title: Neoadjuvant radiochemotherapy in adenocarcinoma of the esophagus: ERCC1 gene polymorphisms for prediction of response and prognosis.
abstract: BACKGROUND
  Neoadjuvant radiochemotherapy (RT/CTx) regimens were primarily designed for treatment of squamous cell carcinoma of the esophagus. Own preliminary results demonstrate that also patients with locally advanced adenocarcinoma of the esophagus may achieve a major response in 30% with a 3-year survival rate of 80%. To identify these patients, ERCC1 (rs11615) gene polymorphisms were analyzed. ERCC1 is a key enzyme of the nucleotide excision and repair (NER) complex to prevent DNA inter- and intra-strand crosslinks.
  
  
  METHODS
  Genomic DNA from 217 patients with cT3/4 adenocarcinoma of the esophagus was extracted from paraffin-embedded tissues. Of these patients, 153 underwent neoadjuvant RT/CTx (CDDP, 5-FU, 36 Gy). For analysis of ERCC1 single nucleotide polymorphisms (SNPs), allelic discrimination was performed by quantitative real-time PCR. Two allele-specific TaqMan probes in competition were used for amplification of ERCC1 (rs11615). Allelic genotyping was correlated with histomorphologic tumor regression after neoadjuvant RT/CTx and survival. Major response (MaHR) was defined as <10% vital residual tumor cells (VRTC).
  
  
  RESULTS
  Analysis of tumor regression revealed a MaHR in 56/153 (36.6%) patients with a 5-year survival rate (5-YSR) of 74% (p < 0.001). ERCC1 gene polymorphisms for all patients showed the following expression pattern: ERCC1 polymorphism (rs11615) CC: n = 27 (12.4%), TT: n = 98 (45.2%), C/T: n = 92 (42.4%). ERCC1 polymorphism CT was identified as a predictor for response to the neoadjuvant RT/CTx (p < 0.001). The 5-YSR for patients with C/T genotype was 51%. Contrary to this, the 5-YSR for the group of patients with a CC/TT polymorphism decreased to 34%.
  
  
  CONCLUSIONS
  Analysis of ERCC1 (rs11615) gene polymorphisms reveals a significant correlation with response and survival in patients with adenocarcinoma of the esophagus treated with a neoadjuvant radiochemotherapy. Single nucleotide polymorphisms of ERCC1 (rs11615) could therefore be applied to further individualize therapy in esophageal cancer.
authors.affiliation: Department of General, Visceral and Cancer Surgery, Center for Integrated Oncology (CIO Cologne Bonn), University Hospital of Cologne, Cologne, Germany. ralf.metzger@uk-koeln.de
authors.forename: Ralf
authors.initials: R
authors.lastname: Metzger
authors.forename: Ute
authors.initials: U
authors.lastname: Warnecke-Eberz
authors.forename: Hakan
authors.initials: H
authors.lastname: Alakus
authors.forename: Fabian
authors.initials: F
authors.lastname: Kütting
authors.forename: Jan
authors.initials: J
authors.lastname: Brabender
authors.forename: Daniel
authors.initials: D
authors.lastname: Vallböhmer
authors.forename: Peter P
authors.initials: PP
authors.lastname: Grimminger
authors.forename: Stefan P
authors.initials: SP
authors.lastname: Mönig
authors.forename: Uta
authors.initials: U
authors.lastname: Drebber
authors.forename: Arnulf H
authors.initials: AH
authors.lastname: Hölscher
authors.forename: Elfriede
authors.initials: E
authors.lastname: Bollschweiler
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology / Q000628:therapy*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D059248:Chemoradiotherapy; D002945:Cisplatin / Q000008:administration & dosage; D004268:DNA-Binding Proteins / Q000235:genetics*; D019583:Dose Fractionation, Radiation; D004720:Endonucleases / Q000235:genetics*; D004938:Esophageal Neoplasms / Q000235:genetics* / Q000473:pathology / Q000628:therapy*; D005472:Fluorouracil / Q000008:administration & dosage; D005838:Genotype; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D020641:Polymorphism, Single Nucleotide; D011237:Predictive Value of Tests; D011379:Prognosis; D016016:Proportional Hazards Models; D012074:Remission Induction; D018709:Statistics, Nonparametric; D055815:Young Adult
chemical_list: D004268:DNA-Binding Proteins; C071447:ERCC1 protein, human; D004720:Endonucleases; D002945:Cisplatin; D005472:Fluorouracil