Association of BRAF Mutations With Survival and Recurrence in Surgically Treated Patients With Metastatic Colorectal Liver Cancer

Importance

BRAFmutations are reportedly associated with aggressive tumor biology. However, in contrast with primary colorectal cancer, the association of V600E and non-V600EBRAFmutations with survival and recurrence after resection of colorectal liver metastases (CRLM) has not been well studied.

Objective

To investigate the prognostic association ofBRAFmutations with survival and recurrence independently and compared with other prognostic determinants, such asKRASmutations.

Design, Setting, and Participants

In this cohort study, all patients who underwent resection for CRLM with curative intent from January 1, 2000, through December 31, 2016, at the institutions participating in the International Genetic Consortium for Colorectal Liver Metastasis and had data onBRAFandKRASmutational status were retrospectively identified. Multivariate Cox proportional hazards regression models were used to assess long-term outcomes.

Interventions

Hepatectomy in patients with CRLM.

Main Outcomes and Measures

The association of V600E and non-V600EBRAFmutations with disease-free survival (DFS) and overall survival (OS).

Results

Of 853 patients who met inclusion criteria (510 men [59.8%] and 343 women [40.2%]; mean [SD] age, 60.2 [12.4] years), 849 were included in the study analyses. Forty-three (5.1%) had a mutated (mut)BRAF/wild-type (wt)KRAS(V600E and non-V600E) genotype; 480 (56.5%), a wtBRAF/wtKRASgenotype; and 326 (38.4%), a wtBRAF/mutKRASgenotype. Compared with the wtBRAF/wtKRASgenotype group, patients with a mutBRAF/wtKRASgenotype more frequently were female (27 [62.8%] vs 169 [35.2%]) and 65 years or older (22 [51.2%] vs 176 [36.9%]), had right-sided primary tumors (27 [62.8%] vs 83 [17.4%]), and presented with a metachronous liver metastasis (28 [64.3%] vs 229 [46.8%]). On multivariable analysis, V600E but not non-V600EBRAFmutation was associated with worse OS (hazard ratio [HR], 2.76; 95% CI, 1.74-4.37;P < .001) and DFS (HR, 2.04; 95% CI, 1.30-3.20;P = .002). The V600EBRAFmutation had a stronger association with OS and DFS than theKRASmutations (β for OS, 10.15 vs 2.94; β for DFS, 7.14 vs 2.27).

Conclusions and Relevance

The presence of the V600EBRAFmutation was associated with worse prognosis and increased risk of recurrence. The V600E mutation was not only a stronger prognostic factor thanKRASbut also was the strongest prognostic determinant in the overall cohort.