Depicting Biomarkers for HER2-Inhibitor Resistance: Implication for Therapy in HER2-Positive Breast Cancer.

Simple Summary: The development of HER2-inhibitors for the treatment of HER2-positive breast cancer represented a breakthrough in targeted tumor therapy. However, as for other targeted therapeutics, drug resistance remains a serious challenge to the treatment of HER2+ BC. Recent research has identified critical biomarkers for HER2-inhibitor resistance and explored more effective treatment regimens in HER2+ breast cancer to overcome drug resistance; however, research on several potential biomarkers and promising alternative therapies remains incomplete. HER2 (human epidermal growth factor receptor 2) is highly expressed in a variety of cancers, including breast, lung, gastric, and pancreatic cancers. Its amplification is linked to poor clinical outcomes. At the genetic level, HER2 is encoded by the ERBB2 gene (v-erb-b2 avian erythroblastic leukemia viral oncogene homolog 2), which is frequently mutated or amplified in cancers, thus spurring extensive research into HER2 modulation and inhibition as viable anti-cancer strategies. An impressive body of FDA-approved drugs, including anti-HER2 monoclonal antibodies (mAbs), antibody–drug conjugates (ADCs), and HER2-tyrosine kinase inhibitors (TKIs), have demonstrated success in enhancing overall survival (OS) and disease progression-free survival (PFS). Yet, drug resistance remains a persistent challenge and raises the risks of metastatic potential and tumor relapse. Research into alternative therapeutic options for HER2+ breast cancer therefore proves critical for adapting to this ever-evolving landscape. This review highlights current HER2-targeted therapies, discusses predictive biomarkers for drug resistance, and introduces promising emergent therapies—especially combination therapies—that are aimed at overcoming drug resistance in the context of HER2+ breast cancer. [ABSTRACT FROM AUTHOR]