<i>BRAF</i>-Mutated Advanced Colorectal Cancer: A Rapidly Changing Therapeutic Landscape.

Abstract

<i>BRAF</i>-mutated advanced colorectal cancer is a relatively small but critical subset of this tumor type on the basis of prognostic and predictive implications. <i>BRAF</i> alterations in colorectal cancer are classified into three functional categories on the basis of signaling mechanisms, with the class I <i>BRAF</i>^<i>V600E</i> mutation occurring most frequently in colorectal cancer. Functional categorization of <i>BRAF</i> mutations in colorectal cancer demonstrates distinct mitogen-activated protein kinase pathway signaling. On the basis of recent clinical trials, current standard-of-care therapies for patients with <i>BRAF</i>^<i>V600E</i><i>-</i>mutated metastatic colorectal cancer include first-line cytotoxic chemotherapy plus bevacizumab and subsequent therapy with the BRAF inhibitor encorafenib and antiepidermal growth factor receptor antibody cetuximab. Treatment regimens currently under exploration in <i>BRAF</i>^<i>V600E</i>-mutant metastatic colorectal cancer include combinatorial options of various pathway-targeted therapies, cytotoxic chemotherapy, and/or immune checkpoint blockade, among others. Circumvention of adaptive and acquired resistance to BRAF-targeted therapies is a significant challenge to be overcome in <i>BRAF</i>-mutated advanced colorectal cancer.