Characterization of immune microenvironment identifies prognostic and immunotherapy benefit for trastuzumab-based therapy

Background and Purpose: The tumor immune microenvironment (TIME) of breast cancer with positive human epidermal growth factor receptor 2 (HER2) is significantly related to the efficacy of trastuzumab, indicating the clinical potential of immunocheckpoint therapy combined with trastuzumab. This study aimed to explore the predictors of HER2-positive breast cancer combination therapy and screen the potential beneficiaries of combination therapy. Methods: Transcriptome and genome data of 509 HER2-positive breast cancer samples of patients receiving trastuzumab treatment from Gene Expression Omnibus (GEO) database and 67 HER2-positive breast cancer samples from The Cancer Genome Atlas (TCGA) databases were collected. Trastuzumab-resistant group’s differentially expressed genes were identified and analyzed for functional enrichment and protein-protein interaction. The log-rank test and multivariate COX proportional hazards regression were used with clinical data to create the prediction model. The TIME landscape was characterized using the CIBERSORT. The immunotherapy benefit was valued by the tumor immune dysfunction and exclusion (TIDE) score. Results: The trastuzumab related genetic prognostic index (TRGPI) consisting of four hub genes (GATA6, TRPV6, AMACR, ZHX2) was constructed by analyzing the immune microenvironment and gene expression characteristics between trastuzumab-remission group and trastuzumab-resistance group. Importantly, the results revealed that patients with lower TRPGI were trastuzumab-sensitive and more likely to benefit from immunotherapy because of the increased percentages of CD8+ T cells, active natural killer cells and programmed death-1 (PD-1) expression. Conclusion: This study redefined the benefit population through TIME and provided a selectable strategy of trastuzumab plus immunotherapy for HER2-positive breast cancer.