title: BRAF-Mutated Colorectal Cancer: What Is the Optimal Strategy for Treatment?
abstract: The BRAF activating mutation, harbored by approximately 10% of colorectal cancers (CRC), confers dramatic prognosis to advanced diseases. In early-stage setting, the identification of the BRAF mutation does not impact the therapeutic decision. Yet, the BRAF mutation could be considered as a stratification factor in adjuvant trials, because of its prognostic impact after relapse. Moreover, both BRAF mutation and mismatch repair (MMR) statuses should be determined in all CRC to help identify sporadic tumors versus Lynch syndrome-related tumors. Indeed, in patients with MMR-deficient (dMMR) tumors and MLH1 loss of expression, the BRAFV600E mutation indicates a sporadic origin. In advanced BRAF-mutated CRC, the standard of care remains fluoropyrimidine-based cytotoxic regimen in combination with bevacizumab. Although a recent meta-analysis showed that there was insufficient data to justify the exclusion of anti-EGFR monoclonal antibodies, antiangiogenic agents should be preferred in the first-line setting. Despite the lack of a randomized phase 3 study dedicated to BRAF-mutated CRC, chemotherapy intensification combining a quadruple association of 5-fluorouracil, oxaliplatin, irinotecan (FOLFOXIRI), and bevacizumab seems like a valid option. Although first results with BRAF inhibitors as single agents in BRAF-mutated CRC were disappointing, their association with therapies targeting the MAPK pathway seems to overcome the primary resistance to BRAF inhibition. In the field of sporadic CRC, the BRAF mutation is strongly associated with MMR deficiency. Considering breakthrough results of immune checkpoint inhibitors in dMMR repair tumors, determination of the MMR status appears to be mandatory. Given the dramatic prognosis conferred by the BRAF mutation, patients with BRAF-mutated advanced CRC need to be systematically identified and proposed for clinical trial enrolment in order to benefit from innovative therapies.
authors.affiliation: Department of Medical Oncology, Saint-Antoine Hospital, APHP, 184 rue du Faubourg Saint-Antoine, 75012, Paris, France.
authors.forename: Romain
authors.initials: R
authors.lastname: Cohen
authors.affiliation: Department of Pathology, Saint-Antoine Hospital, APHP, 184 rue du Faubourg Saint-Antoine, 75012, Paris, France.
authors.forename: Pascale
authors.initials: P
authors.lastname: Cervera
authors.affiliation: Department of Pathology, Saint-Antoine Hospital, APHP, 184 rue du Faubourg Saint-Antoine, 75012, Paris, France.
authors.forename: Magali
authors.initials: M
authors.lastname: Svrcek
authors.affiliation: Department of Medical Oncology, Saint-Antoine Hospital, APHP, 184 rue du Faubourg Saint-Antoine, 75012, Paris, France.
authors.forename: Anna
authors.initials: A
authors.lastname: Pellat
authors.affiliation: Department of Medical Oncology, Saint-Antoine Hospital, APHP, 184 rue du Faubourg Saint-Antoine, 75012, Paris, France.
authors.forename: Chantal
authors.initials: C
authors.lastname: Dreyer
authors.affiliation: Department of Medical Oncology, Institut Hospitalier Franco-Britannique, 4 rue Kléber, 92300, Levallois-Perret, France.|GERCOR, Oncology Multidisciplinary Group, 151 rue du Faubourg Saint Antoine, 75011, Paris, France.
authors.forename: Aimery
authors.initials: A
authors.lastname: de Gramont
authors.affiliation: Department of Medical Oncology, Saint-Antoine Hospital, APHP, 184 rue du Faubourg Saint-Antoine, 75012, Paris, France. thierry.andre@aphp.fr.|GERCOR, Oncology Multidisciplinary Group, 151 rue du Faubourg Saint Antoine, 75011, Paris, France. thierry.andre@aphp.fr.
authors.forename: Thierry
authors.initials: T
authors.lastname: André
mesh_terms: D019943:Amino Acid Substitution; D003062:Codon; D015179:Colorectal Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000628:therapy*; D003131:Combined Modality Therapy; D053843:DNA Mismatch Repair / Q000187:drug effects; D020022:Genetic Predisposition to Disease; D006801:Humans; D053842:Microsatellite Instability; D058990:Molecular Targeted Therapy; D009154:Mutation; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors / Q000235:genetics*
chemical_list: D003062:Codon; D048493:Proto-Oncogene Proteins B-raf
keywords: BRAFV600E; Checkpoint inhibitor; Colorectal cancer; Dabrafenib; FOLFOXIRI; Microsatellite instability; Vemurafenib