Julien Taieb1, Aziz Zaanan2, Karine Le Malicot3, Catherine Julié4, Hélène Blons5, Laurent Mineur6, Jaafar Bennouna7, Josep Tabernero8, Enrico Mini9, Gunnar Folprecht10, Jean Luc Van Laethem11, Come Lepage12, Jean-François Emile4, Pierre Laurent-Puig5. 1. Paris Descartes University, Department of Digestive Oncology, European Georges Pompidou Hospital, Assistance Publique-Hôpitaux de Paris, France. 2. Paris Descartes University, Department of Digestive Oncology, European Georges Pompidou Hospital, Assistance Publique-Hôpitaux de Paris, France2Centre de Recherché UMR-S 1147, Médecine Personnalisée, Pharmacogénomique, Optimisation Thérapeutique, Institut. 3. Department of Statistics, Fédération Francophone de Cancérologie Digestive, Dijon, France. 4. Department of Pathology, Ambroise Paré Hospital, Assistance Publique-Hôpitaux de Paris, Boulogne-Billancourt, France5Versailles Saint-Quentin-en-Yvelines University, Boulogne-Billancourt, France. 5. Centre de Recherché UMR-S 1147, Médecine Personnalisée, Pharmacogénomique, Optimisation Thérapeutique, Institut National de la Santé et de la Recherche Médicale, Paris, France6Paris Descartes University, Department of Biology, European Georges Pompidou Ho. 6. Department of Oncology, Sainte Catherine Institute, Avignon, France. 7. Department of Oncology, Cancérologie de l'Ouest Institute, Nantes, France. 8. Medical Oncology Department, Vall d'Hebron University Hospital and Institute of Oncology, Barcelona, Spain. 9. Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy. 10. First Medical Department, University Hospital Carl Gustav Carus, Dresden, Germany. 11. Department of Gastroenterology, Erasme Hospital University, Brussels, Belgium. 12. Department of Hepato-Gastroenterology, Dijon University Hospital, Dijon, France14Centre de Recherche UMR 866, Lipides, Nutrition, Cancer, Institut National de la Santé et de la Recherche Médicale, Dijon, France.
Abstract
IMPORTANCE: The prognostic value of BRAF and KRAS mutations in patients who have undergone resection for colon cancer and have been treated with combination leucovorin, fluorouracil, and oxaliplatin (FOLFOX)-based adjuvant chemotherapy is controversial, possibly owing to a lack of stratification on mismatch repair status. OBJECTIVE: To examine the prognostic effect of BRAF and KRAS mutations in patients with stage III colon cancer treated with adjuvant FOLFOX with or without cetuximab. DESIGN, SETTING, AND PARTICIPANTS: This study included patients with available tumor blocks of resected stage III colon adenocarcinoma who participated between December 2005 and November 2009 in the PETACC-8 phase III randomized trial. Mismatch repair, BRAF V600E, and KRAS exon 2 mutational status were determined on prospectively collected tumor blocks from 2559 patients enrolled in the PETACC-8 trial. The data were analyzed in April 2015. INTERVENTION: Patients were randomly assigned to receive 6 months of FOLFOX4 or FOLFOX4 plus cetuximab after surgical resection for stage III colon cancer. MAIN OUTCOMES AND MEASURES: Associations between these biomarkers and disease-free survival (DFS) and overall survival (OS) were analyzed with Cox proportional hazards models. Multivariate models were adjusted for covariates (age, sex, tumor grade, T/N stage, tumor location, Eastern Cooperative Oncology Group performance status). RESULTS: Among the 2559 patients enrolled in the PETACC-8 trial (42.9% female; median [range] age, 60.0 [19.0-75.0] years), microsatellite instability (MSI) phenotype, KRAS, and BRAF V600E mutations were detected in, respectively, 9.9% (177 of 1791), 33.1% (588 of 1776), and 9.0% (148 of 1643) of cases. In multivariate analysis, MSI (hazard ratio [HR] for DFS: 1.10 [95% CI, 0.73-1.64], P = .67; HR for OS: 1.02 [95% CI, 0.61-1.69], P = .94) and BRAF V600E mutation (HR for DFS: 1.22 [95% CI, 0.81-1.85], P = .34; HR for OS: 1.13 [95% CI, 0.64-2.00], P = .66) were not prognostic, whereas KRAS mutation was significantly associated with shorter DFS (HR, 1.55 [95% CI, 1.23-1.95]; P < .001) and OS (HR, 1.56 [95% CI, 1.12-2.15]; P = .008). The subgroup analysis showed in patients with microsatellite-stable tumors that both KRAS (HR for DFS: 1.64 [95% CI, 1.29-2.08], P < .001; HR for OS: 1.71 [95% CI, 1.21-2.41], P = .002) and BRAF V600E mutation (HR for DFS: 1.74 [95% CI, 1.14-2.69], P = .01; HR for OS: 1.84 [95% CI, 1.01-3.36], P = .046) were independently associated with worse clinical outcomes. In patients with MSI tumors, KRAS status was not prognostic, whereas BRAF V600E mutation was associated with significantly longer DFS (HR, 0.23 [95% CI, 0.06-0.92]; P = .04) but not OS (HR, 0.19 [95% CI, 0.03-1.24]; P = .08). CONCLUSIONS AND RELEVANCE: BRAF V600E and KRAS mutations were significantly associated with shorter DFS and OS in patients with microsatellite-stable tumors but not in patients with MSI tumors. Future trials in the adjuvant setting will have to take into account mismatch repair, BRAF, and KRAS status for stratification. TRIAL REGISTRATION: EudraCT 2005-003463-23.
