Central nervous system and leptomeningeal metastases in patients with HER2-positive breast cancer: A comprehensive review and therapeutic algorithm proposal

Breast cancer (BC) is the second leading cause of brain metastases (BMs). The incidence of BMs has increased over the last decades as results of both the improvement in imaging detection power and the longer life expectancy of patients with metastatic disease. In human epidermal growth factor receptor 2-positive (HER2 +) advanced BC, the incidence of BMs is especially high and is associated with poor prognosis. The central nervous system (CNS) has historically been considered a sanctuary site since the blood–brain barrier prevents the penetration of most therapeutic agents. Therefore, loco-regional therapies, such as surgery or radiotherapy, have largely represented the only effective strategies for treating intracranial disease. However, the development of several anti-HER2 agents with proven CNS efficacy has resulted in unprecedented disease control, raising the question of the optimal strategy to adopt in the management of both extracranial and intracranial disease. Here, we provide a comprehensive narrative review of the therapeutic management of HER2 + BMs and leptomeningeal disease, highlighting recent advances in the efficacy of both locoregional and systemic strategies and briefly discuss brain imaging screening and biomarkers for BMs risk stratification. Building on this evidence, we propose an updated, integrated treatment algorithm designed to optimize clinical decision-making.