Prognostic significance of ctDNA mutations in advanced HER2-positive breast cancer treated with targeted therapy: A meta-analysis

BACKGROUND: Circulating tumor DNA (ctDNA) is a promising noninvasive biomarker in advanced breast cancer. In patients with advanced HER2-positive disease, responses to targeted therapy vary. The prognostic significance of ctDNA mutations across different genes and treatment regimens remains to be fully clarified. OBJECTIVES: This meta-analysis evaluated the predictive role of ctDNA mutations in guiding anti-HER2 therapy. MATERIAL AND METHODS: We searched PubMed, Embase, the Cochrane Library, and major oncology conference proceedings for studies evaluating associations between ctDNA and progression-free survival (PFS) or overall survival (OS) in breast cancer. Pooled hazard ratios (HRs) and odds ratios (ORs) were calculated using a pre-specified random-effects model. Study quality, publication bias, and robustness were assessed using the Newcastle-Ottawa Scale (NOS), funnel plots, Egger's test, and leave-one-out analyses. RESULTS: A total of 12 studies involving 558 patients were included. Baseline ctDNA mutation status was significantly associated with shorter PFS (HR = 1.73, 95% confidence interval (95% CI): 1.06-2.82, p = 0.03). PIK3CA mutations correlated with worse PFS (HR = 2.12, 95% CI: 1.43-3.15, p = 0.002), whereas ERBB2 mutations showed no significant association. ctDNA mutations predicted poorer PFS in tyrosine kinase inhibitor (TKI)-treated patients (HR = 2.04, 95% CI: 1.29-3.24, p = 0.002), particularly in patients receiving pyrotinib (HR = 2.77, 95% CI: 1.96-3.92, p < 0.001), but not in those receiving non-pyrotinib TKIs. Worse PFS was also observed in monotherapy (HR = 2.65, 95% CI: 1.81-3.88, p < 0.001) and capecitabine-based combination regimens (HR = 2.07, 95% CI: 1.22-3.50, p = 0.007), but not in other combination therapies. CONCLUSION: Circulating tumor DNA mutation status may serve as a prognostic biomarker in patients receiving HER2-targeted therapies. PIK3CA mutations were associated with worse outcomes, whereas ERBB2 mutations showed no significant effect. The prognostic significance of ctDNA was most pronounced in patients treated with TKIs, particularly pyrotinib, and remained evident in monotherapy and capecitabine-based regimens. These findings support the potential utility of ctDNA monitoring for risk stratification and personalized management in advanced HER2-positive breast cancer.