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¹Department of Radiation Oncology, University of Health Sciences, Dr. Lütfi Kırdar Kartal City Hospital, İstanbul-Türkiye DOI : 10.5505/tjo.2025.3 Breast cancer is a biologically complex and heterogeneous disease composed of several molecular subtypes, each characterized by unique genomic alterations and specific therapeutic responses. Despite significant advancements achieved through systemic therapies and radiotherapy (RT), treatment resistance and disease recurrence continue to represent major obstacles, particularly in patients with advanced-stage or high-risk tumors. The introduction of novel targeted and immune-modulating therapies including CDK4/6 inhibitors, PI3K/mTOR pathway inhibitors, PARP inhibitors, HER2-targeted monoclonal antibodies, antibody?drug conjugates (ADCs), and immune checkpoint inhibitors (ICIs) has revolutionized the management of breast cancer by enabling a more personalized approach based on tumor biology. Both experimental and clinical evidence indicate that combining these systemic treatments with radiotherapy can produce synergistic antitumor effects through several biological mechanisms. These mechanisms include the enhancement of radiation-induced DNA damage, inhibition of DNA repair processes, and modulation of the tumor immune microenvironment. Such therapeutic interactions may improve local tumor control, enhance radiosensitivity, and allow for treatment de-escalation in carefully selected patients, provided that close attention is paid to safety, particularly regarding hematologic, gastrointestinal, and pulmonary toxicities. The purpose of this review is to provide a comprehensive understanding of the biological mechanisms, preclinical and clinical evidence, and safety considerations that form the foundation for integrating radiotherapy with emerging systemic therapies in breast cancer. A deeper insight into these interactions could optimize therapeutic outcomes while minimizing adverse effects. Furthermore, strategic optimization of dose, timing, and treatment sequencing holds the potential to develop individualized, balanced, and multimodal treatment strategies for breast cancer in the future. Keywords : CDK4/6 inhibitors; antibody?drug conjugates; breast cancer; HER2-targeted therapy; immunotherapy; PARP inhibitors; radiotherapy; targeted therapy