Subtype-specific APOBEC enrichment links genomic instability to predict immunotherapy response in breast cancer subtypes.

Breast cancer (BRCA), a prevalent malignancy among women, significantly impacts survival quality and life expectancy, with rising incidence and mortality rates posing substantial psychological and economic burdens on patients and families. Current treatment modalities exhibit considerable variability in efficacy, often hindered by resistance and recurrence, thus emphasizing the urgent need for novel biomarkers and therapeutic targets. This study investigates the genomic characteristics of the APOBEC family genes across different BRCA subtypes and their influence on mutation profiles. Utilizing data from multiple databases, including The Cancer Genome Atlas (TCGA) and the Clinical Proteomic Tumor Analysis Consortium (CPTAC), SMC, and Metabric, we conducted a comprehensive analysis of APOBEC mutation enrichment scores (APMs) and tumor mutational burden (TMB). Our findings reveal that APMs are significantly elevated in BRCA compared to other cancers, with distinct variations among subtypes; specifically, HER2+ breast cancer exhibited the highest APMs while triple-negative breast cancer (TNBC) displayed the lowest. We also observed correlations between APMs and TMB, suggesting differential immune microenvironment interactions, particularly in HER2+ versus TNBC and Luminal subtypes. Furthermore, APMs demonstrated a significant association with DNA damage response pathways, with implications for treatment strategies. Our study subsequently investigates the predictive role of the APOBEC mutagenesis-related prognostic risk score (AMrs) in guiding targeted and immunotherapy combinations for different subtypes of BRCA, specifically TNBC, Luminal, and HER2+ breast cancer. By leveraging a multi-center database, we seek to validate the correlation between AMrs scores and the sensitivity of these BRCA subtypes to immunotherapy. Based on in vivo experiments in mice, our research highlights that the administration of specific agents-AZD3759 for HER2+, Vorinostat for TNBC, and SGC0946 for Luminal-when combined with anti-PD-1 therapy, not only boosts therapeutic effectiveness but also transforms the immunological environment within tumors. This synergistic approach led to notable reductions in tumor volume and an increase in cytotoxic T cell density in in vivo and in vitro experiments, further validating the role of AMrs scores in tailoring treatment modalities across BRCA subtypes. Overall, our study elucidates the critical role of APOBEC family genes in BRCA heterogeneity, highlighting their potential as biomarkers for personalized therapeutic approaches and pointing towards future research directions in integrating APOBEC-related mechanisms with immunotherapy.