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Therapeutic implications of B-RAF mutations in colorectal cancer - 09/05/21

Doi : 10.1016/j.jviscsurg.2021.04.002 
H. Lebrun a, A. Turpin b, P. Zerbib a,
a Department of Digestive Surgery and Transplantation, Claude Huriez Hospital, CHRU de Lille, Lille Université Nord de France, Lille, France 
b Medical Oncology Department, Claude Huriez Hospital, CHRU de Lille, Lille Université Nord de France, Lille, France 

Corresponding author.
Sous presse. Épreuves corrigées par l'auteur. Disponible en ligne depuis le Sunday 09 May 2021

Highlights

B-RAF mutation is a recognized poor prognostic factor for patients with CRC, in particular when CRC is metastatic.
First-line bi-chemotherapy associating FOLFOX+Bevacizumab seems better than triple therapy FOLFIRINOX+Bevacizumab, which has recently been called into question.
B-RAF inhibitors are not useful in monotherapy regimens. The French High Health Authority granted marketing authorization for the double association Encorafenib+Cetuximab in the second-line treatment of metastatic CRC but did not approve the triple association (Encorafenib+Cetuximab+Binimetinib) as a possible alternative because of more severe side-effects. First-line triple inhibition (EGFR, B-RAF, MEK) is currently under evaluation for metastatic CRC.
Immunotherapy is effective in patients with the MSI phenotype, including patients who are mutant B-RAF.
Surgery for liver metastases in patients with mutant B-RAF should be considered after thorough search for peritoneal or distant metastases, even if it is recognized that tumor recurrence occurs more often and prognosis is more severe in this setting.

Le texte complet de cet article est disponible en PDF.

Summary

Colorectal cancers (CRC) with B-RAF mutation carry a particularly poor prognosis. In this context, the value of first-line intensified chemotherapy associated with an anti-VEGF (Vascular endothelial growth factor) to treat metastatic CRC has recently been called into question. In patients with mutated B-RAF, the efficacy of first-line anti-EGFR (Epidermal Growth Factor Receptor) associated with chemotherapy for treatment of metastatic CRC is uncertain while that of anti-VEGF has been shown to be effective. The therapeutic pathways involving inhibition of B-RAF activity, although ineffective as monotherapy, have received marketing authorization when used in association with anti-EGFR for second-line treatment of metastatic CRC. Immunotherapy has provided very encouraging results in a recent phase III study in patients with microsatellite instability, irrespective of their B-RAF status. Finally, new therapies, targeting other RAF proteins and other specific receptors are currently under development. Surgery for liver metastases in patients with the B-RAF mutation should be considered whenever possible, after a complete search for peritoneal carcinomatosis and distant metastases, similarly to workup for patients without the B-RAF mutation.

Le texte complet de cet article est disponible en PDF.

Keywords : Colorectal cancer, B-RAF, Immunotherapy, Triple inhibition

Abbreviations : ASCO, B-RAFi, B-RAFmt, B-RAFwt, CEA, CRC, CRCm, CTCAE, EGFR, ERK, ETS, HR, IC, LM, MAPK, MEK, MEKi, MMR, MSI, MSI-H, MSI-H/MMRd, MMS, OR, OS, PFS, PI3K/AKT, RAF (stands for the early experimental origin “rapidly accelerated fibrosarcoma”), RAS protein (stands for Reticular Activating System: named after experiments with the rat sarcoma virus), RAFmt, RASmt, RBD, RFS, VEGF


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