A Narrative Review of the Role of Immunotherapy in Metastatic Carcinoma of the Colon Harboring a BRAF Mutation

Abstract

Patients affected by metastatic carcinoma of the colon/rectum (mCRC) harboring mutations in the BRAF gene (MBRAF) respond poorly to conventional therapy and have a prognosis worse than that of patients without mutations. Despite the promising outcomes of targeted therapy utilizing multi-targeted inhibition of the mitogen-activated protein kinase (MAPK) signaling system, the therapeutic efficacy, especially for the microsatellite stable/DNA proficient mismatch repair (MSS/PMMR) subtype, remains inadequate. Patients with MBRAF/mCRC and high microsatellite instability or DNA deficient mismatch repair (MSI-H/DMMR) exhibit a substantial tumor mutation burden, suggesting a high probability of response to immunotherapy. It is widely acknowledged that MSS/pMMR/mCRC is an immunologically "cold" malignancy that exhibits resistance to immunotherapy. The integration of targeted therapy and immunotherapy may enhance clinical outcomes in patients with MBRAF/mCRC. Efforts to enhance outcomes are exclusively focused on MSS/DMMR-BRAF mutant cancers, which constitute the largest proportion. This review evaluates the clinical efficacy and advancement of novel immune checkpoint blockade therapies for MSI-H/DMMR and MSS/PMMR BRAF mutant mCRC. We examine potential indicators in the tumor immune milieu for forecasting immunotherapeutic response in BRAF mutant mCRC.

Keywords: BRAF; Colon cancer; immunotherapy; microsatellite instability; mutations; review.

Figure 1

Pathways of colorectal carcinogenesis. Activation of the Wnt pathway (primarily via APC mutation) or a mutation in BRAF can initiate colorectal tumorigenesis. BRAF mutations promote tumorigenesis via the serrated neoplasia pathway, leading to MSI with or without hypermutation (indicated in the Figure). Colorectal tumor classifications include CIN, MSI, and the serrated pathway (se CMS). L: Low; H: high; EMT: epithelial to mesenchymal transition (reproduced with permission from Elsevier through Copyright Clearance Center’s RightsLink® service).