H Blons1, J F Emile2, K Le Malicot3, C Julié4, A Zaanan5, J Tabernero6, E Mini7, G Folprecht8, J L Van Laethem9, J Thaler10, J Bridgewater11, L Nørgård-Petersen12, E Van Cutsem13, C Lepage14, M A Zawadi15, R Salazar16, P Laurent-Puig1, J Taieb17. 1. UMR-S1147, INSERM, Paris Paris Descartes University, Paris APHP Department of Biology, Georges Pompidou Hospital, Paris. 2. Department of Pathology, APHP Ambroise Paré Hospital, Boulogne-Billancourt Paris-Ouest University, Versailles Saint-Quentin. 3. Department of Statistics, Fédération Francophone de Cancérologie Digestive, Dijon. 4. Department of Pathology, APHP Ambroise Paré Hospital, Boulogne-Billancourt. 5. APHP Department of Hepatogastroenterology and GI Oncology, Georges Pompidou Hospital, Paris, France. 6. Department of Medical Oncology, Vall d'Hebron University Hospital and Institute of Oncology (VHIO), Barcelona, Spain. 7. Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy. 8. 1st Medical Department, University Hospital Carl Gustav Carus, Dresden, Germany. 9. Deptartment of Gastroenterology, Erasme University Hospital, Brussels, Belgium. 10. Department of Internal Medicine IV, Klinikum Wels-Grieskirchen, Wels, Austria. 11. UCL Cancer Institute, University College London, London, UK. 12. Department of Oncology, Rigshospitalet, København, Denmark. 13. Department of Digestive Oncology, University Hospitals and KULeuven, Leuven, Belgium. 14. Department of Hepato-Gastroenterology, Dijon University Hospital and INSERM U 866, Dijon. 15. GI Oncology, Les Oudairies Hospital, La Roche sur Yon, France. 16. Catalan Institute of Oncology (IDIBELL), Barcelona, Spain. 17. APHP Department of Hepatogastroenterology and GI Oncology, Georges Pompidou Hospital, Paris, France Paris Descartes University, Paris julien.taieb@egp.aphp.fr.
Abstract
BACKGROUND: The prognostic value of KRAS mutations in colon adenocarcinoma is controversial. We examined this question as an ancillary study of the PETACC8 phase III trial. PATIENTS AND METHODS: We analyzed the prognostic impact of KRAS exon 2 mutations in stage III colon cancer patients (n = 1657) receiving adjuvant FOLFOX ± cetuximab therapy included in the PETACC8 trial. Patients with BRAF-mutated cancers were excluded and, as no difference was found for time to recurrence (TTR) and disease-free survival (DFS) between treatment arms, both were pooled for analysis. Associations with TTR and DFS were analyzed using a Cox proportional hazards model. RESULTS: KRAS mutations were found in 638 of 1657 tumors and linked to shorter TTR (P < 0.001). However, when specific mutations were compared with wild-type, codon 12 mutations [hazard ratio (HR) 1.67, 95% confidence interval (CI) 1.35-2.04; P < 0.001] but not codon 13 (HR 1.23, 95% CI 0.85-1.79; P = 0.26) were significantly associated with shorter TTR, independently of other covariates. The interaction test showed that, regarding tumor location (distal versus proximal), KRAS genotype affects differently on recurrence (P = 0.02) and DFS (P = 0.042). Subgroup analysis showed that KRAS only affected TTR and DFS in distal tumors (n = 1043; 692 wild type; 351 mutated), with an increased risk of relapse (HR 1.96, 95% CI 1.51-2.56; P < 0.0001) for KRAS codon 12 mutations and a borderline significance for codon 13 mutations (HR 1.59, 95% CI 1.00-2.56; P = 0.051). CONCLUSION: KRAS exon 2 mutations are independent predictors of shorter TTR in patients with resected stage III distal colon cancers receiving adjuvant therapy. Future clinical trials in the adjuvant setting should consider both the tumor location and KRAS mutations as important stratification factors. CLINICAL TRIAL NUMBER: This is an ancillary study of the PETACC8 trial: EUDRACT 2005-003463-23.
BACKGROUND: The prognostic value of KRAS mutations in colon adenocarcinoma is controversial. We examined this question as an ancillary study of the PETACC8 phase III trial. PATIENTS AND METHODS: We analyzed the prognostic impact of KRAS exon 2 mutations in stage III colon cancerpatients (n = 1657) receiving adjuvant FOLFOX ± cetuximab therapy included in the PETACC8 trial. Patients with BRAF-mutated cancers were excluded and, as no difference was found for time to recurrence (TTR) and disease-free survival (DFS) between treatment arms, both were pooled for analysis. Associations with TTR and DFS were analyzed using a Cox proportional hazards model. RESULTS:KRAS mutations were found in 638 of 1657 tumors and linked to shorter TTR (P < 0.001). However, when specific mutations were compared with wild-type, codon 12 mutations [hazard ratio (HR) 1.67, 95% confidence interval (CI) 1.35-2.04; P < 0.001] but not codon 13 (HR 1.23, 95% CI 0.85-1.79; P = 0.26) were significantly associated with shorter TTR, independently of other covariates. The interaction test showed that, regarding tumor location (distal versus proximal), KRAS genotype affects differently on recurrence (P = 0.02) and DFS (P = 0.042). Subgroup analysis showed that KRAS only affected TTR and DFS in distal tumors (n = 1043; 692 wild type; 351 mutated), with an increased risk of relapse (HR 1.96, 95% CI 1.51-2.56; P < 0.0001) for KRAS codon 12 mutations and a borderline significance for codon 13 mutations (HR 1.59, 95% CI 1.00-2.56; P = 0.051). CONCLUSION:KRAS exon 2 mutations are independent predictors of shorter TTR in patients with resected stage III distal colon cancers receiving adjuvant therapy. Future clinical trials in the adjuvant setting should consider both the tumor location and KRAS mutations as important stratification factors. CLINICAL TRIAL NUMBER: This is an ancillary study of the PETACC8 trial: EUDRACT 2005-003463-23.
Authors: Julien Taieb; Karine Le Malicot; Qian Shi; Frédérique Penault-Llorca; Olivier Bouché; Josep Tabernero; Enrico Mini; Richard M Goldberg; Gunnar Folprecht; Jean Luc Van Laethem; Daniel J Sargent; Steven R Alberts; Jean Francois Emile; Pierre Laurent Puig; Frank A Sinicrope Journal: J Natl Cancer Inst Date: 2016-12-31 Impact factor: 13.506
Authors: Frank A Sinicrope; Michelle R Mahoney; Harry H Yoon; Thomas C Smyrk; Stephen N Thibodeau; Richard M Goldberg; Garth D Nelson; Daniel J Sargent; Steven R Alberts Journal: Clin Cancer Res Date: 2015-07-17 Impact factor: 12.531
Authors: Ketan Thanki; Michael E Nicholls; Aakash Gajjar; Anthony J Senagore; Suimin Qiu; Csaba Szabo; Mark R Hellmich; Celia Chao Journal: Int Biol Biomed J Date: 2017-06-13