Molecular Basis of HER2-Targeted Therapy for HER2-Positive Colorectal Cancer

Human epidermal growth factor receptor 2 (HER2) amplification has emerged as a biomarker in colorectal cancer (CRC), occurring in 1-4% of metastatic CRC (mCRC). In addition to conventional methods, such as immunohistochemistry and fluorescence in situ hybridization, next-generation sequencing-based tissue or circulating tumor DNA analysis has recently been used to identify HER2 amplification and assess HER2 overexpression. Prospective clinical trials have demonstrated the efficacy of HER2-targeted therapies in HER2-positive mCRC. The TRIUMPH study, a phase II study of dual HER2 antibodies, i.e., pertuzumab plus trastuzumab, demonstrated promising efficacy for patients with HER2-positive mCRC confirmed by tissue-and/or blood-based techniques, which led to the regulatory approval of this combination therapy in Japan. The mechanisms associated with efficacy and resistance have also been explored in translational studies that incorporate liquid biopsy in prospective trials. In particular, HER2 copy number and co-alterations have repeatedly been reported as biomarkers related to efficacy. To improve the therapeutic efficacy of the current strategy, many clinical trials with various HER2-targeted agents are ongoing. This review discusses the molecular basis of HER2-targeted therapeutic strategies for patients with HER2-positive mCRC.