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Pharmacogenetic profiling of CD133 is associated with response rate (RR) and progression-free survival (PFS) in patients with metastatic colorectal cancer (mCRC), treated with bevacizumab-based chemotherapy

The Pharmacogenomics Journal volume 13, pages 173–180 (2013)Cite this article

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Abstract

Recent studies suggest CD133, a surface protein widely used for isolation of colon cancer stem cells, to be associated with tumor angiogenesis and recurrence. We hypothesized that gene expression levels and germline variations in CD133 will predict clinical outcome in patients with metastatic colorectal cancer (mCRC), treated in first-line setting with 5-fluorouracil, oxaliplatin and bevacizumab (BV), and we investigated whether there is a correlation with gene expression levels of CD133, vascular endothelial growth factor (VEGF) and its receptors. We evaluated intra-tumoral gene expression levels by quantitative real-time (RT) PCR from 54 patients and three germline variants of the CD133 gene by PCR-restriction-fragment length polymorphism from 91 patients with genomic DNA. High gene expression levels of CD133 (>7.76) conferred a significantly greater tumor response (RR=86%) than patients with low expression levels (⩽7.76, RR=38%, adjusted P=0.003), independent of VEGF or its receptor gene expression levels. Gene expression levels of CD133 were significantly associated with VEGF and its receptors messenger RNA levels (VEGFR-1 (P<0.01), -2 and -3, P<0.05). Combined analyses of two polymorphisms showed a significant association with progression-free survival (PFS) (18.5 months vs 9.8 months, P=0.004) in a multivariate analysis as an independent prognostic factor for PFS (adjusted P=0.002). These results suggest that CD133 is a predictive marker for standard first-line BV-based treatment in mCRC.

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Acknowledgements

This work was funded by the NIH Grant 5 P30CA14089-27I and in honor of Jerome Comet Klein MD by the Irving and Estelle Levy Foundation and performed in the Sharon A. Carpenter Laboratory at USC/Norris CCC.

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Authors and Affiliations

  1. Division of Medical Oncology, Sharon A. Carpenter Laboratory, University of Southern California/Norris Comprehensive Cancer Center, Keck School of Medicine, Los Angeles, CA, USA

    A Pohl, A El-Khoueiry, W Zhang, G Lurje, Y Ning, T Winder, S Hu-Lieskoven, S Iqbal & H-J Lenz

  2. Department of Preventive Medicine, University of Southern California/Norris, Comprehensive Cancer Center, Keck School of Medicine, Los Angeles, CA, USA

    D Yang & H-J Lenz

  3. Response Genetics, Los Angeles, CA, USA

    K D Danenberg

  4. University of Southern California/Department of Biochemistry and Molecular Biology, Center for Stem Cell and Regenerative Medicine, Keck School of Medicine, Los Angeles, CA, USA

    M Kahn & J-L Teo

  5. Department of Radiology, University of Southern California/Norris Comprehensive Cancer Center, Keck School of Medicine, Los Angeles, CA, USA

    J Shriki

  6. Department of Oncology, Imperial College School of Medicine, Imperial College, London, UK

    J Stebbing

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  1. A Pohl
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Correspondence to H-J Lenz.

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Additional information

Parts of this study were presented at the annual ASCO meeting 2009, Orlando, Florida (J Clin Oncol 27:15 s, 2009; suppl; abstr 4062)

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Pohl, A., El-Khoueiry, A., Yang, D. et al. Pharmacogenetic profiling of CD133 is associated with response rate (RR) and progression-free survival (PFS) in patients with metastatic colorectal cancer (mCRC), treated with bevacizumab-based chemotherapy. Pharmacogenomics J 13, 173–180 (2013). https://doi.org/10.1038/tpj.2011.61

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