Prognostic Effect of BRAF and KRAS Mutations in Patients With Stage III Colon Cancer Treated With Leucovorin, Fluorouracil, and Oxaliplatin With or Without Cetuximab: A Post Hoc Analysis of the PETACC-8 Trial | Cancer Biomarkers | JAMA Oncology | JAMA Network
[Skip to Navigation]
Access to paid content on this site is currently suspended due to excessive activity being detected from your IP address 18.207.129.82. Please contact the publisher to request reinstatement.
1.
Jemal  A, Bray  F, Center  MM, Ferlay  J, Ward  E, Forman  D.  Global cancer statistics.  CA Cancer J Clin. 2011;61(2):69-90.PubMedGoogle ScholarCrossref
2.
Ionov  Y, Peinado  MA, Malkhosyan  S, Shibata  D, Perucho  M.  Ubiquitous somatic mutations in simple repeated sequences reveal a new mechanism for colonic carcinogenesis.  Nature. 1993;363(6429):558-561.PubMedGoogle ScholarCrossref
3.
Peltomäki  P, Lothe  RA, Aaltonen  LA,  et al.  Microsatellite instability is associated with tumors that characterize the hereditary non-polyposis colorectal carcinoma syndrome.  Cancer Res. 1993;53(24):5853-5855.PubMedGoogle Scholar
4.
Herman  JG, Umar  A, Polyak  K,  et al.  Incidence and functional consequences of hMLH1 promoter hypermethylation in colorectal carcinoma.  Proc Natl Acad Sci U S A. 1998;95(12):6870-6875.PubMedGoogle ScholarCrossref
5.
Weisenberger  DJ, Siegmund  KD, Campan  M,  et al.  CpG island methylator phenotype underlies sporadic microsatellite instability and is tightly associated with BRAF mutation in colorectal cancer.  Nat Genet. 2006;38(7):787-793.PubMedGoogle ScholarCrossref
6.
Domingo  E, Niessen  RC, Oliveira  C,  et al.  BRAF-V600E is not involved in the colorectal tumorigenesis of HNPCC in patients with functional MLH1 and MSH2 genes.  Oncogene. 2005;24(24):3995-3998.PubMedGoogle ScholarCrossref
7.
Roth  AD, Tejpar  S, Delorenzi  M,  et al.  Prognostic role of KRAS and BRAF in stage II and III resected colon cancer: results of the translational study on the PETACC-3, EORTC 40993, SAKK 60-00 trial.  J Clin Oncol. 2010;28(3):466-474.PubMedGoogle ScholarCrossref
8.
Van Cutsem  E, Köhne  CH, Láng  I,  et al.  Cetuximab plus irinotecan, fluorouracil, and leucovorin as first-line treatment for metastatic colorectal cancer: updated analysis of overall survival according to tumor KRAS and BRAF mutation status.  J Clin Oncol. 2011;29(15):2011-2019.PubMedGoogle ScholarCrossref
9.
Karapetis  CS, Khambata-Ford  S, Jonker  DJ,  et al.  K-ras mutations and benefit from cetuximab in advanced colorectal cancer.  N Engl J Med. 2008;359(17):1757-1765.PubMedGoogle ScholarCrossref
10.
Van Cutsem  E, Labianca  R, Bodoky  G,  et al.  Randomized phase III trial comparing biweekly infusional fluorouracil/leucovorin alone or with irinotecan in the adjuvant treatment of stage III colon cancer: PETACC-3.  J Clin Oncol. 2009;27(19):3117-3125.PubMedGoogle ScholarCrossref
11.
De Roock  W, Claes  B, Bernasconi  D,  et al.  Effects of KRAS, BRAF, NRAS, and PIK3CA mutations on the efficacy of cetuximab plus chemotherapy in chemotherapy-refractory metastatic colorectal cancer: a retrospective consortium analysis.  Lancet Oncol. 2010;11(8):753-762.PubMedGoogle ScholarCrossref
12.
Yokota  T, Ura  T, Shibata  N,  et al.  BRAF mutation is a powerful prognostic factor in advanced and recurrent colorectal cancer.  Br J Cancer. 2011;104(5):856-862.PubMedGoogle ScholarCrossref
13.
Andreyev  HJ, Norman  AR, Cunningham  D, Oates  JR, Clarke  PA.  Kirsten ras mutations in patients with colorectal cancer: the multicenter “RASCAL” study.  J Natl Cancer Inst. 1998;90(9):675-684.PubMedGoogle ScholarCrossref
14.
Gavin  PG, Colangelo  LH, Fumagalli  D,  et al.  Mutation profiling and microsatellite instability in stage II and III colon cancer: an assessment of their prognostic and oxaliplatin predictive value.  Clin Cancer Res. 2012;18(23):6531-6541.PubMedGoogle ScholarCrossref
15.
Yoon  HH, Tougeron  D, Shi  Q,  et al; Alliance for Clinical Trials in Oncology.  KRAS codon 12 and 13 mutations in relation to disease-free survival in BRAF-wild-type stage III colon cancers from an adjuvant chemotherapy trial (N0147 Alliance).  Clin Cancer Res. 2014;20(11):3033-3043.PubMedGoogle ScholarCrossref
16.
