**5. Prognostic significance of BRAF mutation**

BRAF MT CRC is strongly associated with inferior survival compared with BRAF WT disease. Randomised control trials of first line treatment of metastatic CRC demonstrate differences in OS of up to 12 months, shown in **Table 1**.


#### **Table 1.**

*BRAF mutation as a prognostic factor in clinical studies of first-line treatment of metastatic CRC.*

**39**

*BRAF Mutation and Its Importance in Colorectal Cancer*

Venderbosch et al. reported a pooled analysis of the CAIRO, CAIRO2, COIN and FOCUS studies examining mismatch repair and BRAF status [29]. BRAF MT was associated with a poor prognosis with OS of 11.4 vs. 17.2 months, and PFS of 6.2 vs. 7.7 months compared with BRAF WT. This analysis also found dMMR to indicate poor prognosis, despite significant evidence to show that MSI-high tumours confer a better prognosis. However, it is concluded that as there is no interaction between BRAF MT and dMMR, the poor prognostic value of dMMR is likely driven by BRAF MT. There was no difference in OS or PFS between dMMR BRAF MT and pMMR BRAF MT tumours. In a study examining RAS and BRAF mutations, BRAF patients had the worst overall survival. The median OS for WT, KRAS, NRAS and BRAF

Similarly, BRAF MT has been shown to be a negative prognostic factor in stage II and III disease. Data from the PETACC-3 was extracted, with KRAS, BRAF and MSI status examined [31]. MSI-high tumours were associated with better prognosis. BRAF MT was not prognostic of PFS. The MSI-high status appeared to attenuate the negative prognostic effect of BRAF MT on OS; BRAF MT is a negative prognostic factor in MSS CRC. However, more recently, a meta-analysis of 1164 patients with MSI-high non-metastatic CRC has shown that BRAF V600E mutation does correlate

Survival following metastasectomy is also worse for BRAF MT mCRC as demonstrated in a meta-analysis of patients undergoing resection of liver metastases. It showed the BRAF mutation was negatively associated with OS (HR 3.055,

In contrast, non-V600E BRAF mutations have a different prognosis. BRAF codons 594 and 596 mutations, when compared with V600E BRAF mutations, are more frequently rectal, non-mucinous with no peritoneal spread. In a study of 10 patients, all BRAF 594 and 596 tumours were microsatellite stable. OS was significantly longer (62 vs. 12.6 months, P = 0.002) [34]. Jones et al. identified 208 metastatic CRC patients out of 9643 with non-V600E mutations. When compared with V600E BRAF mutation patients, those with non-V600E mutations were found to be younger, more likely male, and had lower grade tumours. In addition, median OS was significantly longer compared with both V600E BRAF mutant and BRAF wild-type patients (60.7 vs. 11.4 vs. 43 months respectively) [35]. This has also been demonstrated in a retrospective study of 98 patients, 6 of whom had non-V600E BRAF mutations. Although only a small sample size, OS was significantly better

Doublet chemotherapy remains the standard of care for metastatic BRAF MT CRC in patients with appropriate performance status [36, 37]. First-line chemotherapy options include 5 fluorouracil, leucovorin and oxaliplatin (FOLFOX), 5-fluorouracil, leucovorin and irinotecan (FOLFIRI) and capecitabine plus oxaliplatin. A retrospective study reported no difference in median PFS between irinotecan-based or oxaliplatin-based chemotherapy regimens in the first line for

A more intensive triplet chemotherapy regime has been proposed based on 5 fluorouracil, leucovorin, oxaliplatin and irinotecan with bevacizumab (FOLFOXIRI+bev). A phase II trial of FOLFOXIRI and bevacizumab in the metastatic CRC population

patients were 49.2, 36.2, 30.1 and 22.5 months, respectively [30].

with adverse overall survival, but not disease recurrence [32].

compared with V600E BRAF MT patients (P = 0.38) [17].

**6. Treatment of BRAF-mutation CRC**

**6.1 Standard treatment**

BRAF-MT CRC [38].

P = 0.00004) [33].

