Treatment of breast cancer brain metastases in the era of novel drugs

Abstract

Brain metastases from breast cancer (BCBMs) are a major cause of morbidity and mortality and remain a critical unmet clinical need across molecular subtypes. Their incidence is rising as improved systemic therapies prolong survival in metastatic breast cancer and advances in neuroimaging allow earlier detection of central nervous system (CNS) disease. Historically, management relied mainly on local approaches such as surgery and radiotherapy because many systemic agents have limited ability to cross the blood–brain barrier. However, the therapeutic landscape is rapidly evolving with the development of systemic treatments showing clinically meaningful intracranial activity. In hormone receptor–positive/HER2-negative disease, treatment options are expanding with targeted and novel endocrine-based therapies that may achieve therapeutically relevant CNS concentrations. In addition, targeting the PI3K/AKT/mTOR pathway and the increasing use of antibody–drug conjugates (ADCs), including trastuzumab deruxtecan in HER2-low and-ultralow disease, may further broaden systemic strategies. In HER2-positive breast cancer, brain-penetrant tyrosine kinase inhibitors and highly active ADCs have significantly improved outcomes. Tucatinib-based combinations and trastuzumab deruxtecan have demonstrated substantial intracranial activity in prospective trials, shifting the treatment paradigm by supporting systemic therapy even in the presence of active brain metastases. Lastly, in triple-negative breast cancer, outcomes remain poor, but ADCs, immunotherapy-based strategies, and PARP inhibitors for germline BRCA-mutated disease are under investigation. A major limitation remains the underrepresentation of patients with brain metastases in clinical trials. This review summarizes current evidence on systemic therapies for BCBM across subtypes and highlights the need for CNS-inclusive trials and the development of effective CNS-active treatments.