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Gene expression signature and response to the use of leucovorin, fluorouracil and oxaliplatin in colorectal cancer patients

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Abstract

Purpose

FOLFOX (a combination of leucovorin, fluorouracil and oxaliplatin) has achieved substantial success in the treatment of colorectal cancer (CRC) patients. However, about half of all patients show resistance to this regimen and some develop adverse symptoms such as neurotoxicity. In order to select patients who would benefit most from this therapy, we aimed to build a predictor for the response to FOLFOX using microarray gene expression profiles of primary CRC samples.

Patients and methods

Forty patients who underwent surgery for primary lesions were examined. All patients had metastatic or recurrent CRC and received modified FOLFOX6. Responders and nonresponders were determined according to the best observed response at the end of the first-line treatment. Gene-expression profiles of primary CRC were determined using Human Genome GeneChip arrays U133. We identified discriminating genes whose expression differed significantly between responders and nonresponders and then carried out supervised class prediction using the k-nearest-neighbour method.

Results

We identified 27 probes that were differentially expressed between responders and nonresponders at significant levels. Based on the expression of these genes, we constructed a FOLFOX response predictor with an overall accuracy of 92.5%. The sensitivity, specificity, positive and negative predictive values were 78.6%, 100%, 100% and 89.7%, respectively.

Conclusion

The present model suggests the possibility of selecting patients who would benefit from FOLFOX therapy both in the metastatic and the adjuvant setting. To our knowledge, this is the first study to establish a prediction model for the response to FOLFOX chemotherapy based on gene expression by microarray analysis.

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Authors and Affiliations

  1. Department of Surgery, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi-ku, Tokyo, 173-8605, Japan

    Toshiaki Watanabe, Takashi Kobunai, Yoko Yamamoto, Keiji Matsuda, Soichiro Ishihara, Keijiro Nozawa & Hisae Iinuma

  2. Tokushima Research Center, Taiho Pharmaceutical Co., Ltd., 224-2, Ebisuno, Hiraishi, Kawauchi-cho, Tokushima, 771-0194, Japan

    Takashi Kobunai & Kiyoshi Eshima

  3. The Cancer Institute Hospital of JFCR, 3-10-6, Ariake, Kotoh-ku, Tokyo, 135-8550, Japan

    Tsuyoshi Konishi & Tetsuichiro Muto

  4. Department of Surgery School of Medicine, Jichi Medical University, Yakushiji 3311-1, Shimotsuke Tochigi, 329-0498, Japan

    Hisanaga Horie

  5. Department of Surgery, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo, 663-8501, Japan

    Hiroki Ikeuchi

Authors
  1. Toshiaki Watanabe
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  2. Takashi Kobunai
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  3. Yoko Yamamoto
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  4. Keiji Matsuda
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  7. Hisae Iinuma
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  8. Tsuyoshi Konishi
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  9. Hisanaga Horie
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  12. Tetsuichiro Muto
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Correspondence to Toshiaki Watanabe.

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Watanabe, T., Kobunai, T., Yamamoto, Y. et al. Gene expression signature and response to the use of leucovorin, fluorouracil and oxaliplatin in colorectal cancer patients. Clin Transl Oncol 13, 419–425 (2011). https://doi.org/10.1007/s12094-011-0676-z

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  • DOI: https://doi.org/10.1007/s12094-011-0676-z

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