title: Mutational status of synchronous and metachronous tumor samples in patients with metastatic non-small-cell lung cancer.
abstract: BACKGROUND
  Despite reported discordance between the mutational status of primary lung cancers and their metastases, metastatic sites are rarely biopsied and targeted therapy is guided by genetic biomarkers detected in the primary tumor. This situation is mostly explained by the apparent stability of EGFR-activating mutations. Given the dramatic increase in the range of candidate drugs and high rates of drug resistance, rebiopsy or liquid biopsy may become widespread. The purpose of this study was to test genetic biomarkers used in clinical practice (EGFR, ALK) and candidate biomarkers identified by the French National Cancer Institute (KRAS, BRAF, PIK3CA, HER2) in patients with metastatic non-small-cell lung cancer for whom two tumor samples were available.
  
  
  METHODS
  A retrospective study identified 88 tumor samples collected synchronously or metachronously, from the same or two different sites, in 44 patients. Mutation analysis used SNaPshot (EGFR, KRAS, BRAF missense mutations), pyrosequencing (EGFR and PIK3CA missense mutations), sizing assays (EGFR and HER2 indels) and IHC and/or FISH (ALK rearrangements).
  
  
  RESULTS
  About half the patients (52%) harbored at least one mutation. Five patients had an activating mutation of EGFR in both the primary tumor and the metastasis. The T790M resistance mutation was detected in metastases in 3 patients with acquired resistance to EGFR tyrosine kinase inhibitors. FISH showed discordance in ALK status between a small biopsy sample and the surgical specimen. KRAS mutations were observed in 36% of samples, six patients (14%) having discordant genotypes; all discordances concerned sampling from different sites. Two patients (5%) showed PI3KCA mutations. One metastasis harbored both PI3KCA and KRAS mutations, while the synchronously sampled primary tumor was mutation free. No mutations were detected in BRAF and HER2.
  
  
  CONCLUSIONS
  This study highlighted noteworthy intra-individual discordance in KRAS mutational status, whereas EGFR status was stable. Intratumoral heterogeneity for ALK rearrangement suggests a limitation of single-biopsy analysis for therapeutic strategy with crizotinib.
authors.affiliation: CHRU de Brest, Institut de Cancérologie et d'Hématologie, Brest, France.
authors.forename: Gilles
authors.initials: G
authors.lastname: Quéré
authors.affiliation: CHRU de Brest, Institut de Cancérologie et d'Hématologie, Brest, France.
authors.forename: Renaud
authors.initials: R
authors.lastname: Descourt
authors.affiliation: CHRU de Brest, Institut de Cancérologie et d'Hématologie, Brest, France.
authors.forename: Gilles
authors.initials: G
authors.lastname: Robinet
authors.affiliation: CHRU de Brest, Hôpital Morvan, Bat 5 bis, Laboratoire de Génétique Moléculaire et d'Histocompatibilité, 2 Avenue Foch, 29200, Brest, France.|Plateforme de Génétique Moléculaire des Cancers (INCa), Brest, France.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Autret
authors.affiliation: CHRU de Brest, Hôpital Morvan, Bat 5 bis, Laboratoire de Génétique Moléculaire et d'Histocompatibilité, 2 Avenue Foch, 29200, Brest, France.|Plateforme de Génétique Moléculaire des Cancers (INCa), Brest, France.
authors.forename: Odile
authors.initials: O
authors.lastname: Raguenes
authors.affiliation: CHRU de Brest, Hôpital Morvan, Bat 5 bis, Laboratoire de Génétique Moléculaire et d'Histocompatibilité, 2 Avenue Foch, 29200, Brest, France.|Plateforme de Génétique Moléculaire des Cancers (INCa), Brest, France.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Fercot
authors.affiliation: Plateforme de Génétique Moléculaire des Cancers (INCa), Brest, France.|CHRU de Brest, Service d'Anatomopathologie, Brest, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Alemany
authors.affiliation: Plateforme de Génétique Moléculaire des Cancers (INCa), Brest, France.|Inserm U1078, Université de Brest, SFR SnInBioS, Brest, France.|CHRU de Brest, Service d'Anatomopathologie, Brest, France.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Uguen
authors.affiliation: CHRU de Brest, Hôpital Morvan, Bat 5 bis, Laboratoire de Génétique Moléculaire et d'Histocompatibilité, 2 Avenue Foch, 29200, Brest, France.|Plateforme de Génétique Moléculaire des Cancers (INCa), Brest, France.|Inserm U1078, Université de Brest, SFR SnInBioS, Brest, France.
authors.forename: Claude
authors.initials: C
authors.lastname: Férec
authors.affiliation: Plateforme de Génétique Moléculaire des Cancers (INCa), Brest, France.|CHRU de Brest, Service d'Anatomopathologie, Brest, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Quintin-Roué
authors.affiliation: CHRU de Brest, Hôpital Morvan, Bat 5 bis, Laboratoire de Génétique Moléculaire et d'Histocompatibilité, 2 Avenue Foch, 29200, Brest, France. gerald.legac@univ-brest.fr.|Plateforme de Génétique Moléculaire des Cancers (INCa), Brest, France. gerald.legac@univ-brest.fr.|Inserm U1078, Université de Brest, SFR SnInBioS, Brest, France. gerald.legac@univ-brest.fr.
authors.forename: Gérald
authors.initials: G
authors.lastname: Le Gac
mesh_terms: D000328:Adult; D000368:Aged; D000077548:Anaplastic Lymphoma Kinase; D014408:Biomarkers, Tumor / Q000235:genetics*; D001706:Biopsy; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000473:pathology; D058534:Class I Phosphatidylinositol 3-Kinases; D066246:ErbB Receptors / Q000235:genetics; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D009154:Mutation; D009362:Neoplasm Metastasis / Q000235:genetics* / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; 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
chemical_list: D000077548:Anaplastic Lymphoma Kinase; D014408:Biomarkers, Tumor; 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
keywords: Genetic biomarkers; Metastatic lesion; Non-small-cell lung cancer; Rebiopsy; Targeted therapy