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document
Response prediction in metastasised colorectal cancer using intratumoural thymidylate synthase : results of a randomised multicentre trial . 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 .
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Intervention_Pharmacological
5-fluorouracil ( FU ) -based
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Intervention_Pharmacological
thymidylate synthase
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Intervention_Pharmacological
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 )
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Outcome_Physical
predict response
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Outcome_Physical
thymidylate synthase ( TS )
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Outcome_Physical
overall response to first-line treatment
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Outcome_Physical
TS levels
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Outcome_Physical
response to FUFA and FOLFIRI