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TS and ERCC-1 mRNA expressions and clinical outcome in patients with metastatic colon cancer in CONFIRM-1 and -2 clinical trials

The Pharmacogenomics Journal volume 12, pages 404–411 (2012)Cite this article

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Abstract

To validate established cutoff levels of thymidylate synthase (TS) and excision repair cross-complementing (ERCC-1) intratumoral mRNA expressions in tumor samples from metastatic colorectal cancer (mCRC) patients treated with PTK787/ZK222584 (PTK/ZK). From 122 samples of patients with mCRC enrolled in CONFIRM-1 (Colorectal Oral Novel Therapy for the Inhibition of Angiogenesis and Retarding of Metastases) or CONFIRM-2, mRNA was isolated of microdissected formalin-fixed paraffin-embedded samples and quantitated using TaqMan-based technology. Existing TS and ERCC-1 cutoff levels were tested for their prognostic value in first-line and second-line therapy. TS expression was associated with overall survival (OS) in first-line, but not second-line therapy. ERCC-1 was associated with OS in patients treated with first-line and second-line FOLFOX4. In first-line FOLFOX4, combination of high TS and/or high ERCC-1 was associated with shorter OS. A correlation was observed between ERCC-1 expression and benefit from PTK/ZK+FOLFOX4 treatment. TS and ERCC-1 expression is associated with clinical outcome in mCRC. Baseline TS and ERCC-1 levels may allow the selection of patients who benefit from FOLFOX4 chemotherapy.

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Acknowledgements

This work was sponsored by Novartis and Bayer Schering Pharma as part of a co-development program. The P30CA number is from Kathy Pfeiffer, Dhont Family Foundation. Editorial assistance was provided by Scientific Connexions (Newtown, PA, USA).

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Authors and Affiliations

  1. Department of Molecular Biology and Biochemistry, University of Southern California/Norris Comprehensive Cancer Center, Keck School of Medicine, Los Angeles, CA, USA

    P P Grimminger & P V Danenberg

  2. Department of General-, Visceral- and Tumor Surgery, University of Cologne, Cologne, Germany

    P P Grimminger & J Brabender

  3. Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA

    M Shi, C Barrett & D Lebwohl

  4. Response Genetics Inc., Los Angeles, CA, USA

    K D Danenberg

  5. Division of Biostatistics, University of Southern California, Keck School of Medicine, Los Angeles, CA, USA

    C L P Vigen

  6. Division of Medical Oncology, University of Southern California/Norris Comprehensive Cancer Center, Keck School of Medicine, Los Angeles, CA, USA

    T Winder & H-J Lenz

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Correspondence to H-J Lenz.

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Previous Presentation: Parts of these results were presented at the ASCO 2008 Annual Meeting in the poster presentation (abstract 4131) and at the ASCO 2010 Annual Meeting (abstract 48363).

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Grimminger, P., Shi, M., Barrett, C. et al. TS and ERCC-1 mRNA expressions and clinical outcome in patients with metastatic colon cancer in CONFIRM-1 and -2 clinical trials. Pharmacogenomics J 12, 404–411 (2012). https://doi.org/10.1038/tpj.2011.29

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