title: Characteristics and Outcomes of Patients with Lung Cancer Harboring Multiple Molecular Alterations: Results from the IFCT Study Biomarkers France.
abstract: Little is known about the prevalence, prognosis, and response to treatment of advanced NSCLC harboring multiple genomic alterations.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.affiliation: Toulouse University Hospital, Paul Sabatier Toulouse University, Toulouse, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Guibert
authors.affiliation: Aix-Marseille University, Assistance Publique Hôpitaux de Marseille, Marseille, France.
authors.forename: Fabrice
authors.initials: F
authors.lastname: Barlesi
authors.affiliation: Brest University Hospital, Brest, France.
authors.forename: Renaud
authors.initials: R
authors.lastname: Descourt
authors.affiliation: Pontchaillou Rennes University Hospital, Rennes, France.
authors.forename: Hervé
authors.initials: H
authors.lastname: Léna
authors.affiliation: Gustave Roussy Cancer Campus, Villejuif, France.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Besse
authors.affiliation: Strasbourg University Hospital, Strasbourg, France.
authors.forename: Michèle
authors.initials: M
authors.lastname: Beau-Faller
authors.affiliation: Rennes University Hospital, Rennes, France.
authors.forename: Jean
authors.initials: J
authors.lastname: Mosser
authors.affiliation: Tours University Hospital, Tours, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Pichon
authors.affiliation: Bordeaux University Hospital, Pessac, France.
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Merlio
authors.affiliation: Aix Marseille University, Marseille, France.
authors.forename: L'Houcine
authors.initials: L
authors.lastname: Ouafik
authors.affiliation: Bordeaux Nord Aquitaine Polyclinic, Bordeaux, France.
authors.forename: François
authors.initials: F
authors.lastname: Guichard
authors.affiliation: Louis Pradel University Hospital, Bron, France.
authors.forename: Bénédicte
authors.initials: B
authors.lastname: Mastroianni
authors.affiliation: Louis Pasteur Hospital, Colmar, France.
authors.forename: Lionel
authors.initials: L
authors.lastname: Moreau
authors.affiliation: Bretagne Atlantique Vannes Hospital, Vannes, France.
authors.forename: Annie
authors.initials: A
authors.lastname: Wdowik
authors.affiliation: Rouen University Hospital, Rouen, France.
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Sabourin
authors.affiliation: Paris-Sud Hospital, Villejuif, France.
authors.forename: Antoinette
authors.initials: A
authors.lastname: Lemoine
authors.affiliation: French Cooperative Thoracic Intergroup, Paris, France.
authors.forename: Pascale
authors.initials: P
authors.lastname: Missy
authors.affiliation: French Cooperative Thoracic Intergroup, Paris, France.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Langlais
authors.affiliation: Grenoble University Hospital, Grenoble, France.
authors.forename: Denis
authors.initials: D
authors.lastname: Moro-Sibilot
authors.affiliation: Toulouse University Hospital, Paul Sabatier Toulouse University, Toulouse, France. Electronic address: mazieres.j@chu-toulouse.fr.
authors.forename: Julien
authors.initials: J
authors.lastname: Mazières
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000235:genetics / Q000401:mortality / Q000473:pathology; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000235:genetics*; D018287:Carcinoma, Large Cell / Q000188:drug therapy / Q000235:genetics / Q000401:mortality / Q000473:pathology; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics / Q000401:mortality* / Q000473:pathology; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000235:genetics / Q000401:mortality / Q000473:pathology; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000401:mortality* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011379:Prognosis; D015996:Survival Rate; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor
keywords: Biomarkers France; EGFR; KRAS; Multiple mutations; NSCLC; Single mutation