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Original Investigation
May 2016

Prognostic Effect of BRAF and KRAS Mutations in Patients With Stage III Colon Cancer Treated With Leucovorin, Fluorouracil, and Oxaliplatin With or Without CetuximabA Post Hoc Analysis of the PETACC-8 Trial

Author Affiliations
  • 1Paris Descartes University, Department of Digestive Oncology, European Georges Pompidou Hospital, Assistance Publique-Hôpitaux de Paris, France
  • 2Centre de Recherché UMR-S 1147, Médecine Personnalisée, Pharmacogénomique, Optimisation Thérapeutique, Institut National de la Santé et de la Recherche Médicale, Paris, France
  • 3Department of Statistics, Fédération Francophone de Cancérologie Digestive, Dijon, France
  • 4Department of Pathology, Ambroise Paré Hospital, Assistance Publique–Hôpitaux de Paris, Boulogne-Billancourt, France
  • 5Versailles Saint-Quentin-en-Yvelines University, Boulogne-Billancourt, France
  • 6Paris Descartes University, Department of Biology, European Georges Pompidou Hospital, Assistance Publique–Hôpitaux de Paris, France
  • 7Department of Oncology, Sainte Catherine Institute, Avignon, France
  • 8Department of Oncology, Cancérologie de l’Ouest Institute, Nantes, France
  • 9Medical Oncology Department, Vall d’Hebron University Hospital and Institute of Oncology, Barcelona, Spain
  • 10Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
  • 11First Medical Department, University Hospital Carl Gustav Carus, Dresden, Germany
  • 12Department of Gastroenterology, Erasme Hospital University, Brussels, Belgium
  • 13Department of Hepato-Gastroenterology, Dijon University Hospital, Dijon, France
  • 14Centre de Recherche UMR 866, Lipides, Nutrition, Cancer, Institut National de la Santé et de la Recherche Médicale, Dijon, France
JAMA Oncol. 2016;2(5):643-653. doi:10.1001/jamaoncol.2015.5225
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

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