Circulating tumour DNA and its clinical relevance in predicting progression-free survival and overall survival in patients with advanced breast cancer: a systematic review and meta-analysis.

PURPOSE: Treatment strategies for advanced breast cancer (ABC) are rapidly evolving, but treatment decisions and monitoring remain dependent on imaging-based assessments. Circulating tumour DNA (ctDNA) has emerged as a minimally invasive biomarker with potential to provide real-time assessments, yet its clinical relevance in ABC has not been established. This systematic review and meta-analysis evaluates the prognostic value of ctDNA in ABC. METHODS: Medline, Embase, and Cochrane databases were systematically searched up to 07/02/2025. Eligible studies analysed associations between ctDNA and progression free survival (PFS) and/or overall survival (OS) in patient with ABC. Study quality was assessed using the Quality in Prognosis Studies Tool. Hazard ratios (HR) with 95% confidence intervals (CI) were extracted, and meta-analyses were performed using random-effects models. RESULTS: Sixty-four studies were included and divided into subgroups. Elevated ctDNA levels at baseline were significantly associated with shorter PFS (n = 2,586, pooled HR = 2.0; 95% CI: 1.8-2.3) and OS (n = 2,454, pooled HR = 2.6; 95% CI: 2.1-3.3). Unfavourable changes in ctDNA levels were associated with reduced PFS (n = 710, pooled HR = 2.5; 95% CI: 1.9-3.4) and OS (n = 154, pooled HR = 2.4; 95% CI: 1.5-3.8). Additionally, analyses on specific genetic alterations in ctDNA and survival outcomes indicated a less favourable prognosis when detected at baseline. However, results were not consistent. CONCLUSIONS: This review supports an association between baseline ctDNA levels, on-treatment changes in ctDNA levels, and survival outcomes in ABC. Furthermore, specific genetic alterations in ctDNA add prognostic information and may support treatment tailoring. TRIAL REGISTRATION: Registered in PROSPERO (CRD42024534851).