Beyond EGFR inhibitors in advanced colorectal cancer: Targeting BRAF and HER2

The addition of antiepidermal growth factor receptor (EGFR) monoclonal antibodies, cetuximab or panitu-mumab, to conventional chemotherapy has improved clinical outcomes for rat sarcoma virus (RAS) wild -type advanced colorectal cancer patients, however, durable responses and 5-year overall survival rates re-main limited. BRAF V600E somatic mutation and human epidermal growth factor receptor (HER2) amplifica-tion/overexpression have been separately implicated in primary resistance to anti-EGFR therapeutic strate-gies via aberrant activation of the mitogen-activated protein kinase (MAPK) signaling pathway, resulting in poorer outcomes. In addition to being a negative predictive biomarker for anti-EGFR therapy, BRAF V600E mutation and HER2 amplification/overexpression serve as positive predictors of response to therapies tar-geting these respective tumor promoters. This review will highlight key clinical studies that support the rational use of v-Raf murine sarcoma viral oncogene homolog B1 (BRAF) and HER2-targeted therapies, of -ten in combination with other targeted agents, cytotoxic chemotherapy, and immune checkpoint inhibitors. We discuss current challenges with BRAF and HER2-targeted therapies in metastatic colorectal cancer and potential opportunities for improvement. & COPY; 2023 Elsevier Inc. All rights reserved.