Current Understanding of the Molecular Mechanisms of Resistance to Targeted Anti-HER2 Breast Cancer Therapy

Abstract

This lecture summarizes current evidence on the molecular and genetic mechanisms of resistance to HER2targeted breast cancer (BC) therapies. Despite marked improvements in HER2-positive BC treatment, the efficacy of targeted therapy remains suboptimal. Within the first two years after completing combined therapy, 10-15% of patients develop locoregional recurrences, and 15-25% of patients develop distant metastases within the first five years of follow-up, which is attributed to drug resistance. The primary mechanisms of resistance are discussed, including impaired binding of targeted drugs to HER2, activating HER2 mutations, HER2 intratumoral heterogeneity, cross-talk between HER2 and estrogen receptors, alterations in intracellular signaling pathways, the role of HER2-HER3 heterodimer, and the tumor microenvironment. Particular emphasis is placed on factors limiting the efficacy of antibody drug conjugates, which are currently a subject of active investigation. Understanding the mechanisms of resistance to HER2-targeted therapies is crucial for optimizing treatment strategies for HER2-positive BC patients. This includes novel drug development, early resistance prevention, and personalized therapy to improve patient outcomes.