Abstract Background: Hormone receptor-positive, HER2-negative (HR+/HER2-) breast cancer represents the most prevalent subtype of breast cancer and generally confers a favorable prognosis. However, its substantial biological heterogeneity poses challenges for risk stratification, as a subset of patients experience aggressive disease and treatment resistance. Aneuploidy is widely recognized as a hallmark of cancer associated with poor prognosis, yet its clinical significance in hormone receptor-positive, HER2-negative (HR+/HER2-) breast cancer remains underexplored. Identifying aneuploid-associated molecular features and therapeutic vulnerabilities within this group is crucial for precision oncology. Methods: We conducted a multi-omics analysis integrating genomic sequencing, transcriptomics, metabolomics, and digital pathology data from a well-annotated cohort of 1,082 breast cancer patients (519 HR+/HER2-). Tumor ploidy was determined using the ASCAT algorithm. Subsequently, we performed comprehensive bioinformatics analyses to characterize genomic instability, transcriptomic and metabolic alterations, immune microenvironment features, and developed a digital pathology-based classifier to predict tumor ploidy. Therapeutic implications were validated using patient-derived organoid (PDO) drug sensitivity assays. Results: Aneuploid tumors constituted a high-risk subgroup within HR+/HER2- breast cancer, associated independently with significantly worse recurrence-free and distant metastasis-free survival. Aneuploid tumors demonstrated extensive genomic instability, elevated homologous recombination deficiency scores, and higher mutation burdens. Transcriptomic profiling revealed pronounced activation of cell cycle pathways, suggesting increased sensitivity to CDK4/6 inhibitors. Metabolic analyses identified heightened nucleotide metabolism, particularly in purine and pyrimidine pathways, indicating potential vulnerability to antimetabolites. Immune analyses showed subtle immunosuppressive features despite comparable overall immune infiltration. Our digital pathology model accurately predicted tumor ploidy, demonstrating high clinical applicability. Functional PDO assays confirmed the enhanced sensitivity of aneuploid tumors to PARP inhibitors, CDK4/6 inhibitors, and antimetabolites. Conclusions: Our study elucidates a distinctive multi-omics landscape of aneuploid HR+/HER2- breast cancer, highlighting critical molecular vulnerabilities suitable for targeted therapies. The development of a robust, scalable digital pathology classifier offers a practical tool for clinical risk stratification and therapeutic decision-making, supporting the integration of ploidy-based personalized treatment strategies into clinical practice. Citation Format: E. Lee, L. Ge, S. Wu, Y. Jiang, Z. Shao. Aneuploid-associated molecular features and therapeutic strategies in hormone receptor-positive HER2-negative breast cancer abstract. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS2-09-10.
Lee et al. (Tue,) studied this question.