterogeneity. Subgroup analysis showed lower heterogeneity with digital PCR and personalized ctDNA assays, and sensitivity testing confirmed result stability (2.47 [1.89; 3.23], I2 = 0%).
CtDNA positivity, detected through mutation-based assays strongly associated with increased risk for early recurrence in early-stage BC. Digital PCR and personalized assays demonstrated superior consistency; however, prospective trials are needed to establish its clinical utility.
Early-stage breast cancer individuals exhibit identical tumor grade, size, and receptor status but experience different relapse rates, highlighting that clinicopathological factors incompletely describe residual disease. ctDNA mutation detection panels offer a minimally invasive method to detect tumor-derived genetic modifications and might exhibit minor residual disease after procedural processes. These findings indicated a pooled ratio of 3.28 for survival-free endpoints (DFS, RFS, or EFS), demonstrating the strong prognostic role of ctDNA mutation detection. Investigation of ctDNA as a biomarker can stratify high-risk patients, guide adjuvant treatment intensification, and refine ctDNA surveillance while emphasizing the need for assay standardization before clinical implementation.