*DOI: http://dx.doi.org/10.5772/intechopen.82571*

*Advances in the Molecular Understanding of Colorectal Cancer*

5-FU/irinotecan or 5-FU/

OPUS [77] FOLFOX ± cetuximab Median OS, 20.7 months with

FOLFOX ± panitumumab Median PFS:

Capecitabine + oxaliplatin + bevacizumab vs. CAPOX + bevacizumab + cetuximab cetuximab + FOLFOX

(HR, 0.934; P = 0.87)

0.908; P = 0.74)

Median OS:

respectively

Capecitabine ± bevacizumab Median OS, 20.8 months in BRAF

*BRAF mutation as a prognostic factor in clinical studies of first-line treatment of metastatic CRC.*

tumours

vs. FOLFIRI), 8.0 vs. 5.6 months

Median OS, 14.1 vs. 10.3 months (HR

BRAF WT (20 vs. 50%; P < 0.001)

Panitumumab + FOLFOX vs. FOLFOX, 6.1 vs. 5.4 months

Panitumumab + FOLFOX vs. FOLFOX, 10.5 vs. 9.2 months

Lower median PFS, 5.9 and 6.6 months in BRAF-MT vs. 12.2 and 10.4 months in BRAF WT tumours with CAPOX + bevacizumab and CAPOX + bevacizumab + cetuximab,

Lower median OS, 15.0 and 15.2 months in BRAF MT vs. 24.6 and 21.5 months in BRAF WT with CB

WT vs. 8.6 months in BRAF MT

and CBC, respectively

FOLFIRI ± cetuximab Median PFS (cetuximab + FOLFIRI

FLOX ± cetuximab BRAF MT had lower ORRs than

Fluoropyrimidine/ oxaliplatin ± cetuximab

oxaliplatin

MRC FOCUS [76]

MRC COIN [43]

CRYSTAL [78]

NORDIC-VII [48]

PRIME [42]

CAIRO2 [10]

AGITG MAX [79]

**Study Treatment regimen Key outcomes in BRAF MT disease Prognostic** 

**finding**

poor OS but no difference in PFS

significantly shorter in patients with BRAF, KRAS or NRAS mutations than in patients with WT KRAS, NRAS, and BRAF tumours, irrespective of treatment (P < 0.0001)

Small numbers precluded definitive conclusions

BRAF MT was strong indicator of poor prognosis

BRAF mutation was a negative prognostic factor

BRAF mutation was a negative prognostic marker

BRAF mutation was a marker of poor prognosis irrespective of treatment

BRAF mutations was a strong negative prognostic factor

HR for OS 1.82 (P = 0.0002) BRAF predicts

OS 8.8 vs. 20.1 months Median OS was

**38**

**Table 1.**

Venderbosch et al. reported a pooled analysis of the CAIRO, CAIRO2, COIN and FOCUS studies examining mismatch repair and BRAF status [29]. BRAF MT was associated with a poor prognosis with OS of 11.4 vs. 17.2 months, and PFS of 6.2 vs. 7.7 months compared with BRAF WT. This analysis also found dMMR to indicate poor prognosis, despite significant evidence to show that MSI-high tumours confer a better prognosis. However, it is concluded that as there is no interaction between BRAF MT and dMMR, the poor prognostic value of dMMR is likely driven by BRAF MT. There was no difference in OS or PFS between dMMR BRAF MT and pMMR BRAF MT tumours. In a study examining RAS and BRAF mutations, BRAF patients had the worst overall survival. The median OS for WT, KRAS, NRAS and BRAF patients were 49.2, 36.2, 30.1 and 22.5 months, respectively [30].

Similarly, BRAF MT has been shown to be a negative prognostic factor in stage II and III disease. Data from the PETACC-3 was extracted, with KRAS, BRAF and MSI status examined [31]. MSI-high tumours were associated with better prognosis. BRAF MT was not prognostic of PFS. The MSI-high status appeared to attenuate the negative prognostic effect of BRAF MT on OS; BRAF MT is a negative prognostic factor in MSS CRC. However, more recently, a meta-analysis of 1164 patients with MSI-high non-metastatic CRC has shown that BRAF V600E mutation does correlate with adverse overall survival, but not disease recurrence [32].

Survival following metastasectomy is also worse for BRAF MT mCRC as demonstrated in a meta-analysis of patients undergoing resection of liver metastases. It showed the BRAF mutation was negatively associated with OS (HR 3.055, P = 0.00004) [33].

In contrast, non-V600E BRAF mutations have a different prognosis. BRAF codons 594 and 596 mutations, when compared with V600E BRAF mutations, are more frequently rectal, non-mucinous with no peritoneal spread. In a study of 10 patients, all BRAF 594 and 596 tumours were microsatellite stable. OS was significantly longer (62 vs. 12.6 months, P = 0.002) [34]. Jones et al. identified 208 metastatic CRC patients out of 9643 with non-V600E mutations. When compared with V600E BRAF mutation patients, those with non-V600E mutations were found to be younger, more likely male, and had lower grade tumours. In addition, median OS was significantly longer compared with both V600E BRAF mutant and BRAF wild-type patients (60.7 vs. 11.4 vs. 43 months respectively) [35]. This has also been demonstrated in a retrospective study of 98 patients, 6 of whom had non-V600E BRAF mutations. Although only a small sample size, OS was significantly better compared with V600E BRAF MT patients (P = 0.38) [17].
