title: ERCC1 isoform expression and DNA repair in non-small-cell lung cancer.
abstract: BACKGROUND
  The excision repair cross-complementation group 1 (ERCC1) protein is a potential prognostic biomarker of the efficacy of cisplatin-based chemotherapy in non-small-cell lung cancer (NSCLC). Although several ongoing trials are evaluating the level of expression of ERCC1, no consensus has been reached regarding a method for evaluation.
  
  
  METHODS
  We used the 8F1 antibody to measure the level of expression of ERCC1 protein by means of immunohistochemical analysis in a validation set of samples obtained from 494 patients in two independent phase 3 trials (the National Cancer Institute of Canada Clinical Trials Group JBR.10 and the Cancer and Leukemia Group B 9633 trial from the Lung Adjuvant Cisplatin Evaluation Biology project). We compared the results of repeated staining of the entire original set of samples obtained from 589 patients in the International Adjuvant Lung Cancer Trial Biology study, which had led to the initial correlation between the absence of ERCC1 expression and platinum response, with our previous results in the same tumors. We mapped the epitope recognized by 16 commercially available ERCC1 antibodies and investigated the capacity of the different ERCC1 isoforms to repair platinum-induced DNA damage.
  
  
  RESULTS
  We were unable to validate the predictive effect of immunostaining for ERCC1 protein. The discordance in the results of staining for ERCC1 suggested a change in the performance of the 8F1 antibody since 2006. We found that none of the 16 antibodies could distinguish among the four ERCC1 protein isoforms, whereas only one isoform produced a protein that had full capacities for nucleotide excision repair and cisplatin resistance.
  
  
  CONCLUSIONS
  Immunohistochemical analysis with the use of currently available ERCC1 antibodies did not specifically detect the unique functional ERCC1 isoform. As a result, its usefulness in guiding therapeutic decision making is limited. (Funded by Eli Lilly and others.).
authors.affiliation: INSERM Unité 981, and Département Hospitalo-Universitaire Thorax Innovation, Institut Gustave-Roussy, Villejuif, France.
authors.forename: Luc
authors.initials: L
authors.lastname: Friboulet
authors.forename: Ken André
authors.initials: KA
authors.lastname: Olaussen
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Pignon
authors.forename: Frances A
authors.initials: FA
authors.lastname: Shepherd
authors.forename: Ming-Sound
authors.initials: MS
authors.lastname: Tsao
authors.forename: Stephen
authors.initials: S
authors.lastname: Graziano
authors.forename: Robert
authors.initials: R
authors.lastname: Kratzke
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Douillard
authors.forename: Lesley
authors.initials: L
authors.lastname: Seymour
authors.forename: Robert
authors.initials: R
authors.lastname: Pirker
authors.forename: Martin
authors.initials: M
authors.lastname: Filipits
authors.forename: Fabrice
authors.initials: F
authors.lastname: André
authors.forename: Eric
authors.initials: E
authors.lastname: Solary
authors.forename: Florence
authors.initials: F
authors.lastname: Ponsonnailles
authors.forename: Angélique
authors.initials: A
authors.lastname: Robin
authors.forename: Annabelle
authors.initials: A
authors.lastname: Stoclin
authors.forename: Nicolas
authors.initials: N
authors.lastname: Dorvault
authors.forename: Frédéric
authors.initials: F
authors.lastname: Commo
authors.forename: Julien
authors.initials: J
authors.lastname: Adam
authors.forename: Elsa
authors.initials: E
authors.lastname: Vanhecke
authors.forename: Patrick
authors.initials: P
authors.lastname: Saulnier
authors.forename: Jürgen
authors.initials: J
authors.lastname: Thomale
authors.forename: Thierry
authors.initials: T
authors.lastname: Le Chevalier
authors.forename: Ariane
authors.initials: A
authors.lastname: Dunant
authors.forename: Vanessa
authors.initials: V
authors.lastname: Rousseau
authors.forename: Gwénaël
authors.initials: G
authors.lastname: Le Teuff
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Brambilla
authors.forename: Jean-Charles
authors.initials: JC
authors.lastname: Soria
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000378:metabolism*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality; D017024:Chemotherapy, Adjuvant; D002945:Cisplatin / Q000627:therapeutic use*; D004260:DNA Repair; D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D004720:Endonucleases / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D018604:Epitope Mapping; D000939:Epitopes; D006801:Humans; D007074:Immunoglobulin G; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; D000939:Epitopes; D007074:Immunoglobulin G; D020033:Protein Isoforms; C071447:ERCC1 protein, human; D004720:Endonucleases; D002945:Cisplatin