Blons  H, Emile  JF, Le Malicot  K,  et al.  Prognostic value of KRAS mutations in stage III colon cancer: post hoc analysis of the PETACC-8 phase III trial dataset.  Ann Oncol. 2014;25(12):2378-2385.PubMedGoogle ScholarCrossref
17.
Popovici  V, Budinska  E, Tejpar  S,  et al.  Identification of a poor-prognosis BRAF-mutant-like population of patients with colon cancer.  J Clin Oncol. 2012;30(12):1288-1295.PubMedGoogle ScholarCrossref
18.
Ogino  S, Shima  K, Meyerhardt  JA,  et al.  Predictive and prognostic roles of BRAF mutation in stage III colon cancer: results from intergroup trial CALGB 89803.  Clin Cancer Res. 2012;18(3):890-900.PubMedGoogle ScholarCrossref
19.
Sinicrope  FA, Mahoney  MR, Smyrk  TC,  et al.  Prognostic impact of deficient DNA mismatch repair in patients with stage III colon cancer from a randomized trial of FOLFOX-based adjuvant chemotherapy.  J Clin Oncol. 2013;31(29):3664-3672.PubMedGoogle ScholarCrossref
20.
Ribic  CM, Sargent  DJ, Moore  MJ,  et al.  Tumor microsatellite-instability status as a predictor of benefit from fluorouracil-based adjuvant chemotherapy for colon cancer.  N Engl J Med. 2003;349(3):247-257.PubMedGoogle ScholarCrossref
21.
Sargent  DJ, Marsoni  S, Monges  G,  et al.  Defective mismatch repair as a predictive marker for lack of efficacy of fluorouracil-based adjuvant therapy in colon cancer.  J Clin Oncol. 2010;28(20):3219-3226.PubMedGoogle ScholarCrossref
22.
Taieb  J, Tabernero  J, Mini  E,  et al; PETACC-8 Study Investigators.  Oxaliplatin, fluorouracil, and leucovorin with or without cetuximab in patients with resected stage III colon cancer (PETACC-8): an open-label, randomised phase 3 trial.  Lancet Oncol. 2014;15(8):862-873.PubMedGoogle ScholarCrossref
23.
Zaanan  A, Cuilliere-Dartigues  P, Guilloux  A,  et al.  Impact of p53 expression and microsatellite instability on stage III colon cancer disease-free survival in patients treated by 5-fluorouracil and leucovorin with or without oxaliplatin.  Ann Oncol. 2010;21(4):772-780.PubMedGoogle ScholarCrossref
24.
Umar  A, Boland  CR, Terdiman  JP,  et al.  Revised Bethesda Guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability.  J Natl Cancer Inst. 2004;96(4):261-268.PubMedGoogle ScholarCrossref
25.
Blons  H, Rouleau  E, Charrier  N,  et al; MOKAECM Collaborative Group.  Performance and cost efficiency of KRAS mutation testing for metastatic colorectal cancer in routine diagnosis: the MOKAECM study, a nationwide experience.  PLoS One. 2013;8(7):e68945.PubMedGoogle ScholarCrossref
26.
Samowitz  WS, Curtin  K, Ma  KN,  et al.  Microsatellite instability in sporadic colon cancer is associated with an improved prognosis at the population level.  Cancer Epidemiol Biomarkers Prev. 2001;10(9):917-923.PubMedGoogle Scholar
27.
Sorbye  H, Dragomir  A, Sundström  M,  et al.  High BRAF mutation frequency and marked survival differences in subgroups according to KRAS/BRAF mutation status and tumor tissue availability in a prospective population-based metastatic colorectal cancer cohort.  PLoS One. 2015;10(6):e0131046.PubMedGoogle ScholarCrossref
28.
Janakiraman  M, Vakiani  E, Zeng  Z,  et al.  Genomic and biological characterization of exon 4 KRAS mutations in human cancer.  Cancer Res. 2010;70(14):5901-5911.PubMedGoogle ScholarCrossref
29.
Popat  S, Hubner  R, Houlston  RS.  Systematic review of microsatellite instability and colorectal cancer prognosis.  J Clin Oncol. 2005;23(3):609-618.PubMedGoogle ScholarCrossref
30.
Lanza  G, Gafà  R, Santini  A, Maestri  I, Guerzoni  L, Cavazzini  L.  Immunohistochemical test for MLH1 and MSH2 expression predicts clinical outcome in stage II and III colorectal cancer patients.  J Clin Oncol. 2006;24(15):2359-2367.PubMedGoogle ScholarCrossref
31.
Halling  KC, French  AJ, McDonnell  SK,  et al.  Microsatellite instability and 8p allelic imbalance in stage B2 and C colorectal cancers.  J Natl Cancer Inst. 1999;91(15):1295-1303.PubMedGoogle ScholarCrossref
32.
Zaanan  A, Fléjou  JF, Emile  JF,  et al.  Defective mismatch repair status as a prognostic biomarker of disease-free survival in stage III colon cancer patients treated with adjuvant FOLFOX chemotherapy.  Clin Cancer Res. 2011;17(23):7470-7478.PubMedGoogle ScholarCrossref
33.
