Unleashing the power of anti-HER2 therapies in metastatic colorectal cancer: paving the way for a brighter future

Colorectal cancer (CRC) constitutes a significant portion of cancer-related deaths in the United States, topping cancer-related mortality among males under 50 years of age. Despite an increase in overall survival throughout the years, the prognosis of metastatic CRC remains poor. In addition to the classic molecular targets in CRC that include epidermal growth factor receptor, BRAF, and vascular endothelial growth factor pathways, human epidermal growth factor receptor 2 (HER2) amplification is an emerging target that has been successfully targeted in advanced CRC, particularly with anti-HER2 monoclonal antibodies and tyrosine kinase inhibitors. With the introduction of potent HER2-directed antibody–drug conjugates, the number of patients who might be eligible for anti-HER2 therapy is expected to increase dramatically as tumors with lower expression of HER2 (termed HER2 low) have shown relevant response rates across several histologies. Yet, several challenges remain to be addressed in this field, including the standardized method to define HER2-low disease and the most efficient payload in this setting, among others. Future studies will help to further characterize HER2-low CRCs, identify additional predictive biomarkers, and assist in the development of better treatments.