title: Thymidylate synthase as a prognostic biomarker for locally advanced rectal cancer after multimodal treatment.
abstract: OBJECTIVE
  For years, 5-fluorouracil (5-FU) has been the backbone of radiochemotherapy (RCT) of locally advanced rectal cancer. Its main target, thymidylate synthase (TS), is speculated to be an important biomarker for response prediction and long-term prognosis. In this study, we analyzed TS expression in the rectal cancer tissue of 208 patients to evaluate its predictive/prognostic potential.
  
  
  METHODS
  All patients included were diagnosed with locally advanced adenocarcinoma of the rectum (UICC II and III) and were treated within randomized clinical trials of the German Rectal Cancer Study Group. Preoperative RCT (50.4 Gy and concomitant either 5-FU or 5-FU and oxaliplatin) was administered in 167 patients followed by surgical resection with total mesorectal excision (TME). Another 41 patients received postoperative RCT. TS levels and further clinicopathological parameters were assessed in univariate and multivariate analyses. Additionally, a TS gene polymorphism was analyzed with respect to the intratumoral protein levels.
  
  
  RESULTS
  Low TS expression in pretreatment biopsies correlated with impaired patient survival (p = 0.015). Analysis of a 28-bp repeat revealed a correlation between the *3/*3 genotype and high TS expression in pretherapeutic biopsies. In this study, a correlation of TS expression and grade of RCT-induced tumor regression was not found. Histopathological examination confirmed a complete tumor remission in 16 patients (9.6%). Analyses of the resection specimen indicated an unfavorable prognosis for patients with low intratumoral TS expression in case of detected lymph node metastases (p = 0.04).
  
  
  CONCLUSIONS
  TS can serve as a prognostic biomarker indicating an unfavorable prognosis for patients with low TS expression.
authors.affiliation: Department of General and Visceral Surgery Department of General and Visceral Surgery, Göttingen University Medical Center, Göttingen, Germany. lena.conradi@med.uni-goettingen.de
authors.forename: Lena-Christin
authors.initials: LC
authors.lastname: Conradi
authors.forename: Annalen
authors.initials: A
authors.lastname: Bleckmann
authors.forename: Markus
authors.initials: M
authors.lastname: Schirmer
authors.forename: Thilo
authors.initials: T
authors.lastname: Sprenger
authors.forename: Peter
authors.initials: P
authors.lastname: Jo
authors.forename: Kia
authors.initials: K
authors.lastname: Homayounfar
authors.forename: Hendrik A
authors.initials: HA
authors.lastname: Wolff
authors.forename: Hilka
authors.initials: H
authors.lastname: Rothe
authors.forename: Peter
authors.initials: P
authors.lastname: Middel
authors.forename: Heinz
authors.initials: H
authors.lastname: Becker
authors.forename: Michael B
authors.initials: MB
authors.lastname: Ghadimi
authors.forename: Tim
authors.initials: T
authors.lastname: Beissbarth
authors.forename: Torsten
authors.initials: T
authors.lastname: Liersch
mesh_terms: D000230:Adenocarcinoma / Q000201:enzymology* / Q000556:secondary / Q000628:therapy; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D003131:Combined Modality Therapy; D004273:DNA, Neoplasm / Q000235:genetics; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D005500:Follow-Up Studies; D006801:Humans; D007124:Immunoenzyme Techniques; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D009364:Neoplasm Recurrence, Local / Q000201:enzymology* / Q000473:pathology / Q000628:therapy; D009367:Neoplasm Staging; D009944:Organoplatinum Compounds / Q000008:administration & dosage; D000077150:Oxaliplatin; D016133:Polymerase Chain Reaction; D012004:Rectal Neoplasms / Q000201:enzymology* / Q000473:pathology / Q000628:therapy; D015996:Survival Rate; D013940:Thymidylate Synthase / Q000235:genetics / Q000378:metabolism*; D016896:Treatment Outcome
chemical_list: D014408:Biomarkers, Tumor; D004273:DNA, Neoplasm; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D013940:Thymidylate Synthase; D005472:Fluorouracil