Barnetson  RA, Tenesa  A, Farrington  SM,  et al.  Identification and survival of carriers of mutations in DNA mismatch-repair genes in colon cancer.  N Engl J Med. 2006;354(26):2751-2763.PubMedGoogle ScholarCrossref
34.
Kim  GP, Colangelo  LH, Wieand  HS,  et al; National Cancer Institute.  Prognostic and predictive roles of high-degree microsatellite instability in colon cancer: a National Cancer Institute-National Surgical Adjuvant Breast and Bowel Project collaborative study.  J Clin Oncol. 2007;25(7):767-772.PubMedGoogle ScholarCrossref
35.
Salahshor  S, Kressner  U, Fischer  H,  et al.  Microsatellite instability in sporadic colorectal cancer is not an independent prognostic factor.  Br J Cancer. 1999;81(2):190-193.PubMedGoogle ScholarCrossref
36.
Roth  AD, Delorenzi  M, Tejpar  S,  et al.  Integrated analysis of molecular and clinical prognostic factors in stage II/III colon cancer.  J Natl Cancer Inst. 2012;104(21):1635-1646.PubMedGoogle ScholarCrossref
37.
Fink  D, Zheng  H, Nebel  S,  et al.  In vitro and in vivo resistance to cisplatin in cells that have lost DNA mismatch repair.  Cancer Res. 1997;57(10):1841-1845.PubMedGoogle Scholar
38.
Carethers  JM, Chauhan  DP, Fink  D,  et al.  Mismatch repair proficiency and in vitro response to 5-fluorouracil.  Gastroenterology. 1999;117(1):123-131.PubMedGoogle ScholarCrossref
39.
Shen  L, Catalano  PJ, Benson  AB  III, O’Dwyer  P, Hamilton  SR, Issa  JP.  Association between DNA methylation and shortened survival in patients with advanced colorectal cancer treated with 5-fluorouracil based chemotherapy.  Clin Cancer Res. 2007;13(20):6093-6098.PubMedGoogle ScholarCrossref
40.
Van Rijnsoever  M, Elsaleh  H, Joseph  D, McCaul  K, Iacopetta  B.  CpG island methylator phenotype is an independent predictor of survival benefit from 5-fluorouracil in stage III colorectal cancer.  Clin Cancer Res. 2003;9(8):2898-2903.PubMedGoogle Scholar
41.
Jover  R, Nguyen  TP, Pérez-Carbonell  L,  et al.  5-Fluorouracil adjuvant chemotherapy does not increase survival in patients with CpG island methylator phenotype colorectal cancer.  Gastroenterology. 2011;140(4):1174-1181.PubMedGoogle ScholarCrossref
42.
Han  SW, Lee  HJ, Bae  JM,  et al.  Methylation and microsatellite status and recurrence following adjuvant FOLFOX in colorectal cancer.  Int J Cancer. 2013;132(9):2209-2216.PubMedGoogle ScholarCrossref
43.
Andreyev  HJ, Norman  AR, Cunningham  D,  et al.  Kirsten ras mutations in patients with colorectal cancer: the “RASCAL II” study.  Br J Cancer. 2001;85(5):692-696.PubMedGoogle ScholarCrossref
44.
Westra  JL, Schaapveld  M, Hollema  H,  et al.  Determination of TP53 mutation is more relevant than microsatellite instability status for the prediction of disease-free survival in adjuvant-treated stage III colon cancer patients.  J Clin Oncol. 2005;23(24):5635-5643.PubMedGoogle ScholarCrossref
45.
Ogino  S, Meyerhardt  JA, Irahara  N,  et al; Cancer and Leukemia Group B; North Central Cancer Treatment Group; Canadian Cancer Society Research Institute; Southwest Oncology Group.  KRAS mutation in stage III colon cancer and clinical outcome following intergroup trial CALGB 89803.  Clin Cancer Res. 2009;15(23):7322-7329.PubMedGoogle ScholarCrossref
46.
Bokemeyer  C, Bondarenko  I, Makhson  A,  et al.  Fluorouracil, leucovorin, and oxaliplatin with and without cetuximab in the first-line treatment of metastatic colorectal cancer.  J Clin Oncol. 2009;27(5):663-671.PubMedGoogle ScholarCrossref
47.
Douillard  JY, Oliner  KS, Siena  S,  et al.  Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer.  N Engl J Med. 2013;369(11):1023-1034.PubMedGoogle ScholarCrossref
48.
Van Cutsem  E, Köhne  CH, Hitre  E,  et al.  Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer.  N Engl J Med. 2009;360(14):1408-1417.PubMedGoogle ScholarCrossref
49.
Van Cutsem  E, Lenz  HJ, Köhne  CH,  et al.  Fluorouracil, leucovorin, and irinotecan plus cetuximab treatment and RAS mutations in colorectal cancer.  J Clin Oncol. 2015;33(7):692-700.PubMedGoogle ScholarCrossref
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 Cetuximab: A 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

×