Radiotherapeutic Strategies to Overcome Resistance of Breast Cancer Brain Metastases by Considering Immunogenic Aspects of Cancer Stem Cells

SIMPLE SUMMARY: Modern radiotherapy offers several options for the treatment of brain metastases from breast cancer. The radioresistant subpopulation of cancer stem cells (CSCs) pose a particular challenge to a complete cure. This is attributable to the enhanced activation of molecular defense mechanisms that prevent cell death as a consequence of DNA damage. Another fundamental feature of CSCs is their evasion of the immune system. Combining inhibitors of both properties with irradiation may be an attractive option to advance existing therapies, and this is the subject of the data summarized here. ABSTRACT: Breast cancer is the most diagnosed cancer in women, and symptomatic brain metastases (BCBMs) occur in 15–20% of metastatic breast cancer cases. Despite technological advances in radiation therapy (RT), the prognosis of patients is limited. This has been attributed to radioresistant breast cancer stem cells (BCSCs), among other factors. The aim of this review article is to summarize the evidence of cancer-stem-cell-mediated radioresistance in brain metastases of breast cancer from radiobiologic and radiation oncologic perspectives to allow for the better interpretability of preclinical and clinical evidence and to facilitate its translation into new therapeutic strategies. To this end, the etiology of brain metastasis in breast cancer, its radiotherapeutic treatment options, resistance mechanisms in BCSCs, and effects of molecularly targeted therapies in combination with radiotherapy involving immune checkpoint inhibitors are described and classified. This is considered in the context of the central nervous system (CNS) as a particular metastatic niche involving the blood–brain barrier and the CNS immune system. The compilation of this existing knowledge serves to identify possible synergistic effects between systemic molecularly targeted therapies and ionizing radiation (IR) by considering both BCSCs’ relevant resistance mechanisms and effects on normal tissue of the CNS.