Response prediction in metastasised colorectal cancer using intratumoural thymidylate synthase: Results of a randomised multicentre trial

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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.

Introduction

Treatment of colorectal cancer (CRC) has improved considerably within the last two decades including all areas of multimodal treatment.1 At least seven new drugs have been licensed for palliative treatment of recurrent and metastasised CRC (mCRC) during the last 15 years.2 Many studies focused on optimising drug combinations and the sequence of application.1, 3 Despite the broad availability of treatment options cure remains a rare event and treatment is still selected on physician preference considering age, co-morbidity, toxicity of drug combinations, possibility of a secondary resection, and recommendations of national guidelines.

Drawbacks of intensified strategies are increased toxicity and costs.2, 4 Therefore, it may be beneficial to establish tumour-tailored treatment pathways based on the individual molecular profile. This strategy may help to direct possibly effective drugs to the patient without delay and to avoid administration of uneffective or even harmful ones. This may result in increased response rates (RR) due to initial use of effective agents as well as in reduction of toxicity and costs due to omission of useless ones. At present, only KRAS is determined as an individual biological marker for resistance to epidermal growth factor receptor (EGFR) targeting.5, 6

Fluoropyrimidines, especially 5-fluorouracil (5-FU), remain for more than 50 years the fundamental compound for systemic treatment of mCRC. One main mechanism of 5-FU action is inhibition of thymidylate synthase (TS), which catalyses a crucial rate-limiting step of DNA synthesis.7 Several studies in mCRC demonstrated that high intratumoural TS levels correlated with resistance to fluoropyrimidine treatment.8, 9 Similar observations were reported for liver metastases of CRC treated with fluoropyrimidine-based hepatic arterial infusion and other gastrointestinal malignancies.10, 11, 12, 13 Despite these promising results as a predictor of response to 5-FU based chemotherapy TS has not been recommended for routine clinical practise nor have other markers.14

The aim of the present study was to evaluate the feasibility of TS determination in a multicentre randomised controlled trial setting using a central facility for measurement and to determine its role as response marker for systemic 5-FU-based treatment of mCRC using a blinded study design.

Section snippets

Trial design

The German ‘Research Group Oncology of Gastrointestinal Tumours’ (FOGT) designed a prospective, multicentre, TS-blinded, randomised controlled trial (FOGT-5) to determine the feasibility of pre-treatment TS determination and its role as predictor for 5-FU response in mCRC. Randomisation was stratified for TS status. The study was conducted conforming to GCP/ICH rules and respecting the Helsinki Declaration (1989). It was approved by the Ethics Committee of the University of Ulm (#32/2001),

Biopsies and TS determination

Biopsies from 168 patients with non-resectable, two-dimensional measurable metastatic or recurrent colorectal cancer (mCRC) were obtained during surgical resection of the primary tumour (127) using open (106) or cutting needle (21) biopsy, during laparoscopy (3) or thoracotomy (1), or using transcutaneous cutting needle (25) or endoscopic (3) biopsy. For nine patients, the procedure was not stated.

TS could be successfully determined for 147 of 168 (87.5%) patients (Fig. 1). It was carried out

Discussion

Individualised tumour tailored treatment of non-resectable metastasised or recurrent colorectal cancer (mCRC) is not established yet.18, 19 In a first step towards an individualised approach the KRAS mutational status is now determined prior to initiating therapy with EGFR antibodies due to higher response rates of wild-type tumours.5, 20 Recent studies evaluating single or double targeting in combination with vascular endothelial growth factor (VEGF) targeting even revealed higher adverse

Contributors

MK, KD, LS, PD, MKr, and KHL contributed to the design of the study, all authors to the performance of the trial, and the writing of the report. MK was responsible for drafting and revising the report, and MKr was responsible for the statistical analysis of the trial results.

Financial support

This trial was supported by Pfizer (Berlin, Germany) and Medac GmbH (Hamburg, Germany).

Conflict of interest statement

None declared.

Acknowledgements

The authors would like to acknowledge all investigators who participated and recruited patients: R. Göb, Klinik für Allgemein-, Viszeral- und Gefäßchirurgie, Katholisches Krankenhaus St. Johann Nepomuk, Erfurt; K.-H. Link, Chirurgisches Zentrum, Asklepios Paulinen Klinik, Wiesbaden; A. Schreiber, Chirurgische Klinik, Werner Forßmann Krankenhaus, Eberswalde, E. Lotspeich, Abteilung für Allgemein- und Viszeralchirurgie, Bundeswehrkrankenhaus Ulm; M. Platz, Abteilung für Allgemein- und

References (29)

  • A. Jimeno et al.

    KRAS mutations and sensitivity to epidermal growth factor receptor inhibitors in colorectal cancer: practical application of patient selection

    J Clin Oncol

    (2009)
  • C.J. Allegra et al.

    American Society of Clinical Oncology provisional clinical opinion: testing for KRAS gene mutations in patients with metastatic colorectal carcinoma to predict response to anti-epidermal growth factor receptor monoclonal antibody therapy

    J Clin Oncol

    (2009)
  • J.R. Bertino et al.

    Is the measurement of thymidylate synthase to determine suitability for treatment with 5-fluoropyrimidines ready for prime time?

    Clin Cancer Res

    (2003)
  • S. Popat et al.

    Thymidylate synthase expression and prognosis in colorectal cancer: a systematic review and meta-analysis

    J Clin Oncol

    (2004)

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