Current Understanding of the Molecular Mechanisms of Resistance to Targeted Anti-HER2 Breast Cancer Therapy
TL;DR
This lecture summarizes current evidence on the molecular and genetic mechanisms of resistance to HER2targeted breast cancer therapies and places particular emphasis on factors limiting the efficacy of antibody drug conjugates, which are currently a subject of active investigation.
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.