BACKGROUND: Breast cancer is the most prevalent malignancy in women, and a common source of brain metastases. The development of these metastases involves complex genetic, epigenetic, angiogenic, and stromal interactions that allow circulating tumor cells to cross the blood-brain barrier (BBB) and adapt to the neural niche. The restrictive nature of the BBB limits the penetration of therapeutic agents, making brain metastases particularly challenging to treat. Current standard interventions, such as stereotactic radiosurgery and whole-brain radiotherapy, have limited effectiveness, posing a significant clinical challenge. AIM OF REVIEW: This review aims to synthesize the current understanding of the biology behind breast cancer brain metastases and to evaluate the landscape of emerging therapeutic strategies. We seek to delineate the process of BBB infiltration and the formation of a supportive tumor microenvironment (TME), assess the limitations of existing therapies, and highlight innovative approaches to overcome the drug delivery bottleneck. KEY SCIENTIFIC CONCEPTS OF REVIEW: We delineate the stepwise biology of BBB infiltration and how a distinctive brain metastatic TME supports colonization. The review evaluates the clinical status and limitations of molecularly targeted therapies and immunotherapies, noting that promising preclinical strategies-including kinase modulators and next-generation immunotherapies-are often hindered by resistance mechanisms. To address the critical drug delivery bottleneck imposed by the BBB and blood-tumor barrier (BTB), we highlight advances in minimally invasive delivery techniques designed to enhance drug penetration and efficacy. Finally, we discuss future directions for multidisciplinary treatment strategies, offering new perspectives for precision intervention.
Yang et al. (Fri,) studied this question.