Diagnosis and Treatment of ERBB2-Positive Metastatic Colorectal Cancer

Importance: Amplification of ERBB2 (formerly referred to as HER2) is present in nearly 3% of patients with metastatic colorectal cancer overall and 5% of patients with KRAS and NRAS wild-type tumors. Despite the availability of several ERBB2-targeted therapeutic options for patients with ERBB2-positive breast and gastric/gastroesophageal tumors, to date, there are currently no approved therapies for patients with ERBB2-positive metastatic colorectal cancer, although ERBB2-targeted therapies are recommended in National Comprehensive Cancer Network guidelines. Recent evidence indicates that anti-ERBB2 therapeutic strategies are active in patients with ERBB2-positive metastatic colorectal cancer and could potentially represent a new standard-of-care. Observations: The protein ERBB2 is a member of a family of epidermal growth factor receptors that also includes epidermal growth factor receptor (ERBB1), ERBB3, and ERBB4. Amplification of ERBB2 leads to overexpression of the ERBB2 tyrosine kinase receptor, resulting in aberrant signaling and cell migration, growth, adhesion, and differentiation. Colorectal tumors that harbor ERBB2 amplification are more likely to originate on the left side of the colon, are associated with primary and acquired resistance to anti-epidermal growth factor receptor therapies, and have increased incidence of central nervous system metastases. Using immunohistochemistry, fluorescence in situ hybridization, next-generation sequencing, and liquid biopsy techniques, several randomized clinical trials have evaluated the efficacy of ERBB2-targeted therapies in patients with ERBB2-positive metastatic colorectal cancer. These therapies include monoclonal antibodies, antibody-drug conjugates, and tyrosine kinase inhibitors, many of which were associated with favorable efficacy and safety profiles when treating patients with ERBB2-positive metastatic colorectal cancer. Conclusions and Relevance: The results of this review suggest the ERBB2 receptor is a promising target for patients with metastatic colorectal cancer; however, to date, no therapies are approved for use in this patient population. Therefore, it is imperative to continue to work to address this unmet need so that patients with ERBB2-positive metastatic colorectal cancer have therapeutic options should they become refractory to treatment with standard therapies.