TY - JOUR
T1 - Association of BRAF mutations with survival and recurrence in surgically treated patients with metastatic colorectal liver cancer
AU - Margonis, Georgios Antonios
AU - Buettner, Stefan
AU - Andreatos, Nikolaos
AU - Kim, Yuhree
AU - Wagner, Doris
AU - Sasaki, Kazunari
AU - Beer, Andrea
AU - Schwarz, Christoph
AU - Løes, Inger Marie
AU - Smolle, Maria
AU - Kamphues, Carsten
AU - He, Jin
AU - Pawlik, Timothy M.
AU - Kaczirek, Klaus
AU - Poultsides, George
AU - Lønning, Per Eystein
AU - Cameron, John L.
AU - Burkhart, Richard A.
AU - Gerger, Armin
AU - Aucejo, Federico N.
AU - Kreis, Martin E.
AU - Wolfgang, Christopher L.
AU - Weiss, Matthew J.
N1 - Publisher Copyright:
© 2018 American Medical Association. All rights reserved.
PY - 2018/7
Y1 - 2018/7
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85051074870&partnerID=8YFLogxK
U2 - 10.1001/jamasurg.2018.0996
DO - 10.1001/jamasurg.2018.0996
M3 - Article
C2 - 29799910
AN - SCOPUS:85051074870
SN - 2168-6254
VL - 153
JO - JAMA surgery
JF - JAMA surgery
IS - 7
M1 - e180996
ER -