title: Cisplatin benefit is predicted by immunohistochemical analysis of DNA repair proteins in squamous cell carcinoma but not adenocarcinoma: theranostic modeling by NSCLC constituent histological subclasses.
abstract: BACKGROUND
  Most non-small-cell lung cancer (NSCLC) patients receive cisplatin-based chemotherapy though clinical response is restricted to a subset of patients. DNA repair protein levels are possible surrogates for cisplatin-induced DNA adduct (and subsequent cell death) repair efficiency and thus molecular determinants of therapeutic efficacy. The International Adjuvant Lung Trial (IALT)-Bio study previously suggested ERCC1 and MSH2 as predictive of cisplatin-based therapeutic benefit.
  
  
  METHODS
  DNA repair protein expression (XPF, BRCA1, ERCC1, MSH2, p53, PARP1, and ATM) was assessed by immunohistochemistry on a large subset of patients (N = 769) from the IALT trial. Tissue Microarray slides were digitally scanned and signal quantified by user-defined macros. Statistical analyses (univariate and multivariate) of 5-year disease-free survival (DFS) and 5-year overall survival used binary cut-offs (H score low/high expression).
  
  
  RESULTS
  In patients with squamous cell carcinoma (SCC), ATM, p53, PARP1, ERCC1, and MSH2 displayed significant (borderline) predictive values, mainly on DFS with chemotherapy efficacy limited to low marker levels. Adenocarcinoma (ADC) results were not significant. BRCA1 and XPF were not significant for predictive modeling in either SCC or ADCs.
  
  
  CONCLUSIONS
  Here predictive utility of DNA repair enzymes co-segregates with SCC histology, focusing their predictive value to this histological subclass of NSCLC. Distinct mechanisms of chemotherapeutic response or resistance might exist among histological subclasses of solid tumors.
authors.affiliation: Applied Molecular Diagnostics Group, On-Q-ity Inc., Waltham, USA.
authors.forename: W E
authors.initials: WE
authors.lastname: Pierceall
authors.affiliation: Institut National de la Sante et de la Recherche Medicale U981, Villejuif; Université Paris-Sud XI, Kremlin-Bicêtre; Clinical and Translational Research Division, Institut Gustave Roussy, Villejuif.
authors.forename: K A
authors.initials: KA
authors.lastname: Olaussen
authors.affiliation: Department of Biostatistics and Epidemiology, Institut Gustave Roussy, Villejuif.
authors.forename: V
authors.initials: V
authors.lastname: Rousseau
authors.affiliation: Department of Anatomy and Cytology, Centre Hospitalo-Universitaire, Albert Michallon, Grenoble, France.
authors.forename: E
authors.initials: E
authors.lastname: Brambilla
authors.affiliation: Applied Molecular Diagnostics Group, On-Q-ity Inc., Waltham, USA.
authors.forename: K M
authors.initials: KM
authors.lastname: Sprott
authors.affiliation: Institut National de la Sante et de la Recherche Medicale U981, Villejuif; Department of Pathology, Brigham and Women's Hospital, Boston, USA.
authors.forename: F
authors.initials: F
authors.lastname: Andre
authors.affiliation: Department of Biostatistics and Epidemiology, Institut Gustave Roussy, Villejuif.
authors.forename: J-P
authors.initials: JP
authors.lastname: Pignon
authors.affiliation: Department of Medicine/Service des Innovations Thérapeutiques Précoces, Institut Gustave Roussy, Villejuif, France.
authors.forename: T
authors.initials: T
authors.lastname: Le Chevalier
authors.affiliation: Department of Medicine I, Medical University Vienna, Vienna, Austria.
authors.forename: R
authors.initials: R
authors.lastname: Pirker
authors.affiliation: Applied Molecular Diagnostics Group, On-Q-ity Inc., Waltham, USA.
authors.forename: C
authors.initials: C
authors.lastname: Jiang
authors.affiliation: Department of Medicine I, Medical University Vienna, Vienna, Austria.
authors.forename: M
authors.initials: M
authors.lastname: Filipits
authors.affiliation: Applied Molecular Diagnostics Group, On-Q-ity Inc., Waltham, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Boston, USA.
authors.forename: J L
authors.initials: JL
authors.lastname: Kutok
authors.affiliation: Applied Molecular Diagnostics Group, On-Q-ity Inc., Waltham, USA.
authors.forename: D T
authors.initials: DT
authors.lastname: Weaver
authors.affiliation: Applied Molecular Diagnostics Group, On-Q-ity Inc., Waltham, USA.
authors.forename: B E
authors.initials: BE
authors.lastname: Ward
authors.affiliation: Institut National de la Sante et de la Recherche Medicale U981, Villejuif; Université Paris-Sud XI, Kremlin-Bicêtre; Clinical and Translational Research Division, Institut Gustave Roussy, Villejuif; Department of Medicine/Service des Innovations Thérapeutiques Précoces, Institut Gustave Roussy, Villejuif, France. Electronic address: soria@igr.fr.
authors.forename: J-C
authors.initials: JC
authors.lastname: Soria
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism* / Q000401:mortality / Q000473:pathology / Q000628:therapy; D000077192:Adenocarcinoma of Lung; D000368:Aged; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism* / Q000401:mortality / Q000473:pathology / Q000628:therapy; D002294:Carcinoma, Squamous Cell / Q000378:metabolism* / Q000401:mortality / Q000473:pathology / Q000628:therapy; D017024:Chemotherapy, Adjuvant; D002945:Cisplatin / Q000494:pharmacology* / Q000627:therapeutic use; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D018572:Disease-Free Survival; D005260:Female; D015870:Gene Expression; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology / Q000628:therapy; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D011379:Prognosis; D016032:Randomized Controlled Trials as Topic; D046888:Tissue Array Analysis; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; D002945:Cisplatin