Genetic interactions reveal distinct biological and therapeutic implications in breast cancer

Co-occurrence and mutual exclusivity of genomic alterations may reflect the existence of genetic interactions, potentially shaping distinct biological phenotypes and impacting therapeutic response in breast cancer. However, our understanding of them remains limited. Herein, we investigate a large-scale multi-omics cohort (n = 873) and a real-world clinical sequencing cohort (n = 4,405) including several clinical trials with detailed treatment outcomes and perform functional validation in patient-derived organoids, tumor fragments, and in vivo models. Through this comprehensive approach, we construct a network comprising co-alterations and mutually exclusive events and characterize their therapeutic potential and underlying biological basis. Notably, we identify associations between TP53mut-AURKAamp and endocrine therapy resistance, germline BRCA1mut-MYCamp and improved sensitivity to PARP inhibitors, and TP53mut-MYBamp and immunotherapy resistance. Furthermore, we reveal that precision treatment strategies informed by co-alterations hold promise to improve patient outcomes. Our study highlights the significance of genetic interactions in guiding genome-informed treatment decisions beyond single driver alterations. [Display omitted] •We built a large multi-omics cohort and a real-world clinical sequencing cohort•A genetic interaction network involves co-occurring and mutually exclusive events•Co-alterations influence treatment outcomes across diverse clinical scenarios•Genome-informed treatment decisions should extend beyond single driver alterations Lin et al. leverage a large-scale multi-omics cohort and a real-world clinical sequencing cohort to explore genetic interactions and their impact on treatment outcomes across various clinical scenarios in breast cancer. These findings underscore the importance of making genome-informed precision treatment decisions that consider individual driver alterations and beyond.