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

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

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

Georgios Antonios Margonis, MD, PhD¹; Stefan Buettner, MD^1,2; Nikolaos Andreatos, MD¹; et alYuhree Kim, MD, MPH¹; Doris Wagner, MD³; Kazunari Sasaki, MD⁴; Andrea Beer, MD⁵; Christoph Schwarz, MD, PhD⁵; Inger Marie Løes, MD, PhD^6,7; Maria Smolle, MD⁸; Carsten Kamphues, MD⁹; Jin He, MD, PhD¹; Timothy M. Pawlik, MD, MPH, PhD^10,11; Klaus Kaczirek, MD⁵; George Poultsides, MD¹²; Per Eystein Lønning, MD, PhD^6,7; John L. Cameron, MD¹; Richard A. Burkhart, MD¹; Armin Gerger, MD⁸; Federico N. Aucejo, MD⁴; Martin E. Kreis, MD⁹; Christopher L. Wolfgang, MD, PhD¹; Matthew J. Weiss, MD¹

Author Affiliations

JAMA Surg. Published online May 16, 2018. doi:10.1001/jamasurg.2018.0996

Key Points

Questions  What is the prognostic association of BRAF mutations with survival and recurrence in patients with metastatic colorectal liver cancer, and how does it compare with KRAS mutations?

Findings  In this study of 853 patients with colorectal liver metastases, those with a mutant BRAF/wild-type KRAS genotype more commonly were female and 65 years or older, had right-sided primary tumors, and presented with metachronous liver metastasis. V600E but not non-V600E BRAF mutation was associated with worse overall and disease-free survival, and V600E BRAF mutations had a stronger association with overall and disease-free survival than KRAS mutations.

Meaning  The presence of the BRAF V600E mutation was associated with worse prognosis and increased risk of recurrence and was the strongest prognostic determinant in the overall cohort.

Abstract

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

Objective  To investigate the prognostic association of BRAF mutations with survival and recurrence independently and compared with other prognostic determinants, such as KRAS mutations.

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 on BRAF and KRAS mutational 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-V600E BRAF mutations 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/wtKRAS genotype; and 326 (38.4%), a wtBRAF/mutKRAS genotype. Compared with the wtBRAF/wtKRAS genotype group, patients with a mutBRAF/wtKRAS genotype 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-V600E BRAF mutation 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 V600E BRAF mutation had a stronger association with OS and DFS than the KRAS mutations (β for OS, 10.15 vs 2.94; β for DFS, 7.14 vs 2.27).

Conclusions and Relevance  The presence of the V600E BRAF mutation was associated with worse prognosis and increased risk of recurrence. The V600E mutation was not only a stronger prognostic factor than KRAS but also was the strongest prognostic determinant in the overall cohort.