Correlation between the efficacy of anti-HER-2 targeted therapy and ctDNA status: A meta-analysis.

e13014 Background: Circulating tumor DNA (ctDNA) is a promising biomarker for cancer prognosis and therapeutic monitoring. While HER2-targeted therapies improve outcomes in cancers like breast cancer, their efficacy varies. Evidence suggests ctDNA mutation status may predict progression-free survival (PFS) in anti-HER2 therapies, but its role across different regimens remains unclear. This meta-analysis evaluates the prognostic value of ctDNA mutations to guide personalized treatment strategies. Methods: A systematic search of PubMed, Embase, and the Cochrane Library (up to September 1, 2024) was conducted, supplemented by manual searches of oncology conferences. Eligible studies included those linking ctDNA status to PFS or OS in breast cancer patients. The pooled OR and HR values were considered statistically significant if the upper limit of 95% CI was below 1.0, with the significance level set at P < 0.05 (two-sided). Pooled HRs and ORs were calculated using fixed- or random-effects models based on heterogeneity (I²> 50%). Publication bias and sensitivity analyses were performed to ensure result reliability. Results: A total of 429 records were identified, with 12 studies involving 578 patients included in the final analysis. ctDNA mutation status was significantly associated with shorter PFS in patients receiving anti-HER therapies (HR = 0.55, 95% CI: 0.34–0.88, P = 0.01). PIK3CA mutations were linked to reduced PFS (HR = 0.48, 95% CI: 0.33–0.69, P < 0.0001), while ERBB2 mutations had no significant impact. Subgroup analyses showed that in TKI-treated patients, ctDNA mutations predicted poorer PFS (HR = 0.46, 95% CI: 0.30–0.72, P = 0.0005), whereas no significant association was found in non-TKI-treated patients. Similarly, ctDNA mutations predicted shorter PFS in pyrotinib-treated patients (HR = 0.36, 95% CI: 0.25–0.51, P < 0.00001) but not in those treated with non-pyrotinib TKIs. ctDNA mutations significantly reduced PFS in monotherapy (HR = 0.42, 95% CI: 0.28–0.63, P < 0.0001), but no significant association was observed in combination therapies. In capecitabine-based combination therapies, ctDNA mutations predicted shorter PFS (HR = 0.36, 95% CI: 0.24–0.53, P < 0.00001), while other combinations showed no significant association. Conclusions: ctDNA mutation status is a significant predictor of poor prognosis, strongly associated with shorter PFS in monotherapy and capecitabine-based combinations. PIK3CA mutations predict worse outcomes in HER-targeted therapies, whereas ERBB2 mutations show inconsistent effects, likely influenced by other factors. In TKI-treated patients, ctDNA mutations, especially with pyrotinib, are robust predictors of reduced PFS, while their predictive value is limited in non-TKI therapies and non-capecitabine combinations. Dynamic ctDNA monitoring is essential for identifying high-risk patients and optimizing treatment strategies to improve clinical outcomes.