Introduction and Evolution of Antibody Drug Conjugates in Breast Cancer

Dr. Irene Kang from City of Hope Orange County and Dr. Megan Kruse from Cleveland Clinic introduce this OncLive Insights program reviewing HER2 and TROP2-directed antibody drug conjugates (ADCs) in breast cancer. Dr. Kruse emphasizes that 2025 and 2026 represent a transformative period for ADCs, with expanding utility across all breast cancer subtypes and treatment settings. Previously confined to later-line therapy or HER2-positive disease, ADCs now have indications spanning hormone receptor-positive, HER2-positive, and triple-negative breast cancer (TNBC) across first-line, second-line, and later-line settings, with increasing penetration into early-stage disease.

Dr. Kang explains the mechanistic rationale for HER2 and TROP2 as effective ADC targets. HER2 evolved from established monoclonal antibody success, with trastuzumab deruxtecan (T-DXd) demonstrating activity across the HER2 expression spectrum from positive to low to ultra-low expression levels, as shown in DESTINYBreast-06. TROP2 emerged from efforts to identify tumor-selective targets, with sacituzumab govitecan (SG) initially developed for TNBC where over 90% of tumors express TROP2. However, benefit occurs regardless of TROP2 expression levels, establishing these targets as effective delivery mechanisms for potent chemotherapy payloads.

Resistance patterns remain under active investigation through studies like SOLTI-2201, examining pre- and post-treatment samples to understand changes in target expression, immune system function, and tumor microenvironment. Resistance unfortunately affects most patients receiving ADCs, making this an increasingly important area of research as these agents become cornerstone therapies replacing traditional cytotoxic chemotherapy approaches.