BRAF V600E and metastatic colorectal cancer

BRAF V600E and metastatic colorectal cancer

BRAF is a serine-threonine kinase playing a key role as downstream RAS effector in the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) signal transduction cascade

BRAF V600E mutation accounts for 8-10% of metastatic colorectal cancer (mCRC) patients and it is an established prognostic factor (1,2)

• is recognized as a poor prognostic factor with a median overall survival inferior to 20 months (1)
  
  
• BRAF V600E mutant mCRCs are frequently characterized by hypermethylation, microsatellite instability (MSI) and consensus molecular subtype 1 (CMS1)
  
  
• BRAF mutations account for 8-10% of mCRCs and more than 90% are missense mutations occurring in codon 600, leading to an aminoacidic substitution of a valine for a glutamic acid (V600E)
  
  
• BRAF mutations different from V600E (BRAFnon-V600E) account for about 2% of mCRCs and they have been associated with specific clinicopathological features and a better clinical outcome
  
  
• MSI mCRCs harboring BRAFV600E mutation are always sporadic and do not arise in the context of Lynch Syndrome
  
  
• BRAFV600E mutation is also a target of treatment in various types of malignancies such as melanoma, non-small cell lung cancer (NSCLC), and hairy-cell leukemia
  • BRAF inhibitors in monotherapy do not have the same clinical activity for colorectal cancer relative to other solid tumors harboring an oncogenic BRAF V600E mutation, combination approaches targeting BRAF + MEK +EGFR hold promise for patients BRAF V600E colorectal cancer (3)

Reference:

• Mauri G, Bonazzina E, Amatu A, Tosi F, Bencardino K, Gori V, Massihnia D, Cipani T, Spina F, Ghezzi S, Siena S, Sartore-Bianchi A. The Evolutionary Landscape of Treatment for BRAFV600E Mutant Metastatic Colorectal Cancer. Cancers (Basel). 2021 Jan 4;13(1):137.
• Sveen A, Kopetz S, Lothe RA. Biomarker-guided therapy for colorectal cancer: strength in complexity. Nat Rev Clin Oncol. 2020 Jan;17(1):11-32.
• Morris VK. Systemic Therapy in BRAF V600E-Mutant Metastatic Colorectal Cancer: Recent Advances and Future Strategies. Current Colorectal Cancer Reports. 2019 Apr;15(2):53-60.