Abstract

HER2-positive breast cancer represents a subtype characterized by overexpression of the human epidermal growth factor receptor 2 (HER2), which drives aggressive tumor growth and poorer prognosis. Targeted therapies such as HER2-directed monoclonal antibodies (trastuzumab, pertuzumab) and tyrosine kinase inhibitors (lapatinib,neratinib) have transformed treatment outcomes. However, resistance mechanisms often limit their long-term efficacy. This review explores current understanding of resistance mechanisms in HER2-targeted therapies, including HER2 alterations, downstream signaling pathways, and immune evasion strategies. Emerging strategies to overcome resistance, such as combination therapies, novel HER2-targeted agents, and immune checkpoint inhibitors, are discussed. Advances in biomarker development and personalized medicine approaches are also highlighted to optimize treatment selection and improve outcomes for HER2-positive breast cancer patients