Treatment options in BRAF-mutant metastatic colorectal cancer

Abstract

B-type Raf kinase (BRAF) mutations occur in approximately 10% of patients with metastatic colorectal cancers (mCRC). Tumors harboring this mutation have a unique molecular profile and clinical phenotype. Response rate to systemic chemotherapy is poor and associated with shorter survival rate. Although BRAF inhibition dramatically changed treatment for melanoma patients, similar clinical responses were not observed in BRAF-mutant CRC, proposing a distinct mechanism of carcinogenesis. The aggressive biology of BRAF-mutated mCRC has underlined the importance of developing new therapeutic agents to improve outcomes in these patients. Despite numerous attempts, chemotherapy regimens are limited for this population. Reactivation of mitogen activated protein kinase pathway may explain the resistance to monotherapy, thus different combinations to target the pathway at different levels have been studied. This article will describe most suitable treatment options for CRC patients with BRAF mutation and discuss new emerging agents.

The genetics of ductal adenocarcinoma of the pancreas in the year 2020: dramatic progress, but far to go

“…Some of the genetic alterations described above produce cellular changes in the neoplastic cells that are potentially targetable therapeutically. For example, somatic BRAF mutations occur in 1-3% of pancreatic cancers, and BRAF mutations have proven targetable in a number of tumor types [220,221]. In fact, the Food and Drug Administration recently approved the combination of Encorafenib and Cetuximab for metastatic colon cancer with BRAF mutations [220].…”

“…For example, somatic BRAF mutations occur in 1-3% of pancreatic cancers, and BRAF mutations have proven targetable in a number of tumor types [220,221]. In fact, the Food and Drug Administration recently approved the combination of Encorafenib and Cetuximab for metastatic colon cancer with BRAF mutations [220]. Furthermore, although rare, some pancreatic cancers harbor potentially targetable gene fusions [15,[222][223][224][225][226].…”

Contemporary treatment approaches for metastatic colorectal cancer driven by BRAF V600 mutations

“…A relatively small proportion (10%-15%) of patients with metastatic colorectal cancer (mCRC) have activating mutations in the BRAF gene[ 1 , 2 ]. The majority of these mutations involve exon 15 of the gene that encodes the activation loop within the kinase domain of BRAF protein, resulting in the substitution of valine at amino acid position 600 of the BRAF protein by a different amino acid, such as glutamate (V600E), aspartate (V600D), or lysine (V600K)[ 3 , 4 ].…”

“…BRAF mutations initiate and drive the malignant transformation of colonic epithelial cells in the serrated pathway of colorectal tumorigenesis[ 10 ]. BRAF-mutant serrated colorectal cancer (CRC) mostly displays microsatellite instability (MSI), and extensive deoxyribonucleic acid (DNA) methylation[ 2 , 11 ]. DNA methylation at the CpG islands leads to epigenetic inactivation of the DNA mismatch repair protein MLH1, inducing an MSI phenotype.…”

BRAF V600E mutated metastatic colorectal cancer: current progress and future directions

“…In particular, the presence of the BRAF V600E mutation, which is seen in approximately 10% of mCRC, is associated with a worse prognosis [3]. BRAF V600E mut mCRC exhibits unique clinicopathological features including older age and higher stage at diagnosis, predilection for females, right-sided tumor location, poor differentiation, and MSI-high phenotype [3,4]. Tumors tend to exhibit lower response rates and shorter duration of response to standard chemotherapies and can develop resistance to anti-estimated glomerular filtration rate (EGFR) antibodies due to constitutive activation of the mitogen-activated protein kinase (MAPK) pathway [4].…”