title: Immunohistochemistry evaluation of biomarker expression in non-small cell lung cancer (Pharmacogenoscan study).
abstract: OBJECTIVE
  Platinum-based chemotherapy regimens are the standard treatment of non-small cell lung cancer (NSCLC). In this study, our objective was to identify tumor tissue protein biomarkers that might predict a benefit from these treatments.
  
  
  METHODS
  The Pharmacogenoscan study prospectively included consecutive chemotherapy-naive NSCLC patients at any stage between 2005 and 2010 at six hospitals in the Rhône-Alpes-Auvergne region of France. Of the 537 patients in the full analysis set, 460 had a complete histological diagnosis. We used the tumor tissue samples for an immunohistochemical evaluation of eight biomarkers: ERCC1, BRCA1, p53, p27kip1, class III β-tubulin (TUBB3), Bax, Fas, and FasL. We looked for associations between these biomarkers and the disease control rate (DCR) after 2/3 cycles of platinum-based chemotherapy, progression-free survival (PFS), and overall survival (OS).
  
  
  RESULTS
  A tissue sample adequate for testing at least one biomarker was available for 289 patients. We found no significant association between biomarker expression levels and clinical or pathological variables; TUBB3 showed a trend toward higher expression in adenocarcinomas (P=0.005). For none of the biomarkers were significant associations found between expression level and DCR, PFS, or OS. TUBB3-negative and FasL-negative tumors showed associations of borderline significance with higher DCR.
  
