Characteristics of BRAF V600E Mutant, Deficient Mismatch Repair/Proficient Mismatch Repair, Metastatic Colorectal Cancer: A Multicenter Series of 287 Patients

Abstract

Background. BRAF V600E mutations occurring in about 10% of metastatic colorectal cancers (mCRCs) are usually associated with a poor outcome. However, their prognostic factors are unknown. Materials and Methods. We built a multicenter clinicobiological database gathering data from patients with BRAF V600E -mutant mCRC treated in one of the 16 French centers from 2006 to 2017. The primary endpoint was to identify prognostic factors using a Cox model. Results. We included 287 patients (median age, 67 years [28-95]; female, 57%). Their median overall survival was 20.8 months (95% confidence interval [CI], 17.97-27.04), and median progression-free survival in the first-line setting was 4.34 months (95% CI, 3.81-5.03). Chemotherapy regimen and biological agents (antiangiogenic or anti-epidermal growth factor receptor) were not associated with overall and progression-free survival. Stage IV disease (synchronous metastases) and absence of curative-intent surgery were statistically associated with poor overall survival. Among the 194 patients with mismatch repair (MMR) status available, overall survival was significantly longer in patients with deficient MMR tumors compared with those with proficient MMR tumors (adjusted hazard ratio = 0.56; p = .009). Conclusion. Despite that BRAF V600E -mutant mCRCs are associated with poor overall and progression-free-survival, patients with deficient MMR tumors and/or resectable disease experienced a longer survival. These results highlight the importance of MMR testing and resectability discussion in patients with BRAF V600E mCRC in day-to-day practice. The Oncologist 2019;24:e1331-e1340 Implications for Practice: Mismatch repair (MMR) testing and resectability discussion in patients with BRAF V600E metastatic colorectal cancer (mCRC) should be performed in day-to-day practice to steer treatment decision making in patients with BRAF V600E -mutant mCRC.

Prognosis and chemosensitivity of deficient MMR phenotype in patients with metastatic colorectal cancer: An AGEO retrospective multicenter study

“…In our study, BRAF mutation and sporadic dMMR/MSI CRC were identified as prognostic factors in univariable analysis, but because of colinearity between Lynch syndrome, BRAF status and age, only age was included in the multivariable Cox model. The value of the BRAF mutation as a poor prognostic factor, while evident in pMMR/MSS mCRC, is debated in dMMR/MSI mCRC . In a pooled analysis of the CAIRO, CAIRO2, COIN and FOCUS studies, the BRAF mutation was associated with worse outcomes in pMMR/MSS mCRC, but not in dMMR/MSI mCRC .…”

“…Some reports suggest shorter overall survival (OS) in dMMR/MSI CRC as compared to proficient MMR (pMMR) CRC . The prognostic impact of the BRAF mutation in dMMR/MSI mCRC remains to be clarified . A retrospective study of 55 patients with dMMR/MSI mCRC suggested no significant difference in progression‐free survival (PFS) or OS between oxaliplatin‐ and irinotecan‐based chemotherapy .…”

Molecular Targets for the Treatment of Metastatic Colorectal Cancer

“…BRAF V600E mCRC patients have a lower probability to receive second-line treatments than the BRAF WT population. As a matter of fact, intensification strategies seem effective for these patients [ 51 , 52 , 53 ]. In the TRIBE study, first-line FOLFOXIRI (folinic acid, fluorouracil, oxaliplatin, and irinotecan) plus bevacizumab was associated with a non-significant improvement of overall survival for BRAF V600E mutants, compared to FOLFIRI (folinic acid, fluorouracil, and irinotecan) plus bevacizumab ( n = 28) [ 54 ].…”

Microsatellite Instability in Colorectal Cancers: Carcinogenesis, Neo-Antigens, Immuno-Resistance and Emerging Therapies

“…BRAF V600E mutation is present in about 8% of metastatic CRCs (mCRCs), 30–40% of dMMR/MSI CRCs [ 14 ], and 60% of sporadic dMMR/MSI CRCs with MLH1 promoter hypermethylation [ 15 ]. BRAF V600E mutation is of bad prognosis, independently of the dMMR/MSI status of the CRC [ 16 , 17 ]. However, in some publications, this mutation is no longer a poor prognostic factor for patients with dMMR/MSI CRC [ 17 ].…”

“…BRAF V600E mutation is of bad prognosis, independently of the dMMR/MSI status of the CRC [ 16 , 17 ]. However, in some publications, this mutation is no longer a poor prognostic factor for patients with dMMR/MSI CRC [ 17 ]. Concerning immunotherapy efficacy in dMMR/MSI mCRC, there is no difference in response according to this BRAF mutation [ 18 ].…”