High Expression of Complement 3 Enhances the Efficacy of Neoadjuvant Chemotherapy Prior to Oncoplastic Surgery for HER2-Positive Breast Cancer

<b><i>Background:</i></b> Neoadjuvant chemotherapy for breast cancer (BC) improves patient prognosis, but its efficacy is hindered by the disease's high heterogeneity. This study enhances effectiveness of targeted therapy to improve clinical outcomes. <b><i>Methods:</i></b> This study enrolled 335 patients from three centers. Differentially expressed genes were identified using DESeq2, and Venn analysis was applied to identify hub Complement genes. Hub gene expression was validated through public databases and IHC in real-world samples. In addition, associations between these genes and clinical factors were evaluated. Survival analysis, using the log-rank test, assessed overall survival (OS), disease-specific survival (DSS), and progression-free interval (PFI) as end points. The authors also locate hub Complement 3 gene position by immunofluorescence. <b><i>Results:</i></b> The study identified <i>C3</i> as a hub Complement gene associated with trastuzumab sensitivity. C3 shows higher expression in normal than tumor tissues. C3 was highly expressed in HER2-negative and early-stage BC, but showed no differences in lymph node or metastasis subgroups. High C3 expression correlated with better OS, DSS, and PFI, particularly in HER2+ patients. IHC analysis confirmed higher C3 expression in normal tissues with the lowest in triple-negative BC. Immunofluorescence findings suggest that C3 recruits complement receptor 2 to enhance trastuzumab efficacy in HER2+ patients. <b><i>Conclusions:</i></b> This finding highlights the potential of complement 3 to improve therapeutic outcomes and pave the way for more personalized treatment strategies in BC.