  
  CONCLUSIONS
  In a large cohort of patients with predominantly advanced or metastatic NSCLC, none of eight tested immunohistochemical biomarkers predicted the chemotherapy response or survival. Our data indicate limited usefulness of protein biomarkers in metastatic NSCLC and a need for further research based on molecular signatures of greater complexity.
authors.affiliation: Université Grenoble 1, INSERM, U 823, Institut A Bonniot, Université J Fourier, Rond-point de la Chantourne, 38706 La Tronche Cedex, France; Thoracic Oncology Unit, Teaching Hospital A Michallon, BP217, 38043 Grenoble Cedex 9, France. Electronic address: AToffart@chu-grenoble.fr.
authors.forename: Anne-Claire
authors.initials: AC
authors.lastname: Toffart
authors.affiliation: Université Grenoble 1, INSERM, U 823, Institut A Bonniot, Université J Fourier, Rond-point de la Chantourne, 38706 La Tronche Cedex, France; Medical Intensive Care Unit, Teaching Hospital A Michallon, BP217, 38043 Grenoble Cedex 9, France.
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Timsit
authors.affiliation: Pulmonology Department, Centre Hospitalier Lyon Sud, Hospices Civils de Lyon, 69495 Pierre Bénite Cedex, France; Lyon Sud Faculty of Medicine, Lyon 1 University, 165 chemin du Petit Revoyet, BP 12, 69921 Oullins Cedex, France.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Couraud
authors.affiliation: Respiratory Medicine, Thoracic Oncology Unit, Centre Hospitalier Universitaire G. Montpied, 58 Rue Montalembert, 63003 Clermont Ferrand Cedex 1, France; EA 7283, Université d'Auvergne, INSERM CIC 501, Bât.3C, Faculté de médecine, 63001 Clermont-Ferrand Cedex, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Merle
authors.affiliation: Université Grenoble 1, INSERM, U 823, Institut A Bonniot, Université J Fourier, Rond-point de la Chantourne, 38706 La Tronche Cedex, France; Thoracic Oncology Unit, Teaching Hospital A Michallon, BP217, 38043 Grenoble Cedex 9, France.
authors.forename: Denis
authors.initials: D
authors.lastname: Moro-Sibilot
authors.affiliation: Thoracic Oncology Unit, Croix-Rousse Hospital, Hospices Civils de Lyon, 103 Grande Rue de la Croix-Rousse, 69317 Lyon Cedex 04, France.
authors.forename: Maurice
authors.initials: M
authors.lastname: Perol
authors.affiliation: Respiratory Medicine Service, Hôpital Louis Pradel, Hospices Civils de Lyon, 59 boulevard Pinel, 69677 Bron Cedex, France.
authors.forename: Bénédicte
authors.initials: B
authors.lastname: Mastroianni
authors.affiliation: Pulmonology Department, Centre Hospitalier Lyon Sud, Hospices Civils de Lyon, 69495 Pierre Bénite Cedex, France; Lyon Sud Faculty of Medicine, Lyon 1 University, 165 chemin du Petit Revoyet, BP 12, 69921 Oullins Cedex, France.
authors.forename: Pierre-Jean
authors.initials: PJ
authors.lastname: Souquet
authors.affiliation: Respiratory Medicine Service, Hôpital Louis Pradel, Hospices Civils de Lyon, 59 boulevard Pinel, 69677 Bron Cedex, France; Université Claude Bernard Lyon 1, 43 boulevard du 11 Novembre 1918, 69622 Villeurbanne Cedex, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Girard
authors.affiliation: Respiratory Medicine, Thoracic Oncology Unit, Centre Hospitalier Universitaire G. Montpied, 58 Rue Montalembert, 63003 Clermont Ferrand Cedex 1, France.
authors.forename: Gaëlle
authors.initials: G
authors.lastname: Jeannin
authors.affiliation: Respiratory Medicine Service, Hôpitaux du Leman, 3 avenue de la Dame, BP 526, 74203 Thonon Les Bains, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Romand
authors.affiliation: Respiratory Medicine Service, Centre Hospitalier Alpes Leman, 558 route de Findrol, BP 20 500, 74130 Contamine sur Arve, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Chatellain
authors.affiliation: Université Grenoble 1, INSERM, U 823, Institut A Bonniot, Université J Fourier, Rond-point de la Chantourne, 38706 La Tronche Cedex, France.
authors.forename: Aurélien
authors.initials: A
authors.lastname: Vesin
authors.affiliation: Université Grenoble 1, INSERM, U 823, Institut A Bonniot, Université J Fourier, Rond-point de la Chantourne, 38706 La Tronche Cedex, France; Thoracic Oncology Unit, Teaching Hospital A Michallon, BP217, 38043 Grenoble Cedex 9, France.
authors.forename: Christian
authors.initials: C
authors.lastname: Brambilla
authors.affiliation: Université Grenoble 1, INSERM, U 823, Institut A Bonniot, Université J Fourier, Rond-point de la Chantourne, 38706 La Tronche Cedex, France; Department of Pathology, Teaching Hospital A Michallon, BP217, 38043 Grenoble Cedex 9, France.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Brambilla
mesh_terms: D019313:BRCA1 Protein / Q000378:metabolism; D054316:Biomarkers, Pharmacological; D014408:Biomarkers, Tumor / Q000378:metabolism; D002289:Carcinoma, Non-Small-Cell Lung / Q000175:diagnosis* / Q000401:mortality / Q000473:pathology; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D053222:Fas Ligand Protein / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000175:diagnosis* / Q000401:mortality / Q000473:pathology; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D011237:Predictive Value of Tests; D011379:Prognosis; D011446:Prospective Studies; D016019:Survival Analysis; D014404:Tubulin / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D019014:fas Receptor / Q000378:metabolism
chemical_list: D019313:BRCA1 Protein; D054316:Biomarkers, Pharmacological; D014408:Biomarkers, Tumor; D053222:Fas Ligand Protein; D014404:Tubulin; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D019014:fas Receptor; D050760:Cyclin-Dependent Kinase Inhibitor p27
keywords: BRCA1; CI; DCR; DNA; Disease control rate; Drug response biomarkers; ERCC1; Fas ligand; FasL; HES; IHC; IQR; Immunohistochemistry; Lung neoplasms; MIA; NER; NSCLC; OS; PFS; PS; Prognosis; Survival; TUBB3; breast cancer susceptibility gene 1; class III β-tubulin; confidence interval; deoxyribonucleic acid; disease control rate; enzyme repair cross-complementation group 1; hematoxylin–eosin–saffron; immunohistochemistry; interquartile range; microtubule-interfering agents; non-small cell lung cancer; nucleotide excision repair; overall survival; performance status; progression-free survival