J Taieb1, R Balogoun2, K Le Malicot3, J Tabernero4, E Mini5, G Folprecht6, J-L Van Laethem7, J-F Emile8, C Mulot9, S Fratté10, C-B Levaché11, L Saban-Roche12, J Thaler13, L N Petersen14, J Bridgewater15, G Perkins2,16, C Lepage17, E Van Cutsem18, A Zaanan2,19, P Laurent-Puig2. 1. Paris Descartes University, Paris Sorbonne cité, Department of Digestive Oncology, HEGP, Paris, France. 2. Biology, Université Paris Descartes, Sorbonne Paris Cité; Assistance Publique Hôpitaux de Paris, Hôpital Européen Georges Pompidou, INSERM UMR-S1147, Paris, France. 3. Fédération Francophone de Cancérologie Digestive (FFCD), Dijon, France. 4. Medical Oncology Department, Vall d'Hebron University Hospital and Institute of Oncology (VHIO), Barcelona, Universitat Autònoma de Barcelona, Spanish Gastrointestinal Tumours TTD Group, Barcelona, Spain. 5. Department of Experimental and Clinical Medicine, Section of Internal Medicine, University of Florence, Florence, Italy. 6. Medical Department I, University Hospital Carl Gustav Carus, Dresden, Germany. 7. Department of Gastroenterology, Hôpital Universitaire Erasme, Brussels, Belgium. 8. Pathology Department, Ambroise Paré Hospital, Boulogne, France. 9. Université Paris Descartes, Sorbonne Paris Cité, CRB EPIGENETEC, INSERM UMR-S1147, Paris, France. 10. Department of Gastroenterology, Centre Hospitalier de Belfort-Montbeliard, Belfort, France. 11. Department of Radiotherapy and Medical Oncology, Polyclinique Francheville, Périgueux, France. 12. Department of medical Oncology, Institut de Cancerologie de la Loire, Saint-Priest-En-Jarez, France. 13. Department of Internal Medicine IV, Klinikum Wels-Grieskirchen, Wels, Austria. 14. Department of Oncology, Rigshospitalet, København, Denmark. 15. UCL Cancer Institute, University College London, London, UK. 16. Université Sorbonne Paris Cité, INSERM UMR-S1147, CNRS SNC 5014, Centre Universitaire des Saints-Pères, Equipe labélisée LIGUE Contre le Cancer, Paris, France. 17. Hepato-Gastroenterology Department, Dijon University Hospital and INSERM U 866, Dijon, France. 18. Digestive Oncology, University Hospitals Leuven and KU Leuven, Leuven, Belgium. 19. Department of Digestive Oncology, European Georges Pompidou Hospital, Assistance Publique des Hôpitaux de Paris, Paris, France.
Abstract
Background: RAS mutations have been shown to confer resistance to anti- epidermal growth factor receptor (EGFR) treatment. We analysed the results of the PETACC8 trial (cetuximab + FOLFOX vs FOLFOX) in full RAS and BRAF wildtype (WT) patients (pts) with resected stage III colon cancer. Patients and methods: Exons 2, 3 and 4 of KRAS and NRAS, and BRAF exons 11 and 15, were sequenced using the Ampliseq colon-lung cancer panel version 2, in PETACC8 trial pts who consented to translational research. The impact of cetuximab on time to recurrence (TTR), disease-free survival (DFS) and overall survival (OS) was investigated in pts with tumours harbouring RAS and BRAF WT, and RAS mutations. The prognostic value of each individual mutation was also tested. Results: Among the 2559 pts analysed, 745 pts (29%) were known to have KRAS exon 2 mutations and 163 pts (6.4%) the BRAF V600E mutation. Of the remaining 1651 pts, 1054 were assessed by NGS, showing that a further 227 pts (21%) had KRAS exon 2, 3, 4 or NRAS exon 2, 3, 4 mutations, and that 46 pts (4.4%) had a newly diagnosed BRAF mutation. Cetuximab added to FOLFOX did not significantly improve TTR, DFS or OS in pts with RAS WT or RAS and BRAF WT tumours (HR 0.77-1.03, all P > 0.05). Cetuximab addition was not either significantly deleterious in RAS mutant pts or in pts with rare RAS or BRAF mutations. In the overall trial population, NRAS and KRAS codon 61 mutations were the only rare mutations with the same pejorative prognostic value as KRAS exon 2 or BRAF V600E mutations. Conclusion: Though not significant, the clinically relevant 0.76 adjusted HR observed for DFS in favour of adding cetuximab to FOLFOX, in full RAS and BRAF WT stage III colon cancer pts, may justify a new randomized controlled trial testing EGFR inhibitors in this setting. Clinical trial number: This is an ancillary study of the PETACC8 trial: EUDRACT 2005-003463-23.
RCT Entities:
Background: RAS mutations have been shown to confer resistance to anti- epidermal growth factor receptor (EGFR) treatment. We analysed the results of the PETACC8 trial (cetuximab + FOLFOX vs FOLFOX) in full RAS and BRAF wildtype (WT) patients (pts) with resected stage III colon cancer. Patients and methods: Exons 2, 3 and 4 of KRAS and NRAS, and BRAF exons 11 and 15, were sequenced using the Ampliseq colon-lung cancer panel version 2, in PETACC8 trial pts who consented to translational research. The impact of cetuximab on time to recurrence (TTR), disease-free survival (DFS) and overall survival (OS) was investigated in pts with tumours harbouring RAS and BRAF WT, and RAS mutations. The prognostic value of each individual mutation was also tested. Results: Among the 2559 pts analysed, 745 pts (29%) were known to have KRAS exon 2 mutations and 163 pts (6.4%) the BRAFV600E mutation. Of the remaining 1651 pts, 1054 were assessed by NGS, showing that a further 227 pts (21%) had KRAS exon 2, 3, 4 or NRAS exon 2, 3, 4 mutations, and that 46 pts (4.4%) had a newly diagnosed BRAF mutation. Cetuximab added to FOLFOX did not significantly improve TTR, DFS or OS in pts with RAS WT or RAS and BRAF WT tumours (HR 0.77-1.03, all P > 0.05). Cetuximab addition was not either significantly deleterious in RAS mutant pts or in pts with rare RAS or BRAF mutations. In the overall trial population, NRAS and KRAS codon 61 mutations were the only rare mutations with the same pejorative prognostic value as KRAS exon 2 or BRAFV600E mutations. Conclusion: Though not significant, the clinically relevant 0.76 adjusted HR observed for DFS in favour of adding cetuximab to FOLFOX, in full RAS and BRAF WT stage III colon cancerpts, may justify a new randomized controlled trial testing EGFR inhibitors in this setting. Clinical trial number: This is an ancillary study of the PETACC8 trial: EUDRACT 2005-003463-23.
Authors: Julien Taieb; Hampig Raphael Kourie; Jean-François Emile; Karine Le Malicot; Ralyath Balogoun; Josep Tabernero; Enrico Mini; Gunnar Folprecht; Jean-Luc Van Laethem; Claire Mulot; Olivier Bouché; Thomas Aparicio; Pierre Michel; Josef Thaler; John Bridgewater; Eric Van Cutsem; Géraldine Perkins; Come Lepage; Ramon Salazar; Pierre Laurent-Puig Journal: JAMA Oncol Date: 2018-07-12 Impact factor: 31.777
Authors: Daan Geert Knapen; Nathan I Cherny; Panagiota Zygoura; Nicola Jane Latino; Jean-Yves Douillard; Urania Dafni; Elisabeth G E de Vries; Derk Jan de Groot Journal: ESMO Open Date: 2020-09