title: Genetic variation in radiation and platinum pathways predicts severe acute radiation toxicity in patients with esophageal adenocarcinoma treated with cisplatin-based preoperative radiochemotherapy: results from the Eastern Cooperative Oncology Group.
abstract: OBJECTIVE
  Germline genetic variations may partly explain the clinical observation that normal tissue tolerance to radiochemotherapy varies by individual. Our objective was to evaluate the association between single-nucleotide polymorphisms (SNPs) in radiation/platinum pathways and serious treatment-related toxicity in subjects with esophageal adenocarcinoma who received cisplatin-based preoperative radiochemotherapy.
  
  
  METHODS
  In a multicenter clinical trial (E1201), 81 eligible treatment-naïve subjects with resectable esophageal adenocarcinoma received cisplatin-based chemotherapy concurrent with radiotherapy, with planned subsequent surgical resection. Toxicity endpoints were defined as grade ≥3 radiation-related or myelosuppressive events probably or definitely related to therapy, occurring during or up to 6 weeks following the completion of radiochemotherapy. SNPs were analyzed in 60 subjects in pathways related to nucleotide/base excision- or double stranded break repair, or platinum influx, efflux, or detoxification.
  
  
  RESULTS
  Grade ≥3 radiation-related toxicity (mostly dysphagia) and myelosuppression occurred in 18 and 33% of subjects, respectively. The variant alleles of the XRCC2 5' flanking SNP (detected in 28% of subjects) and of GST-Pi Ile-105-Val (detected in 65% of subjects) were each associated with higher odds of serious radiation-related toxicity compared to the major allele homozygote (47% vs. 9%, and 31% vs. 0%, respectively; P = 0.005). No SNP was associated with myelosuppression.
  
  
  CONCLUSIONS
  This novel finding in a well-characterized cohort with robust endpoint data supports further investigation of XRCC2 and GST-Pi as potential predictors of radiation toxicity.
authors.affiliation: Division of Medical Oncology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA. yoon.harry@mayo.edu
authors.forename: H H
authors.initials: HH
authors.lastname: Yoon
authors.forename: P
authors.initials: P
authors.lastname: Catalano
authors.forename: M K
authors.initials: MK
authors.lastname: Gibson
authors.forename: T C
authors.initials: TC
authors.lastname: Skaar
authors.forename: S
authors.initials: S
authors.lastname: Philips
authors.forename: E A
authors.initials: EA
authors.lastname: Montgomery
authors.forename: M J
authors.initials: MJ
authors.lastname: Hafez
authors.forename: M
authors.initials: M
authors.lastname: Powell
authors.forename: G
authors.initials: G
authors.lastname: Liu
authors.forename: A A
authors.initials: AA
authors.lastname: Forastiere
authors.forename: A B
authors.initials: AB
authors.lastname: Benson
authors.forename: L R
authors.initials: LR
authors.lastname: Kleinberg
authors.forename: K M
authors.initials: KM
authors.lastname: Murphy
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000628:therapy*; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage; D002945:Cisplatin / Q000008:administration & dosage*; D003131:Combined Modality Therapy; D004268:DNA-Binding Proteins / Q000235:genetics*; D004938:Esophageal Neoplasms / Q000235:genetics / Q000628:therapy*; D005260:Female; D014644:Genetic Variation; D051549:Glutathione S-Transferase pi / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011832:Radiation Injuries
chemical_list: D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; C113187:XRCC2 protein, human; D051549:Glutathione S-Transferase pi; D002945:Cisplatin