New Frontiers in the Treatment of Patients with HER2+ Cancer and Brain Metastases: Is Radiotherapy Always Useful?

Abstract

Brain metastases (BM) pose a significant challenge in the management of HER2+ breast cancer since almost 50% of patients with HER2+ breast cancer develop brain tumors. The complex process of brain metastases involves genetic mutations, adaptations and mechanisms to overcome the blood-brain barrier. While radiotherapy is still fundamental in local therapy, its use is associated with cognitive adverse effects and limited long-term control, necessitating the exploration of alternative treatments. Targeted therapies, including tyrosine kinase inhibitors, monoclonal antibodies, and antibody-drug conjugates, offer promising options for HER2+ breast cancer patients with BM. Clinical trials have demonstrated the efficacy of these agents in controlling tumor growth and improving patient outcomes, posing the question of whether radiotherapy is always the unique choice in treating this cancer. Ongoing research into novel anti-HER2 antibodies and innovative combination therapies holds promise for advancing treatment outcomes and enhancing patient care in this clinical scenario. This narrative review provides a comprehensive overview of traditional medical treatments, molecularly targeted therapy and investigational agents in the management of HER2+ breast cancer with BM, highlighting the evolving landscape and potential future directions in treatment strategies to improve patient survival and quality of life.

Keywords: anti-HER drugs; brain metastases; breast cancer; radiotherapy.

Figure 1

HER2 signaling pathway. Human epidermal growth factor receptors (EGFRs), including HER1 (EGFR), HER2, HER3 and HER4, are receptors that are characterized by extracellular ligand-binding domains, transmembrane domains and intracellular tyrosine kinase domains. Upon binding of specific ligands, the receptors undergo activation via phosphorylation. Notably, HER2 does not require ligand binding for activation. Dimerization triggers subsequent phosphorylation events, initiating downstream signaling cascades, such as the PI3K/AKT and RAF/MEK/MAPK pathways. Activation of these pathways is linked with cell survival, proliferation and progression through the cell cycle. This network of molecular interactions regulates critical cellular processes, contributing to cancer development [6]. Image created with BioRender.com.