Lin, Po‐Han

Abstract Neoadjuvant therapy (NAT) with HER2-targeted agents is the standard treatment for patients with HER2-positive early breast cancer (HER2 + EBC). Although high levels of tumor-infiltrating lymphocytes (TILs) are associated with higher pathologic complete response (pCR) rates and improved recurrence-free survival (RFS), the specific immune components responsible remain unclear. In this study, pretreatment tumor biopsies from 188 patients receiving HER2-targeted NAT were analyzed. Univariate analysis revealed that enrichment of TIL-B cells in tumors, high HER2 mRNA and low ESR1 mRNA expression were linked to pCR (both p < 0.01). Multivariate analysis confirmed TIL-B-cell enrichment as an independent predictor of pCR. Mature IgD/IgM-high B cells, but not immature RAG1 + B cells, independently predicted pCR. Transcriptomic profiling identified 265 upregulated genes in pCR tumors enriched in MHC class II antigen presentation pathways. Immunofluorescence demonstrated increased spatial interaction of mature B cells with CD4 + T cells in pCR tumors, consistent with active antigen presentation. The antigen presenting B-cell signature, integrated mature B-cell and MHC II profile, was the strongest independent predictor of pCR (OR = 3.008, 95% CI: 1.196–7.544, p = 0.019) and was also significantly associated with improved RFS (HR = 0.109, 95% CI: 0.014–0.872), highlighting B-cell–mediated antigen presentation as a clinically relevant biomarker in HER2 + EBC.