HER2-low expression in breast oncology: treatment implications in the smart chemotherapy era

Human epidermal growth factor 2 (HER2)-low breast cancers, defined as tumors exhibiting a HER2 IHC score of 1+ or 2+ nonamplified, represent an emerging targetable entity in the clinicopathologic landscape of breast cancer. Traditionally considered as not sensitive to HER2-targeting agents, these tumors have shown to be susceptible to a new class of drugs, namely antibody-drug conjugates (ADCs). Indeed, the DESTINY-Breast04 phase 3 trial demonstrated the remarkable activity of trastuzumab deruxtecan for treating both hormone-receptor (HR)-positive and triple-negative metastatic breast cancers that show HER2-low expression, reshaping treatment algorithms for these diseases. Concomitantly, the TROPiCS-02 and the ASCENT phase 3 trials have established the role of the anti-Trop-2 ADC sacituzumab govitecan for HR-positive and triple-negative breast cancer, respectively. A careful evaluation of these trials, with their inclusion/exclusion criteria, efficacy and toxicity results, is required in order to understand how best to treat HER2-low metastatic breast cancer in the context of a rapidly evolving therapeutic landscape. The purpose of this narrative review is to recapitulate the available evidence on the use of ADCs in the treatment of HER2-low breast cancer, providing a perspective on their current role in clinical practice.