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disease is radically resected, BRAF-mutated tumors tends to relapse early with extra-hepatic lesions [42,43] .
A specific carcinogenesis pathway and a distinct gene signature have also been associated with BRAF
[44]
[45]
V600E mutation. More recently, gene expression analyses allowed to identify two different BRAF V600E
subtypes in a large cohort of BRAF V600E mutated patients unselected for tumor stage: the BM1 subtype
characterized by KRAS/AKT activation, mTOR/4EBP deregulation and EMT, and the BM2 subtype
characterized by cell cycle and checkpoint pathway deregulation . In contrast with BRAF V600E mutation,
[46]
metastatic tumors harboring rare mutations of BRAF codons 594 and 596 (less than 1% of CRCs) have been
shown to have different prognosis and clinical outcome. These rare mutations are associated with a non-
mucinous histology, a rectal primary tumor location, microsatellite stability, and lack of peritoneal disease.
Moreover, no negative prognostic impact was observed although in a small series of patients (median OS
62.0 vs. 12.6 months; HR, 0.36; 95% CI, 0.20-0.64; P = 0.002 for BRAF 594 or 596 mutant vs. BRAF V600E) .
[47]
Similar results on the impact and characteristics of BRAF nonV600E mutations were confirmed in a recent
retrospective evaluation of a large cohort of patients .
[48]

Although still debated, growing evidence is accumulating on the role of BRAF mutations as a negative
predictive marker for anti-EGFR agents activity. Retrospective series showed that the response rate to
anti-EGFR treatment with or without chemotherapy was significantly lower in BRAF-mutated vs. WT
patients [22,23,49] . On the other hand, BRAF V600E mutation failed to demonstrate its predictive value in several
sub-group analyses of phase III trials, possibly because of the small number of BRAF-mutated patients and
lack of statistical power [24,50] . More recently, two meta-analyses showed a lack of improvement in PFS and OS
in patients with BRAF-mutated mCRCs when treated with either cetuximab- or panitumumab-containing
regimens compared to chemotherapy alone [51,52] . Additionally, a retrospective evaluation of the randomized
phase III FIRE-3 trial, comparing FOLFIRI plus cetuximab or bevacizumab as first-line treatment in KRAS
exon 2 WT mCRC patients, confirmed poorer survival outcomes for BRAF-mutated tumors irrespective
of cetuximab and bevacizumab administration . Based on these data, it appears that anti-EGFRs do not
[53]
demonstrate a clear outcome benefit in BRAF-mutated tumors, and their use should be restricted to patients
with no alternative therapeutic options. Notably, however, in FIRE-3 cetuximab arm a small subgroup of
BRAF-mutated tumors achieving an early tumor shrinkage ≥ 20% (9/17) showed significantly longer median
PFS (9.0 vs. 1.9 months, log-rank test P = 0.002; HR = 0.14) and OS (29.8 vs. 5.9 months, log-rank test P =
0.047; HR = 0.3) than those not achieving it . Despite the limitations due to the retrospective nature of this
[53]
evaluation and the small patients numbers, these results highlight a significant heterogeneity among BRAF-
mutated mCRCs warranting further investigation.

While FOLFOXIRI plus bevacizumab represents the most promising treatment option in the first-line
setting for clinically selected BRAF-mutated patients [2,54] , outcomes are still unsatisfactory. An extensive
effort has been made in the last few years aiming to develop possible effective anti-BRAF strategies for
mCRC patients. In contrast to melanoma, the use of BRAF inhibitors, such as vemurafenib and dabrafenib,
as single-agents did not show significant activity in BRAF-mutated mCRC . Dual blockade of BRAF and
[55]
alternative survival pathways, such as MEK and EGFR, have been tested as well in clinical trials without
convincing results [56-58] . Promising results are coming instead from a triple inhibition strategy combining
BRAF-inhibitors, MEK-inhibitors and EGFR-inhibitors [59,60] . An additional strategy under study to increase
the activity of dual targeted BRAF inhibition is its association with standard cytotoxic chemotherapy, such
as the combination of vemurafenib with cetuximab plus irinotecan which have been explored in the SWOG
1406 trial with encouraging results . Moreover, several other promising strategies designed to overcome
[61]
resistance pathways to BRAF-inhibitors are currently under investigation [62,63] . Final results from ongoing
trials are warranted to improve targeted treatment options for BRAF-mutated patients.

Microsatellite Instability
MMR is a highly conserved DNA repair mechanism that ensures genomic integrity by correcting mispaired
or unpaired bases which have escaped the proofreading activity of DNA polymerases during DNA replication