Advancing therapies for HER2-positive metastatic breast cancer: Navigating a wealth of treatment options

The therapeutic landscape of HER2-positive metastatic breast cancer (HER2-positive mBC) has been transformed by increasingly effective HER2-directed therapies. Following the establishment of trastuzumab and pertuzumab as first-line standard treatment, highly active antibody-drug conjugates (ADCs), particularly trastuzumab deruxtecan (T-DXd), together with HER2-selective tyrosine kinase inhibitors (TKIs) such as tucatinib, have substantially improved progression-free and overall survival (PFS, OS) while expanding treatment opportunities, including for patients with central nervous system (CNS) metastases. Consequently, the major clinical challenge has shifted from drug availability to treatment optimisation. Defining the optimal sequence of HER2-directed therapies, balancing efficacy with cumulative toxicity, identifying predictive biomarkers and integrating emerging therapeutic combinations remain unresolved. This review critically examines the evolution of treatment strategies for HER2-positive mBC, focusing on first-line treatment selection, maintenance, CNS management, post-T-DXd sequencing, long responders, mechanisms of resistance and biomarker development. Finally, we discuss emerging therapeutic strategies and future clinical-trial designs that are expected to shape the next generation of personalised HER2-directed therapy. Methods This narrative review synthesised current evidence, prioritising randomised phase III trials, pivotal phase II studies, international guidelines and clinically relevant translational research published or presented up to August 2026. Earlier landmark studies were included when necessary to contextualise current treatment strategies.