BRAF mutant colorectal cancer as a distinct subset of colorectal cancer: clinical characteristics, clinical behavior, and response to targeted therapies

Abstract

Despite new and more effective cytotoxic chemotherapy, limitations to conventional agents have been reached in a subset of patients with advanced colorectal cancer (CRC). The identification of novel prognostic and predictive biomarkers to guide individualized treatment plans is critical to overcoming therapeutic resistance. Mutation of the BRAF proto-oncogene is linked to a variety of cancers and is increasingly being used as a prognostic tool and therapeutic target. This paper is a comprehensive review of the literature that summarizes the clinical, pathologic, and molecular features of BRAF mutated CRC that support the hypothesis that BRAF mutant cancers represent a distinct subset of CRC with its own clinical implications with regard to prognosis, treatments and emerging therapeutic strategies.

Keywords: BRAF; Colorectal cancer (CRC); prognostic biomarker; targeted therapy.

Figure 1

Molecular pathways leading to CRC. The classic pathway accounts for 30-70% of CRCs and results in the progression from adenoma to carcinoma. Germline mismatch repair mutations lead to Lynch Syndrome, which accounts for approximately one quarter of all MSI CRCs. These inherited mutations lead to carcinoma when a second hit occurs to result in loss of the wild-type copy. The Serrated/Methylated pathway occurs due to the epigenetic inactivation of MLH1 by hypermethylation resulting in a sporadic MSI phenotype. CRC, colorectal cancer; MSI, microsatellite instability.

Figure 2

MAPK signaling pathway in CRC. Mutations in KRAS and BRAF result in constitutive activation of the signaling cascade resulting in uninhibited cellular proliferation and tumor growth. These effects occur downstream of the EGFR receptor, rendering this mutant tumors resistant to anti EGFR therapies. CRC, colorectal cancer; EGFR, epidermal growth factor receptor; MEK, mitogen-activated protein kinase

Figure 3

Venn diagram showing the relationship between MSI, CIMP and BRAF mutation in CRC. While these numbers vary greatly depending on the stage of disease, approximately 17% of CRC are MSI-high (MSI-H) (33). Lynch Syndrome accounts for one quarter of these tumors while the rest result from BRAF mutant hypermethylation (34). CIMP-high (CIMP-H) tumors account for approximately 20% of all CRCs with BRAF mutation contributing about one third of these tumors (19,23,35). Table 1 provides a summary of the data supporting the incidence of these tumor types in CRC. MSI, microsatellite instability; CIMP, CpG island methylation phenotype; CRC, colorectal cancer.