Exploring biological heterogeneity and implications on novel treatment paradigm in BRAF-mutant metastatic colorectal cancer. (May 2022)

• Record Type: Journal Article
• Authors: Rodriquenz, Maria Grazia; Ciardiello, Davide; Latiano, Tiziana Pia; Maiorano, Brigida Anna; Martinelli, Erika; Silvestris, Nicola; Ciardiello, Fortunato; Maiello, Evaristo
• Is Part Of: Critical reviews in oncology/hematology. Volume 173(2022)
• Publication Date: 2022-05
• Subjects: AE adverse event -- BRAFMT BRAF-mutant -- BRAFi BRAF inhibitor -- CARG Cancer and Ageing Research Group -- cfDNA cell free DNA -- ctDNA circulating tumor DNA -- CDK4 cyclin-dependent kinase 4 -- CIMP CpG island methylator phenotype -- CMS consensus molecular subtype -- cORR confirmed overall response rate -- CRASH Chemotherapy Risk Assessment scale for High-Age Patients -- CRC colorectal cancer -- DCR disease control rate -- dMMR deficient mismatch repair -- DOR duration of response -- EMA European Medicines Agency -- EMT epithelial mesenchymal transition -- FDA Food and drug administration -- ICI immune checkpoint inhibitor -- mAbs monoclonal antibodies -- MAF mutant allele fraction -- mCRC metastatic colorectal cancer -- MEK mitogen extracellular kinase -- MEKi MEK-inhibitor -- MET mesenchymal epithelial transition MSI-H: high microsatellite instability -- MSS microsatellite stable -- NF-1 neurofibromatosis 1 -- NGS next-generation sequencing -- ORR overall response rate -- OS overall survival -- PS performance status -- PI3K phosphatidylinositol 3 kinase -- PTEN phosphatase and tensin homolog -- QoL quality of life -- PFS progression free survival -- RAC1 Ras-related C3 botolinum toxin substrate 1 -- RCT randomized clinical trial -- RNAseq RNA sequencing -- RNF43 ring finger protein -- TKI tyrosine kinase inhibitor -- WES whole-exome sequencing -- WTS whole-transcriptome sequencing; BRAF -- Colorectal cancer -- V600E mutation -- Non-V600E mutation -- Targeted therapy -- Treatment algorithm -- Secondary resistance -- Immunotherapy; Oncology -- Periodicals; Hematology -- Periodicals; 616.994
• DOI: 10.1016/j.critrevonc.2022.103657
• Languages: English
• ISSNs: 1040-8428

Abstract

Abstract: Approximatively 8–15% of patients with metastatic colorectal cancer (mCRC) harbor mutation in BRAF gene. Recent advances in molecular biology enabled a better knowledge of the molecular heterogeneity within BRAF mutant (BRAF MT ) CRCs, including high rate of overlapping with MSI-H status and detection of non-V600E mutations related to more favorable behavior. Treatment armamentarium has been rapidly growing in this subgroup and includes targeted combinations and immunotherapy for concomitant MSI-H patients, thereby making BRAF MT mCRC an innovative model for precision oncology. Nevertheless, duration of responses to targeted strategies remains unsatisfactory due to the development of secondary resistance, which is currently the field of major clinical research on BRAF MT mCRC. This review explores the molecular, clinical and therapeutic landscape of BRAF MT mCRC as well as an update on current treatment strategies and future perspectives in light of the heterogeneity of BRAF-mutated disease. Furthermore, a novel treatment algorithm for BRAF MT mCRC will be proposed. Highlights: Wide clinical and molecular heterogeneity is seen among patients with BRAF MT mCRC. Encorafenib plus binimetinib combination is superior to chemo in 2nd and 3rd line. Immunotherapy showed encouraging results in concomitant BRAF MT MSI patients. Understanding resistance mechanisms will help to develop new anti-BRAF strategies. New treatment algorithm should consider BRAF molecular profile and clinical features. Novel treatment algorithm will improve outcomes and personalization of the cure.