Michèle Beau-Faller1, Matthieu Texier2, Hélène Blons3, Nicolas Richard4, Fabienne Escande5, Samia Melaabi6, Sarab Lizard7, Florence De Fraipont8, Elisabeth Longchampt9, Franck Morin10, Gérard Zalcman11, Jean-Pierre Pignon12, Jacques Cadranel13. 1. Laboratoire de Biologie Moléculaire, Hôpital de Hautepierre, Strasbourg, France; Unité INSERM U1113, Streinth Lab, Strasbourg, France; Intergroupe Francophone de Cancérologie Thoracique (IFCT), Paris, France. Electronic address: michele.faller@chru-strasbourg.fr. 2. Service de Biostatistique et d'Epidémiologie, Gustave-Roussy, Villejuif, France. 3. Intergroupe Francophone de Cancérologie Thoracique (IFCT), Paris, France; Département de Biologie, Hôpital Européen Georges Pompidou, AP-HP, Paris, France; Université Paris Descartes, Paris, France. 4. Service de Génétique, Laboratoire de Génétique Moléculaire, CHU de Caen, Caen, France. 5. Laboratoire Oncologie et Génétique Moléculaires, Pôle de Biochimie et de Biologie Moléculaire, Centre de Biologie Pathologie, CHRU de Lille, Lille, France. 6. Service de Génétique, Unité de Pharmacogénomique, Institut Curie, Paris, France. 7. Unité de Biologie Moléculaire, Centre GF Leclerc, Dijon, France. 8. UM Biochimie des Cancers et Biothérapies, CHU Grenoble Alpes, Grenoble, France; Université Grenoble Alpes, Grenoble, France. 9. Service d'Anatomie Pathologique, Hôpital Foch, Suresnes, France. 10. Intergroupe Francophone de Cancérologie Thoracique (IFCT), Paris, France. 11. Intergroupe Francophone de Cancérologie Thoracique (IFCT), Paris, France; UMR 830 INSERM et Service d'Oncologie Thoracique, Assistance Publique Hôpitaux de Paris, Hôpital Bichat-Claude Bernard, Université Paris-Diderot (Paris 7), Paris, France. 12. Service de Biostatistique et d'Epidémiologie, Gustave-Roussy, Villejuif, France; CESP INSERM U1018, Université Paris-Sud, Villejuif, France. 13. Intergroupe Francophone de Cancérologie Thoracique (IFCT), Paris, France; Service de Pneumologie, Assistance Publique Hôpitaux de Paris, Hôpital Tenon, GRC-04 Theranoscan, Université Paris VI, 75970 Paris, France.
Abstract
INTRODUCTION: Evaluation of EGFR Mutation status for the administration of EGFR-TKIs in non-small cell lung Carcinoma (ERMETIC) was a prospective study designed to validate the prognostic value of EGFR/KRAS mutations in patients with advanced non-small-cell lung cancer (NSCLC), all receiving a first-generation tyrosine kinase inhibitor, erlotinib. ERMETIC2 was an ancillary project evaluating the clinical value of common EGFR/KRAS-mutated subclones regarding prognosis using highly sensitive molecular detection methods. MATERIALS AND METHODS: Tumor samples from 228 patients with NSCLC (59% adenocarcinoma, 37% women, and 19% never/former smokers) were available for reanalysis using alternative highly sensitive molecular techniques. A multivariate Cox model was used for prognostic analysis. RESULTS: Using alternative highly sensitive techniques, 16 EGFR and 51 KRAS supplementary mutations were newly identified, all still exclusive, leading to an overall rate of 12.3% (n = 28) and 33.3% (n = 76), respectively. Using real-time polymerase chain reaction (hybridization probe), they were significantly associated with progression-free survival (P = .02) and overall survival (OS) (P = .01), which were better for EGFR-mutated patients for progression-free survival (hazard ratio [HR], 0.46; 95% confidence interval [CI], 0.28-0.78) and OS (HR, 0.56; 95% CI, 0.31-1), and worse for KRAS mutations and OS (HR, 1.63; 95% CI, 1.09-2.44). Using the most sensitive technique detection for KRAS-clamp polymerase chain reaction-KRAS mutated subclones did not impact OS. CONCLUSIONS: KRAS and EGFR mutations were detected in higher proportions by alternative highly sensitive molecular techniques compared with direct Sanger sequencing. However, minor KRAS-mutated subclones offered no prognostic value when representing less than 1% of the tumor cells.
INTRODUCTION: Evaluation of EGFR Mutation status for the administration of EGFR-TKIs in non-small cell lung Carcinoma (ERMETIC) was a prospective study designed to validate the prognostic value of EGFR/KRAS mutations in patients with advanced non-small-cell lung cancer (NSCLC), all receiving a first-generation tyrosine kinase inhibitor, erlotinib. ERMETIC2 was an ancillary project evaluating the clinical value of common EGFR/KRAS-mutated subclones regarding prognosis using highly sensitive molecular detection methods. MATERIALS AND METHODS:Tumor samples from 228 patients with NSCLC (59% adenocarcinoma, 37% women, and 19% never/former smokers) were available for reanalysis using alternative highly sensitive molecular techniques. A multivariate Cox model was used for prognostic analysis. RESULTS: Using alternative highly sensitive techniques, 16 EGFR and 51 KRAS supplementary mutations were newly identified, all still exclusive, leading to an overall rate of 12.3% (n = 28) and 33.3% (n = 76), respectively. Using real-time polymerase chain reaction (hybridization probe), they were significantly associated with progression-free survival (P = .02) and overall survival (OS) (P = .01), which were better for EGFR-mutated patients for progression-free survival (hazard ratio [HR], 0.46; 95% confidence interval [CI], 0.28-0.78) and OS (HR, 0.56; 95% CI, 0.31-1), and worse for KRAS mutations and OS (HR, 1.63; 95% CI, 1.09-2.44). Using the most sensitive technique detection for KRAS-clamp polymerase chain reaction-KRAS mutated subclones did not impact OS. CONCLUSIONS:KRAS and EGFR mutations were detected in higher proportions by alternative highly sensitive molecular techniques compared with direct Sanger sequencing. However, minor KRAS-mutated subclones offered no prognostic value when representing less than 1% of the tumor cells.