Nicolas Guibert1, Fabrice Barlesi2, Renaud Descourt3, Hervé Léna4, Benjamin Besse5, Michèle Beau-Faller6, Jean Mosser7, Eric Pichon8, Jean-Philippe Merlio9, L'Houcine Ouafik10, François Guichard11, Bénédicte Mastroianni12, Lionel Moreau13, Annie Wdowik14, Jean-Christophe Sabourin15, Antoinette Lemoine16, Pascale Missy17, Alexandra Langlais17, Denis Moro-Sibilot18, Julien Mazières19. 1. Toulouse University Hospital, Paul Sabatier Toulouse University, Toulouse, France. 2. Aix-Marseille University, Assistance Publique Hôpitaux de Marseille, Marseille, France. 3. Brest University Hospital, Brest, France. 4. Pontchaillou Rennes University Hospital, Rennes, France. 5. Gustave Roussy Cancer Campus, Villejuif, France. 6. Strasbourg University Hospital, Strasbourg, France. 7. Rennes University Hospital, Rennes, France. 8. Tours University Hospital, Tours, France. 9. Bordeaux University Hospital, Pessac, France. 10. Aix Marseille University, Marseille, France. 11. Bordeaux Nord Aquitaine Polyclinic, Bordeaux, France. 12. Louis Pradel University Hospital, Bron, France. 13. Louis Pasteur Hospital, Colmar, France. 14. Bretagne Atlantique Vannes Hospital, Vannes, France. 15. Rouen University Hospital, Rouen, France. 16. Paris-Sud Hospital, Villejuif, France. 17. French Cooperative Thoracic Intergroup, Paris, France. 18. Grenoble University Hospital, Grenoble, France. 19. Toulouse University Hospital, Paul Sabatier Toulouse University, Toulouse, France. Electronic address: mazieres.j@chu-toulouse.fr.
Abstract
INTRODUCTION: Little is known about the prevalence, prognosis, and response to treatment of advanced NSCLC harboring multiple genomic alterations. METHODS: The French Biomarkers France database, which includes 17,664 patients, was used. The prevalence of multiple alterations, their associations, their impact on prognosis (overall survival [OS]), and their response to targeted or conventional treatments (progression-free survival [PFS] and objective response rate) were assessed and compared with those of patients harboring single or no mutation. RESULTS: We identified 162 patients (0.9%) with double alterations and three with triple mutations. Multiple molecular alterations preferentially involved KRAS (67.3%), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha gene (PIK3CA) (53.3%), and EGFR (42.4%). Patients with multiple alterations were more likely to be male (56.4%), be never-smokers (25.8 versus 34.7%, p < 0.001), and exhibit adenocarcinomas (83.6%). OS did not differ between single and multiple alterations. Patients with EGFR/KRAS and EGFR/PIK3CA mutations experienced worse PFS than did patients with only EGFR mutations (7.1 and 7.1 versus 14.9 months, p = 0.02 and 0.002, respectively). Concomitant mutations in patients harboring anaplastic lymphoma receptor tyrosine kinase gene (ALK) rearrangement bore little impact on OS (17.7 versus 20.3 months, p = 0.57) or PFS (10.3 versus 12.1 months, p = 0.93). Patients harboring KRAS mutations plus another alteration had an OS time (13.4 versus 11.2 months, p = 0.28), PFS time (6.4 versus 7.2 months, p = 0.78), and objective response rate under first-line chemotherapy (41.7% versus 37.2%) similar to those of patients harboring KRAS mutations only. CONCLUSIONS: With almost 1% of patients harboring multiple alterations, the dogma of mutually exclusive mutations should be reconsidered. Although double mutations do not decrease OS, they do alter PFS under first-line treatment for patients with EGFR mutations. Among limited numbers of patients, therapies targeting the dominant oncogene seem to usually remain active.
INTRODUCTION: Little is known about the prevalence, prognosis, and response to treatment of advanced NSCLC harboring multiple genomic alterations. METHODS: The French Biomarkers France database, which includes 17,664 patients, was used. The prevalence of multiple alterations, their associations, their impact on prognosis (overall survival [OS]), and their response to targeted or conventional treatments (progression-free survival [PFS] and objective response rate) were assessed and compared with those of patients harboring single or no mutation. RESULTS: We identified 162 patients (0.9%) with double alterations and three with triple mutations. Multiple molecular alterations preferentially involved KRAS (67.3%), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha gene (PIK3CA) (53.3%), and EGFR (42.4%). Patients with multiple alterations were more likely to be male (56.4%), be never-smokers (25.8 versus 34.7%, p < 0.001), and exhibit adenocarcinomas (83.6%). OS did not differ between single and multiple alterations. Patients with EGFR/KRAS and EGFR/PIK3CA mutations experienced worse PFS than did patients with only EGFR mutations (7.1 and 7.1 versus 14.9 months, p = 0.02 and 0.002, respectively). Concomitant mutations in patients harboring anaplastic lymphoma receptor tyrosine kinase gene (ALK) rearrangement bore little impact on OS (17.7 versus 20.3 months, p = 0.57) or PFS (10.3 versus 12.1 months, p = 0.93). Patients harboring KRAS mutations plus another alteration had an OS time (13.4 versus 11.2 months, p = 0.28), PFS time (6.4 versus 7.2 months, p = 0.78), and objective response rate under first-line chemotherapy (41.7% versus 37.2%) similar to those of patients harboring KRAS mutations only. CONCLUSIONS: With almost 1% of patients harboring multiple alterations, the dogma of mutually exclusive mutations should be reconsidered. Although double mutations do not decrease OS, they do alter PFS under first-line treatment for patients with EGFR mutations. Among limited numbers of patients, therapies targeting the dominant oncogene seem to usually remain active.
Authors: Giuseppe Lo Russo; Martina Imbimbo; Giulia Corrao; Claudia Proto; Diego Signorelli; Milena Vitali; Monica Ganzinelli; Laura Botta; Nicoletta Zilembo; Filippo de Braud; Marina Chiara Garassino Journal: Oncotarget Date: 2017-04-26
Authors: Jessica Garcia; Julien Forestier; Eric Dusserre; Anne-Sophie Wozny; Florence Geiguer; Patrick Merle; Claire Tissot; Carole Ferraro-Peyret; Frederick S Jones; Daniel L Edelstein; Valérie Cheynet; Claire Bardel; Gaelle Vilchez; Zhenyu Xu; Pierre Paul Bringuier; Marc Barritault; Karen Brengle-Pesce; Marielle Guillet; Marion Chauvenet; Brigitte Manship; Marie Brevet; Claire Rodriguez-Lafrasse; Valérie Hervieu; Sébastien Couraud; Thomas Walter; Léa Payen Journal: Oncotarget Date: 2018-04-20