title: Routine molecular profiling of patients with advanced non-small-cell lung cancer: results of a 1-year nationwide programme of the French Cooperative Thoracic Intergroup (IFCT).
abstract: BACKGROUND
  The molecular profiling of patients with advanced non-small-cell lung cancer (NSCLC) for known oncogenic drivers is recommended during routine care. Nationally, however, the feasibility and effects on outcomes of this policy are unknown. We aimed to assess the characteristics, molecular profiles, and clinical outcomes of patients who were screened during a 1-year period by a nationwide programme funded by the French National Cancer Institute.
  
  
  METHODS
  This study included patients with advanced NSCLC, who were routinely screened for EGFR mutations, ALK rearrangements, as well as HER2 (ERBB2), KRAS, BRAF, and PIK3CA mutations by 28 certified regional genetics centres in France. Patients were assessed consecutively during a 1-year period from April, 2012, to April, 2013. We measured the frequency of molecular alterations in the six routinely screened genes, the turnaround time in obtaining molecular results, and patients' clinical outcomes. This study is registered with ClinicalTrials.gov, number NCT01700582.
  
  
  RESULTS
  18,679 molecular analyses of 17,664 patients with NSCLC were done (of patients with known data, median age was 64·5 years [range 18-98], 65% were men, 81% were smokers or former smokers, and 76% had adenocarcinoma). The median interval between the initiation of analysis and provision of the written report was 11 days (IQR 7-16). A genetic alteration was recorded in about 50% of the analyses; EGFR mutations were reported in 1947 (11%) of 17,706 analyses for which data were available, HER2 mutations in 98 (1%) of 11,723, KRAS mutations in 4894 (29%) of 17,001, BRAF mutations in 262 (2%) of 13,906, and PIK3CA mutations in 252 (2%) of 10,678; ALK rearrangements were reported in 388 (5%) of 8134 analyses. The median duration of follow-up at the time of analysis was 24·9 months (95% CI 24·8-25·0). The presence of a genetic alteration affected first-line treatment for 4176 (51%) of 8147 patients and was associated with a significant improvement in the proportion of patients achieving an overall response in first-line treatment (37% [95% CI 34·7-38·2] for presence of a genetic alteration vs 33% [29·5-35·6] for absence of a genetic alteration; p=0·03) and in second-line treatment (17% [15·0-18·8] vs 9% [6·7-11·9]; p<0·0001). Presence of a genetic alteration was also associated with improved first-line progression-free survival (10·0 months [95% CI 9·2-10·7] vs 7·1 months [6·1-7·9]; p<0·0001) and overall survival (16·5 months [15·0-18·3] vs 11·8 months [10·1-13·5]; p<0·0001) compared with absence of a genetic alteration.
  
  
  CONCLUSIONS
  Routine nationwide molecular profiling of patients with advanced NSCLC is feasible. The frequency of genetic alterations, acceptable turnaround times in obtaining analysis results, and the clinical advantage provided by detection of a genetic alteration suggest that this policy provides a clinical benefit.
  
