Int J Mol Sci. 2026 Aug 28. pii: 7719. [Epub ahead of print]27(17):
Despite advances in systemic therapy, many early breast cancer patients experience recurrence due to subclinical minimal residual disease (MRD). Circulating tumor DNA (ctDNA) and circulating tumor cells (CTCs) have emerged as promising liquid biopsy markers for post-treatment MRD detection. This pre-registered systematic review and meta-analysis (PROSPERO/PRISMA 2020) evaluated their comparative prognostic significance. Seven databases were searched from inception to March 2026. Eligible studies included early breast cancer patients undergoing post-treatment ctDNA or CTC assessment after neoadjuvant or adjuvant therapy, reporting survival outcomes with extractable hazard ratios. Quality was assessed using the QUIPS tool; random-effects meta-analyses used the REML estimator. Seventeen studies (thirteen ctDNA, four CTCs; n = 3030) were included. Post-treatment CTC positivity was significantly associated with poorer survival (pooled HR = 2.99, 95% CI: 1.99-4.49; I2 = 17.2%). ctDNA positivity demonstrated a substantially stronger prognostic effect (pooled HR = 10.28, 95% CI: 6.32-16.70; I2 = 47.3%). Subgroup analyses identified assessment timing as a key heterogeneity source, with stronger effects after adjuvant (HR = 20.62; k = 4) versus neoadjuvant therapy (HR = 6.07; k = 9); given the small number of post-adjuvant studies, this finding is hypothesis-generating. No significant publication bias was detected. Both markers were significant prognostic markers of MRD. ctDNA showed a stronger pooled prognostic association, although no study assessed both biomarkers within the same cohort and direct head-to-head comparisons therefore remain lacking. Prospective randomized trials are needed to evaluate MRD-guided treatment strategies.
Keywords: circulating tumor DNA; circulating tumor cells; early breast cancer; liquid biopsy; meta-analysis; minimal residual disease; prognostic biomarker; systematic review