Georgios Antonios Margonis1, Stefan Buettner1,2, Nikolaos Andreatos1, Yuhree Kim1, Doris Wagner3, Kazunari Sasaki4, Andrea Beer5, Christoph Schwarz5, Inger Marie Løes6,7, Maria Smolle8, Carsten Kamphues9, Jin He1, Timothy M Pawlik10,11, Klaus Kaczirek5, George Poultsides12, Per Eystein Lønning6,7, John L Cameron1, Richard A Burkhart1, Armin Gerger8, Federico N Aucejo4, Martin E Kreis9, Christopher L Wolfgang1, Matthew J Weiss1. 1. Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland. 2. Department of Surgery, Erasmus MC University Medical Center, Rotterdam, the Netherlands. 3. Department of General Surgery, Medical University of Graz, Graz, Austria. 4. Department of General Surgery, Digestive Disease Institute, Cleveland Clinic, Cleveland, Ohio. 5. Department of General Surgery, Medical University of Vienna, Vienna, Austria. 6. Department of Clinical Science, University of Bergen, Bergen, Norway. 7. Department of Oncology, Haukeland University Hospital, Bergen, Norway. 8. Division for Oncology, Department of Internal Medicine, Medical University of Graz, Graz, Austria. 9. Department of General, Visceral and Vascular Surgery, Charité Campus Benjamin Franklin, University of Berlin-Charité, Berlin, Germany. 10. Department of Surgery, The Ohio State University Wexner Medical Center, Columbus. 11. Deputy Editor. 12. Department of Surgery, Stanford University School of Medicine, Stanford, California.
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.
Importance: BRAF mutations are reportedly associated with aggressive tumor biology. However, in contrast with primary colorectal cancer, the association of V600E and non-V600EBRAF 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-V600EBRAF 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-V600EBRAF 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 V600EBRAF 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 V600EBRAF 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.
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