title: Response prediction in metastasised colorectal cancer using intratumoural thymidylate synthase: results of a randomised multicentre trial.
abstract: BACKGROUND
  Molecular markers to predict response to 5-fluorouracil (FU)-based treatment of recurrent or metastasised colorectal cancer (mCRC) are not established. The aim of this trial was to determine the value of thymidylate synthase (TS), a key enzyme of DNA synthesis and target of 5-FU, to predict response to chemotherapy of mCRC.
  
  
  METHODS
  Tumour tissue was obtained from 168 patients with mCRC for relative thymidylate synthase (TS) mRNA quantitation. Patients were randomised to receive either 5-FU/folinic acid (FA, FUFA) alone or in combination with irinotecan 5-fluorouracil/folinic acid and irinotecan (FOLFIRI) stratified by TS (low versus high). Primary end-point was overall response to first-line treatment among TS high patients. All parties, except for the randomisation centre, were blinded for TS status.
  
  
  RESULTS
  Biopsies (n=168) were taken without complications. TS levels were available for 147 patients (87.5%). Analysing response to FUFA and FOLFIRI in the per protocol set (n=119) after un-blinding TS in the data base revealed a trend to better overall response to FOLFIRI (9/19, 47%) in TS high compared to FUFA (5/23, 22%, p=0.077). In patients with biopsies taken from liver lesions (n=91) overall response to FOLFIRI and FUFA in TS high was 53% (9/17) and 18% (3/17), respectively (p=0.035). In patients with low TS, no remarkable difference in overall response to FOLFIRI and FUFA was observed.
  
  
  CONCLUSIONS
  Taking a pre-treatment biopsy is a safe and feasible procedure in mCRC. After validation of our data in a larger group TS determination may have the potential to better help direct systemic treatment in patients with primarily non-resectable mCRC.
authors: Department of General, Visceral, and Transplantation Surgery, University of Ulm, Germany. marko.kornmann@uniklinik-ulm.de
authors: Marko
authors: M
authors: Kornmann
authors: Holger
authors: H
authors: Hebart
authors: Kathleen
authors: K
authors: Danenberg
authors: Roland
authors: R
authors: Goeb
authors: Ludger
authors: L
authors: Staib
authors: Martina
authors: M
authors: Kron
authors: Doris
authors: D
authors: Henne-Bruns
authors: Peter
authors: P
authors: Danenberg
authors: Karl-Heinrich
authors: KH
authors: Link
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001706:Biopsy; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D005260:Female; D005472:Fluorouracil / Q000494:pharmacology; D006801:Humans; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D011743:Pyrimidines / Q000627:therapeutic use; D011788:Quality of Life; D013940:Thymidylate Synthase / Q000008:administration & dosage*; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D011743:Pyrimidines; D013940:Thymidylate Synthase; D005472:Fluorouracil