title: X-ray cross-complementing group 1 and thymidylate synthase polymorphisms might predict response to chemoradiotherapy in rectal cancer patients.
abstract: OBJECTIVE
  5-Fluorouracil-based chemoradiotherapy before total mesorectal excision is currently the standard treatment of Stage II and III rectal cancer patients. We used known predictive pharmacogenetic biomarkers to identify the responders to preoperative chemoradiotherapy in our series.
  
  
  METHODS
  A total of 93 Stage II-III rectal cancer patients were genotyped using peripheral blood samples. The genes analyzed were X-ray cross-complementing group 1 (XRCC1), ERCC1, MTHFR, EGFR, DPYD, and TYMS. The patients were treated with 225 mg/m(2)/d continuous infusion of 5-fluorouracil concomitantly with radiotherapy (50.4 Gy) followed by total mesorectal excision. The outcomes were measured by tumor regression grade (TRG) as a major response (TRG 1 and TRG 2) or as a poor response (TRG3, TRG4, and TRG5).
  
  
  RESULTS
  The major histopathologic response rate was 47.3%. XRCC1 G/G carriers had a greater probability of response than G/A carriers (odds ratio, 4.18; 95% confidence interval, 1.62-10.74, p = .003) Patients with polymorphisms associated with high expression of thymidylate synthase (2R/3G, 3C/3G, and 3G/3G) showed a greater pathologic response rate compared with carriers of low expression (odds ratio, 2.65; 95% confidence interval, 1.10-6.39, p = .02) No significant differences were seen in the response according to EGFR, ERCC1, MTHFR_C677 and MTHFR_A1298 expression.
  
  
  CONCLUSIONS
  XRCC1 G/G and thymidylate synthase (2R/3G, 3C/3G, and 3G/3G) are independent factors of a major response. Germline thymidylate synthase and XRCC1 polymorphisms might be useful as predictive markers of rectal tumor response to neoadjuvant chemoradiotherapy with 5-fluorouracil.
authors.affiliation: Oncology Pharmacy Unit, Complejo Hospitalario Universitario of Santiago, Santiago de Compostela, Spain. mlamasd@yahoo.es
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Lamas
authors.forename: Goretti
authors.initials: G
authors.lastname: Duran
authors.forename: Antonio
authors.initials: A
authors.lastname: Gomez
authors.forename: Emilia
authors.initials: E
authors.lastname: Balboa
authors.forename: Urbano
authors.initials: U
authors.lastname: Anido
authors.forename: Beatriz
authors.initials: B
authors.lastname: Bernardez
authors.forename: Pablo
authors.initials: P
authors.lastname: Rana-Diez
authors.forename: Rafael
authors.initials: R
authors.lastname: Lopez
authors.forename: Angel
authors.initials: A
authors.lastname: Carracedo
authors.forename: Francisco
authors.initials: F
authors.lastname: Barros
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use; D059248:Chemoradiotherapy; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000235:genetics; D004334:Drug Administration Schedule; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D004720:Endonucleases / Q000235:genetics; D005260:Female; D005472:Fluorouracil / Q000627:therapeutic use; D018773:Genes, erbB-1 / Q000235:genetics; D006801:Humans; D008297:Male; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics; D008875:Middle Aged; D060787:Neoplasm Grading; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011879:Radiotherapy Dosage; D012004:Rectal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D012074:Remission Induction / Q000379:methods; D013940:Thymidylate Synthase / Q000235:genetics* / Q000378:metabolism; D016896:Treatment Outcome; D047368:Tumor Burden / Q000187:drug effects / Q000528:radiation effects; D000076105:X-ray Repair Cross Complementing Protein 1
chemical_list: D000964:Antimetabolites, Antineoplastic; D004268:DNA-Binding Proteins; D000076105:X-ray Repair Cross Complementing Protein 1; C000619371:XRCC1 protein, human; D042943:Dihydrouracil Dehydrogenase (NADP); D042965:Methylenetetrahydrofolate Reductase (NADPH2); D013940:Thymidylate Synthase; C071447:ERCC1 protein, human; D004720:Endonucleases; D005472:Fluorouracil