  
  BACKGROUND
  French National Cancer Institute (INCa).
authors.affiliation: Assistance Publique Hôpitaux de Marseille, Multidisciplinary Oncology and Therapeutic Innovations Department, Aix Marseille University, Centre d'Investigation Clinique, Marseille, France. Electronic address: fabrice.barlesi@ap-hm.fr.
authors.forename: Fabrice
authors.initials: F
authors.lastname: Barlesi
authors.affiliation: Hôpital Larrey, Centre Hospitalier Universitaire, Université Paul Sabatier, Toulouse, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Mazieres
authors.affiliation: Centre Hospitalier Universitaire de Bordeaux, Pôle Biologie et Anatomie Pathologique, Pessac, France; Université de Bordeaux, Histologie et Pathologie Moléculaires des Tumeurs, Bordeaux, France.
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Merlio
authors.affiliation: Hôpital Emile Muller, Service de Pneumologie, Mulhouse, France.
authors.forename: Didier
authors.initials: D
authors.lastname: Debieuvre
authors.affiliation: Centre Hospitalier Universitaire de Rennes, Département de Génomique et Génétique Moléculaire, Plateforme INCA, Rennes, France.
authors.forename: Jean
authors.initials: J
authors.lastname: Mosser
authors.affiliation: Hôpital Pontchaillou, Service de Pneumologie, Centre Hospitalier Universitaire, Rennes, France.
authors.forename: Hervé
authors.initials: H
authors.lastname: Lena
authors.affiliation: Assistance Publique Hôpitaux de Marseille, Service de Transfert d'Oncologie Biologique, Aix Marseille University, Marseille, France.
authors.forename: L'Houcine
authors.initials: L
authors.lastname: Ouafik
authors.affiliation: Gustave Roussy, Cancer Campus, Villejuif, France; University Paris-Sud, Châtenay-Malabry, France.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Besse
authors.affiliation: Institut Universitaire du Cancer de Toulouse, Oncopôle, Service d'Anatomie Pathologique, Toulouse, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Rouquette
authors.affiliation: Université de Franche-Comté, EA3181, Centre Hospitalier Universitaire Jean Minjoz, Service de Pneumologie, Besançon, France.
authors.forename: Virginie
authors.initials: V
authors.lastname: Westeel
authors.affiliation: Centre Hospitalier Universitaire de Lille, Département de Biochimie et Biologie Moléculaire, Centre de Biologie Pathologie, Lille, France.
authors.forename: Fabienne
authors.initials: F
authors.lastname: Escande
authors.affiliation: Centre Hospitalier Intercommunal de Créteil, Service de Pneumologie et de Pathologie Professionnelle, Créteil, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Monnet
authors.affiliation: Assistance Publique-Hôpitaux de Paris, Groupe Hospitalier des Hôpitaux Universitaires Paris-Sud, Service d'Oncogénétique- Oncomolpath, Université Paris 11, Villejuif, France.
authors.forename: Antoinette
authors.initials: A
authors.lastname: Lemoine
authors.affiliation: Centre Hospitalier Universitaire de Bordeaux, Service des Maladies Respiratoires, Pessac, France.
authors.forename: Rémi
authors.initials: R
authors.lastname: Veillon
authors.affiliation: UMR-S1147, INSERM, Université Paris Descartes, Assistance Publique Hôpitaux de Paris Département de Biologie, Hôpital Européen Georges Pompidou, Paris, France.
authors.forename: Hélène
authors.initials: H
authors.lastname: Blons
authors.affiliation: Centre Hospitalier Sainte Musse, Service de Pneumologie, Toulon, France.
authors.forename: Clarisse
authors.initials: C
authors.lastname: Audigier-Valette
authors.affiliation: Hôpital Edouard Herriot, Service d'Anatomie et de Cytologie Pathologique, Hospices Civils de Lyon, Université Claude Bernard Lyon 1, Lyon Cancer Research Center, UMR 1057 INSERM, Lyon, France.
authors.forename: Pierre-Paul
authors.initials: PP
authors.lastname: Bringuier
authors.affiliation: Centre Hospitalier de Bretagne Sud, Service d'Oncologie Médicale, Lorient, France.
authors.forename: Régine
authors.initials: R
authors.lastname: Lamy
authors.affiliation: Centre Hospitalier Universitaire de Hautepierre, Laboratoire de Biochimie et de Biologie Moléculaire & Plate-forme de Génomique des Cancers, Strasbourg, France.
authors.forename: Michèle
authors.initials: M
authors.lastname: Beau-Faller
authors.affiliation: Centre Hospitalier Universitaire de Montpellier, Unité d'Oncologie Thoracique, Pôle Cœur Poumon, Hôpital Arnaud de Villeneuve, Montpellier, France.
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Pujol
authors.affiliation: Centre Hospitalier Universitaire de Rouen, Département d'Anatomie et de Cytologie Pathologiques, Rouen, France.
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Sabourin
authors.affiliation: Centre Jean Perrin, Département d'Anatomie et de Cytologie Pathologique, Clermont-Ferrand, France.
authors.forename: Frédérique
authors.initials: F
authors.lastname: Penault-Llorca
authors.affiliation: Centre Hospitalier Universitaire de Nantes, Laboratoire de Biochimie, Nantes, France.
authors.forename: Marc G
authors.initials: MG
authors.lastname: Denis
authors.affiliation: Centre Hospitalier Universitaire A Michallon, Département d'Anatomie et Cytologie Pathologiques DACP, Institut de Biologie et de Pathologie, Université Joseph Fourier-INSERM U 823, Institut Albert Bonniot, Grenoble, France.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Lantuejoul
authors.affiliation: Clinical Research Unit, French Cooperative Thoracic Intergroup (IFCT), Paris, France.
authors.forename: Franck
authors.initials: F
authors.lastname: Morin
authors.affiliation: Clinical Research Unit, French Cooperative Thoracic Intergroup (IFCT), Paris, France.
authors.forename: Quân
authors.initials: Q
authors.lastname: Tran
authors.affiliation: Clinical Research Unit, French Cooperative Thoracic Intergroup (IFCT), Paris, France.
authors.forename: Pascale
authors.initials: P
authors.lastname: Missy
authors.affiliation: Biostatistics Unit, French Cooperative Thoracic Intergroup (IFCT), Paris, France.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Langlais
authors.affiliation: Assistance Publique Hôpitaux de Paris, Hôpital Tenon, Service de Pneumologie, Sorbonne Universités, UPMC Université Paris 06, Paris, France.
authors.forename: Bernard
authors.initials: B
authors.lastname: Milleron
authors.affiliation: Assistance Publique Hôpitaux de Paris, Hôpital Tenon, Service de Pneumologie, Sorbonne Universités, UPMC Université Paris 06, Paris, France.
authors.forename: Jacques
authors.initials: J
authors.lastname: Cadranel
authors.affiliation: Gustave Roussy, Cancer Campus, Villejuif, France; University Paris-Sud, Châtenay-Malabry, France.
authors.forename: Jean-Charles
authors.initials: JC
authors.lastname: Soria
authors.affiliation: Centre Hospitalier Universitaire de Caen, Service de Pneumologie et Oncologie Thoracique, Centre de Recherche Clinique, Université de Caen-Basse Normandie, Caen, France.
authors.forename: Gérard
authors.initials: G
authors.lastname: Zalcman
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000077548:Anaplastic Lymphoma Kinase; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000401:mortality / Q000628:therapy; D058534:Class I Phosphatidylinositol 3-Kinases; D066246:ErbB Receptors / Q000235:genetics; D005260:Female; D005602:France / Q000453:epidemiology; D020869:Gene Expression Profiling; D015321:Gene Rearrangement; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000401:mortality / Q000628:therapy; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D011446:Prospective Studies; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics; D055815:Young Adult
chemical_list: D000077548:Anaplastic Lymphoma Kinase; D058534:Class I Phosphatidylinositol 3-Kinases; D066246:ErbB Receptors; D019869:Phosphatidylinositol 3-Kinases; D048493:Proto-Oncogene Proteins B-raf; D016283:Proto-Oncogene Proteins p21(ras); D020794:Receptor Protein-Tyrosine Kinases; D018719:Erb-b2 Receptor Tyrosine Kinases; C117307:KRAS protein, human; C484760:PIK3CA protein, human; C000626173:ALK protein, human; C512478:EGFR protein, human; C508053:ERBB2 protein, human; C482119:BRAF protein, human