Exploration of neoadjuvant therapy regimens and prediction of immune effects for HER2-positive locally advanced breast cancer.

Abstract

e12614 Background: Neoadjuvant therapy (NAT) is currently the main strategy for treating locally advanced HER2-positive breast cancer. However, the heterogeneity in treatment responses necessitates a deeper understanding of the optimal neoadjuvant treatment regimen. This study aims to evaluate the efficacy of a preoperative treatment strategy based on inetetamab. Methods: A stable 4T1-hHER2-luc cell line overexpressing human HER2 was established to assess the antitumor efficacy of inetetamab and trastuzumab. Therapeutic effects were quantified by measuring tumor growth inhibition rates in the Balb/c mouse orthotopic breast cancer model. Further in vivo experiments exploring the efficacy of anti-HER2 targeted therapy in combination with anti-PD-1 (RMP1-14) and chemotherapy were conducted using Mass Cytometry. Phase II clinical trial included HER2-positive LABC patients (stages IIA-IIIC), who received 6-8 cycles of TCbIP (inetetamab combined with pertuzumab, paclitaxel, and carboplatin) regimen. Lymphocyte subset analysis was performed at baseline to assess the correlation between HER2-targeted therapy efficacy and immune system status. The primary endpoint evaluated was the pathologic complete response (pCR) rate. Results: In the in vivo experiments of animal models, inetetamab demonstrated comparable antitumor efficacy to trastuzumab. On day 21 post-treatment, combination therapy with inetetamab (or trastuzumab) plus anti-PD-1 and carboplatin significantly enhanced tumor growth inhibition rates (TGI) compared to dual-targeted therapy combined with chemotherapy group (61.82% vs. 64.52% vs. 36.29%). Mass cytometry of mouse spleen single cells shows that combining anti-PD-1 monoclonal antibody with anti-HER2 therapy more effectively reshapes the immune environment than chemotherapy with anti-HER2, potentially enhancing systemic anti-tumor immunity. In the investigator-initiated trial, the pCR rate among HER2-positive LABC patients was 56.8% (25/44). Further analysis revealed significant differences ( p ＜0.05) in baseline lymphocyte subsets between pCR and non-pCR groups, particularly in Th cells ( p =0.027), activated CD8 + cells ( p =0.031) and suppressor T cells ( p =0.032). Conclusions: In the NAT of HER2-positive breast cancer, the efficacy of inetetamab is comparable to trastuzumab. In vivo experiments confirm that the addition of immunotherapy can effectively reshape the immune environment and enhance systemic anti-tumor immune responses. The results of the clinical study further highlight the potential of inetetamab to improve therapeutic efficacy. This study supports the potential of an inetetamab-based treatment regimen, combining HER2 targeting with anti-PD-1 strategies, to improve treatment outcomes in patients with HER2-positive LABC. Clinical trial information: NCT05749016 .