title: ERCC5/XPG, ERCC1, and BRCA1 gene status and clinical benefit of trabectedin in patients with soft tissue sarcoma.
abstract: BACKGROUND
  The objective of this study was to determine whether specific single nucleotide polymorphisms (SNPs) from nucleotide excision repair (NER) and homologous recombination (HR) DNA repair pathways are associated with sensitivity to trabectedin in patients with soft tissue sarcoma (STS).
  
  
  METHODS
  The authors analyzed excision repair cross-complementation group 5/xeroderma pigmentosum group G (ERCC5/XPG) (NER), excision repair cross-complementation group 1 (ERCC1) (NER), and breast cancer 1 (BRCA1) (HR) SNPs and messenger RNA expression levels in tumor specimens from 113 patients with advanced STS who were enrolled in previously published phase 2 trials or in a compassionate-use program. The 6-month progression-free rate (PFR), progression-free survival (PFS), and overall survival (OS) were analyzed according to ERCC5, ERCC1, and BRCA1 status using log-rank tests.
  
  
  RESULTS
  High expression of the common allele (aspartic acid at codon 1104) of ERCC5, high expression of ERCC1, and BRCA1 haplotype were associated significantly with improved PFR, PFS, and OS. The ERCC1 thymine-to-cytosine (T→C) SNP at codon 19007 and BRCA1 expression were not associated with outcome. On univariate analysis, tumor histology, favorable NER status (high expression of common ERCC5 and/or high ERCC1 expression status), and favorable BRCA1 haplotype (at least 1 triple-adenine plus guanine [AAAG] allele) were the sole variables associated significantly with PFS and OS.
  
  
  CONCLUSIONS
  In the current study, ERCC5, ERCC1, and BRCA1 status represented a potential DNA repair signature that could be used for the prediction of clinical response to trabectedin in patients with STS.
authors.affiliation: Department of Medical Oncology, Institut Bergonié, Bordeaux, France.
authors.forename: Antoine
authors.initials: A
authors.lastname: Italiano
authors.forename: Armelle
authors.initials: A
authors.lastname: Laurand
authors.forename: Audrey
authors.initials: A
authors.lastname: Laroche
authors.forename: Paolo
authors.initials: P
authors.lastname: Casali
authors.forename: Roberta
authors.initials: R
authors.lastname: Sanfilippo
authors.forename: Axel
authors.initials: A
authors.lastname: Le Cesne
authors.forename: Ian
authors.initials: I
authors.lastname: Judson
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Blay
authors.forename: Isabelle
authors.initials: I
authors.lastname: Ray-Coquard
authors.forename: Binh
authors.initials: B
authors.lastname: Bui
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Coindre
authors.forename: Antonio
authors.initials: A
authors.lastname: Nieto
authors.forename: Juan-Carlos
authors.initials: JC
authors.lastname: Tercero
authors.forename: Jose
authors.initials: J
authors.lastname: Jimeno
authors.forename: Jacques
authors.initials: J
authors.lastname: Robert
authors.forename: Philippe
authors.initials: P
authors.lastname: Pourquier
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use*; D017209:Apoptosis; D001483:Base Sequence; D002461:Cell Line, Transformed; D017931:DNA Primers; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000235:genetics*; D004149:Dioxoles / Q000627:therapeutic use*; D004720:Endonucleases / Q000235:genetics*; D005260:Female; D005434:Flow Cytometry; D019398:Genes, BRCA1; D006801:Humans; D008297:Male; D008875:Middle Aged; D009687:Nuclear Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D012333:RNA, Messenger / Q000235:genetics; D011995:Recombination, Genetic; D012509:Sarcoma / Q000188:drug therapy* / Q000473:pathology; D044005:Tetrahydroisoquinolines / Q000627:therapeutic use*; D000077606:Trabectedin; D014157:Transcription Factors / Q000235:genetics*; D000099250:DNA Excision Repair Protein ERCC-5
chemical_list: D018906:Antineoplastic Agents, Alkylating; D017931:DNA Primers; D004268:DNA-Binding Proteins; D004149:Dioxoles; D004720:Endonucleases; D009687:Nuclear Proteins; D012333:RNA, Messenger; D044005:Tetrahydroisoquinolines; D000077606:Trabectedin; D014157:Transcription Factors; D000099250:DNA Excision Repair Protein ERCC-5; C071447:ERCC1 protein, human