title: Impact of ABCB1 C3435T polymorphism on lymph node regression in multimodality treatment of locally advanced esophageal cancer.
abstract: OBJECTIVE
  Neoadjuvant treatment strategies have been developed to improve the survival of patients with locally advanced esophageal cancer. Since patients with major histopathological response are the ones who mainly benefit from this therapy, we are looking for causes of nonresponse. The multidrug resistance protein ABCB1 belongs to the ATP-binding cassette superfamily of membrane transporters. By exporting positively charged drugs it plays a role in the acquisition of resistance in anticancer therapy. We examined the ABCB1 gene polymorphism C3435T to predict response and prognosis to neoadjuvant radiochemotherapy (cisplatin, 5-fluorouracil and 36 Gy) in locally advanced esophageal cancer patients.
  
  
  METHODS
  A total of 262 patients (216 male; 46 female; median age: 62 years) with locally advanced esophageal cancer (squamous cell cancer: n = 116, adenocarcinoma: n = 146) were included in this study. All patients received a neoadjuvant radiochemotherapy (36.0 Gy, 5-fluorouracil, cisplatin) followed by surgery. Histomorphologic regression was classified according to the Cologne Regression Grade with major response being classifed as having less than 10% vital tumor cells (n = 107) and minor response when 10% or more vital tumor cells (n = 155) were detected in the surgical specimen. Genomic DNA was extracted from paraffin-embedded tissues of all study patients. Allelic genotyping was performed for ABCB1 rs1045642 by real-time PCR using two allele-specific TaqMan(®) probes in competition. Allelic genotyping was correlated with therapy response and prognosis.
  
  
  RESULTS
  Allelic discrimination revealed a TT genotype in 27%, a CC in 19% and a CT genotype in 54% of the study patients. This SNP was not predictive for response of the primary tumor to neoadjuvant radiochemotherapy. The ABCB1 genotype CC was associated with lymph node formation (p = 0.012) and distant metastases (p = 0.019). Patients with a TT genotype exhibited a significantly less positive lymph node status (ypN1 35%) after chemoradiation compared with patients with a CC (ypN1 = 60%) or CT (ypN1 = 46%) genotype. Moreover, patients bearing the TT genotype exhibited no distant metastasis, while five patients with a CC and two patients with CT genotype had distant metastases. In Kaplan-Meier curves, adenocarcinoma patients with a CC genotype showed a worse survival rate than patients with TT or CT (p = 0.048).
  
  
  CONCLUSIONS
  Our data supports the impact of ABCB1 on effectiveness of esophageal cancer treatment. SNPs of ABCB1 could be helpful in predicting lymph node regression in the multimodality treatment of locally advanced esophageal cancer.
authors.affiliation: Department of General, Visceral & Cancer Surgery, Center for Integrated Oncology (CIO), University of Cologne, Kerpener Strasse 62, 50937 Cologne, Germany.
authors.forename: Kosuke
authors.initials: K
authors.lastname: Narumiya
authors.forename: Ralf
authors.initials: R
authors.lastname: Metzger
authors.forename: Elfriede
authors.initials: E
authors.lastname: Bollschweiler
authors.forename: Hakan
authors.initials: H
authors.lastname: Alakus
authors.forename: Jan
authors.initials: J
authors.lastname: Brabender
authors.forename: Uta
authors.initials: U
authors.lastname: Drebber
authors.forename: Arnulf H
authors.initials: AH
authors.lastname: Hölscher
authors.forename: Ute
authors.initials: U
authors.lastname: Warnecke-Eberz
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics*; D000230:Adenocarcinoma / Q000473:pathology / Q000628:therapy*; D000368:Aged; D002294:Carcinoma, Squamous Cell / Q000473:pathology / Q000628:therapy*; D003131:Combined Modality Therapy; D004938:Esophageal Neoplasms / Q000473:pathology / Q000628:therapy*; D005260:Female; D056726:Genetic Association Studies; D006801:Humans; D008198:Lymph Nodes / Q000473:pathology; D008297:Male; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D011110:Polymorphism, Genetic
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1