title: Importance of excision repair cross-complementation group 1 and ribonucleotide reductase M1 as prognostic biomarkers in malignant pleural mesothelioma treated with platinum-based induction chemotherapy followed by surgery.
abstract: OBJECTIVE
  Survival and response to platinum-based induction chemotherapy are heterogeneous among patients with malignant pleural mesothelioma. The aim of the present study was to assess the prognostic role of DNA repair markers, such as excision repair cross-complementation group 1 and ribonucleotide reductase M1, in multimodally treated patients with malignant pleural mesothelioma.
  
  
  METHODS
  Tumor tissue of a malignant pleural mesothelioma cohort (n = 107) treated with platinum/gemcitabine (n = 46) or platinum/pemetrexed (n = 61) induction chemotherapy followed by extrapleural pneumonectomy was assembled on a tissue microarray. Immunohistochemical expression of excision repair cross-complementation group 1 (nuclear) and ribonucleotide reductase M1 (nuclear and cytoplasmic) was assessed for its prognostic impact (association with overall survival or freedom from recurrence).
  
  
  RESULTS
  Patients with high nuclear ribonucleotide reductase M1 expression before chemotherapy showed significantly longer freedom from recurrence (P = .03). When specifically analyzed in the subgroup of patients receiving platinum/gemcitabine followed by extrapleural pneumonectomy, high nuclear ribonucleotide reductase M1 was associated with prolonged freedom from recurrence (P = .03) and overall survival (P = .02). Low excision repair cross-complementation group 1 expression in prechemotherapy tumor tissues was associated with significantly longer freedom from recurrence (P = .04). Nuclear ribonucleotide reductase M1 and excision repair cross-complementation group 1 were independent prognosticators of freedom from recurrence in addition to pT stage in multivariate analysis.
  
  
  CONCLUSIONS
  In the present study, nuclear ribonucleotide reductase M1 and excision repair cross-complementation group 1 expression were identified as independent prognosticators for freedom from recurrence of malignant pleural mesothelioma in patients undergoing induction chemotherapy followed by extrapleural pneumonectomy.
authors.affiliation: Institute of Surgical Pathology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Lukas
authors.initials: L
authors.lastname: Frischknecht
authors.affiliation: Division of Thoracic Surgery, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Mayura
authors.initials: M
authors.lastname: Meerang
authors.affiliation: Institute of Surgical Pathology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Alex
authors.initials: A
authors.lastname: Soltermann
authors.affiliation: Laboratory of Molecular Oncology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Rolf
authors.initials: R
authors.lastname: Stahel
authors.affiliation: Institute of Surgical Pathology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Holger
authors.initials: H
authors.lastname: Moch
authors.affiliation: Division of Biostatistics, ISPM, University Zurich, Zurich, Switzerland.
authors.forename: Burkhardt
authors.initials: B
authors.lastname: Seifert
authors.affiliation: Division of Thoracic Surgery, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Walter
authors.initials: W
authors.lastname: Weder
authors.affiliation: Division of Thoracic Surgery, University Hospital Zurich, Zurich, Switzerland. Electronic address: isabelle.schmitt-opitz@usz.ch.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Opitz
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000032:analysis*; D017024:Chemotherapy, Adjuvant; D004268:DNA-Binding Proteins / Q000032:analysis*; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D018450:Disease Progression; D018572:Disease-Free Survival; D004720:Endonucleases / Q000032:analysis*; D005260:Female; D005971:Glutamates / Q000008:administration & dosage; D006147:Guanine / Q000008:administration & dosage / Q000031:analogs & derivatives; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000201:enzymology / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D008297:Male; D008654:Mesothelioma / Q000201:enzymology / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D000086002:Mesothelioma, Malignant; D008875:Middle Aged; D015999:Multivariate Analysis; D020360:Neoadjuvant Therapy; D009364:Neoplasm Recurrence, Local; D009367:Neoplasm Staging; D000068437:Pemetrexed; D017671:Platinum Compounds / Q000008:administration & dosage; D010997:Pleural Neoplasms / Q000201:enzymology / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D011013:Pneumonectomy; D011237:Predictive Value of Tests; D016016:Proportional Hazards Models; D012262:Ribonucleoside Diphosphate Reductase; D012307:Risk Factors; D013997:Time Factors; D046888:Tissue Array Analysis; D016896:Treatment Outcome; D025521:Tumor Suppressor Proteins / Q000032:analysis*; D000093542:Gemcitabine
chemical_list: D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; D005971:Glutamates; D017671:Platinum Compounds; D025521:Tumor Suppressor Proteins; D000068437:Pemetrexed; D003841:Deoxycytidine; D006147:Guanine; C475286:RRM1 protein, human; D012262:Ribonucleoside Diphosphate Reductase; C071447:ERCC1 protein, human; D004720:Endonucleases; D000093542:Gemcitabine
keywords: ERCC1; RRM1; mesothelioma; multimodality treatment; prognostic factor