IMPORTANCE: The prognostic value of BRAF and KRAS mutations in patients who have undergone resection for colon cancer and have been treated with combination leucovorin, fluorouracil, and oxaliplatin (FOLFOX)-based adjuvant chemotherapy is controversial, possibly owing to a lack of stratification on mismatch repair status. OBJECTIVE: To examine the prognostic effect of BRAF and KRAS mutations in patients with stage III colon cancer treated with adjuvant FOLFOX with or without cetuximab. DESIGN, SETTING, AND PARTICIPANTS: This study included patients with available tumor blocks of resected stage III colon adenocarcinoma who participated between December 2005 and November 2009 in the PETACC-8 phase III randomized trial. Mismatch repair, BRAF V600E, and KRAS exon 2 mutational status were determined on prospectively collected tumor blocks from 2559 patients enrolled in the PETACC-8 trial. The data were analyzed in April 2015. INTERVENTION: Patients were randomly assigned to receive 6 months of FOLFOX4 or FOLFOX4 plus cetuximab after surgical resection for stage III colon cancer. MAIN OUTCOMES AND MEASURES: Associations between these biomarkers and disease-free survival (DFS) and overall survival (OS) were analyzed with Cox proportional hazards models. Multivariate models were adjusted for covariates (age, sex, tumor grade, T/N stage, tumor location, Eastern Cooperative Oncology Group performance status). RESULTS: Among the 2559 patients enrolled in the PETACC-8 trial (42.9% female; median [range] age, 60.0 [19.0-75.0] years), microsatellite instability (MSI) phenotype, KRAS, and BRAF V600E mutations were detected in, respectively, 9.9% (177 of 1791), 33.1% (588 of 1776), and 9.0% (148 of 1643) of cases. In multivariate analysis, MSI (hazard ratio [HR] for DFS: 1.10 [95% CI, 0.73-1.64], P = .67; HR for OS: 1.02 [95% CI, 0.61-1.69], P = .94) and BRAF V600E mutation (HR for DFS: 1.22 [95% CI, 0.81-1.85], P = .34; HR for OS: 1.13 [95% CI, 0.64-2.00], P = .66) were not prognostic, whereas KRAS mutation was significantly associated with shorter DFS (HR, 1.55 [95% CI, 1.23-1.95]; P < .001) and OS (HR, 1.56 [95% CI, 1.12-2.15]; P = .008). The subgroup analysis showed in patients with microsatellite-stable tumors that both KRAS (HR for DFS: 1.64 [95% CI, 1.29-2.08], P < .001; HR for OS: 1.71 [95% CI, 1.21-2.41], P = .002) and BRAF V600E mutation (HR for DFS: 1.74 [95% CI, 1.14-2.69], P = .01; HR for OS: 1.84 [95% CI, 1.01-3.36], P = .046) were independently associated with worse clinical outcomes. In patients with MSI tumors, KRAS status was not prognostic, whereas BRAF V600E mutation was associated with significantly longer DFS (HR, 0.23 [95% CI, 0.06-0.92]; P = .04) but not OS (HR, 0.19 [95% CI, 0.03-1.24]; P = .08). CONCLUSIONS AND RELEVANCE: BRAF V600E and KRAS mutations were significantly associated with shorter DFS and OS in patients with microsatellite-stable tumors but not in patients with MSI tumors. Future trials in the adjuvant setting will have to take into account mismatch repair, BRAF, and KRAS status for stratification. TRIAL REGISTRATION: EudraCT 2005-003463-23.
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Authors: B C Odisio; S Yamashita; S Y Huang; S Harmoush; S E Kopetz; K Ahrar; Y Shin Chun; C Conrad; T A Aloia; S Gupta; M E Hicks; J-N Vauthey Journal: Br J Surg Date: 2017-02-27 Impact factor: 6.939