Investigating the tumor microenvironment and neoadjuvant therapy response in HER2-positive breast cancer with invasive micropapillary carcinoma component.

e12621 Background: Invasive micropapillary carcinoma (IMPC) is a rare histopathological subtype of breast carcinoma (BC) that shows a high rate of HER2-positive subtype. However, limited studies have evaluated the efficacy of current standard treatment for this special subtype of BC. Methods: HER2-positive BC patients who were treated with neoadjuvant H (trastuzumab) -based or HP (trastuzumab and pertuzumab)-based systemic treatment between 2015 and 2023 at Sun Yat-sen University Cancer Center were reviewed and analyzed. Patients were classified into the IMPC group and the non-IMPC group based on the presence of IMPC component in pre-neoadjuvant tumor samples. Baseline clinical and pathological characteristics, pathological complete response (pCR) rate, and survival outcomes were compared between the two groups. Gene expression profiles and immune infiltration were analyzed using GSE66418 dataset obtained from the Gene Expression Omnibus (GEO) and ImmuCellAI database. Matched pre-neoadjuvant tumor samples from the two groups were obtained to confirm the bioinformatics findings. Results: A total of 244 patients were included, 38 were identified to have IMPC component (IMPC group), and 206 have not (non-IMPC group). Patients in the IMPC group showed a significantly lower pCR rate than those in the non-IMPC group: 21.6% vs. 47.1% ( P =0.004), and 15.0% vs. 28.4% ( P =0.223) and 27.8% vs. 57.6% ( P =0.017) in patients treated with H-based and HP-based neoadjuvant therapy, respectively. Patients in IMPC group also showed a worse disease-free survival (DFS) ( P ＜0.001 ) and overall survival (OS) ( P =0.0482 ) compared with those in the non-IMPC group. Bioinformatics analysis identified the CTNNB1 gene, which encodes the β-catenin protein, was the most highly expressed gene in IMPC patients. Immune profiling showed reduced CD4 + T-cell and CD8 + T-cell infiltration, alongside increased macrophage levels in the IMPC tumor microenvironment. Matched tumor samples confirmed a decrease in tumor-infiltrating lymphocytes (TILs), CD4 + T-cells, and CD8 + T-cells, as well as an increase in M2 macrophages and PD-L1 (programmed death-ligand 1) expression in the IMPC group. Conclusions: HER2-positive BC with IMPC feature shows a immunosuppressive tumor microenvironment and poor response to current standard H or HP-based neoadjuvant therapy. Further investigation in a larger cohort of samples is warranted to validate these findings.