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Gene-expression profiles correlate with the efficacy of anti-EGFR therapy and chemotherapy for colorectal cancer

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Abstract

Background

Comprehensive gene-expression analysis is very useful for classifying specific cancers into subgroups on the basis of their biological characteristics; it is used both prognostically and predictively. The purpose of this study was to classify unresectable advanced or recurrent colorectal cancer (CRC) by gene-expression profiling of formalin-fixed paraffin-embedded tissues and to correlate CRC subgroups with clinicopathological and molecular features and clinical outcomes.

Methods

One hundred patients with advanced or recurrent CRC were enrolled. RNA extracted from FFPE tissues was subjected to gene-expression microarray analysis.

Results

The patients were stratified into four subgroups (subtypes A1, A2, B1, and B2) by unsupervised hierarchical clustering. By use of principle-components analysis (PCA), the patients were divided into subtypes A and B on the basis of component 1 and into subtypes 1 and 2 on the basis of component 2. Subtype A was significantly enriched among patients without the KRAS mutation and with an earlier clinical stage at diagnosis. With regard to anti-EGFR therapy, progression-free survival (PFS) was better for patients in subtype A without the KRAS mutation than for those with the KRAS mutation (P = 0.047). PFS for patients without the KRAS mutation in subtype B was comparable with that for patients with the KRAS mutation (P = 0.55). Similar results were observed in a validation set.

Conclusion

We found that gene-expression profiles enabled stratification of CRC patients into four subgroups. The efficacy of anti-EGFR therapy was correlated with component 1 from PCA. This comprehensive study may explain the heterogeneity of unresectable advanced or recurrent CRC and could be useful for identifying novel biomarkers for CRC treatment.

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References

  1. Kopetz S, Chang GJ, Overman MJ et al (2009) Improved survival in metastatic colorectal cancer is associated with adoption of hepatic resection and improved chemotherapy. J Clin Oncol 27(22):3677–3683

    Article  PubMed Central  PubMed  Google Scholar 

  2. Goldberg RM, Sargent DJ, Morton RF et al (2004) A randomized controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer. J Clin Oncol 22(1):23–30

    Article  CAS  PubMed  Google Scholar 

  3. Cassidy J, Clarke S, Diaz-Rubio E et al (2008) Randomized phase III study of capecitabine plus oxaliplatin compared with fluorouracil/folinic acid plus oxaliplatin as first-line therapy for metastatic colorectal cancer. J Clin Oncol 26(12):2006–2012

    Article  CAS  PubMed  Google Scholar 

  4. Fuchs CS, Marshall J, Mitchell E et al (2007) Randomized, controlled trial of irinotecan plus infusional, bolus, or oral fluoropyrimidines in first-line treatment of metastatic colorectal cancer: results from the BICC-C Study. J Clin Oncol 25(30):4779–4786

    Article  CAS  PubMed  Google Scholar 

  5. Yoshioka T, Kato S, Gamoh M et al (2009) Phase I/II study of sequential therapy with irinotecan and S-1 for metastatic colorectal cancer. Br J Cancer 101(12):1972–1977

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  6. Zerbini G, Lorenzi M, Palini A (2008) Tumor angiogenesis. N Engl J Med 358(7):2039–2049

    Google Scholar 

  7. Scaltriti M, Baselga J (2006) The epidermal growth factor receptor pathway: a model for targeted therapy. Clin Cancer Res 12(18):5268–5272

    Article  CAS  PubMed  Google Scholar 

  8. Saltz LB, Meropol NJ, Loehrer PJ et al (2004) Phase II trial of cetuximab in patients with refractory colorectal cancer that expresses the epidermal growth factor receptor. J Clin Oncol 22(7):1201–1208

    Article  CAS  PubMed  Google Scholar 

  9. Saltz LB, Clarke S, Díaz-Rubio E et al (2008) Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol 26(12):2013–2019

    Article  CAS  PubMed  Google Scholar 

  10. Karapetis CS, Khambata-Ford S, Jonker DJ et al (2008) K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med 359(17):1757–1765

    Article  CAS  PubMed  Google Scholar 

  11. Amado RG, Wolf M, Peeters M et al (2008) Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol 26(10):1626–1634

    Article  CAS  PubMed  Google Scholar 

  12. Bokemeyer C, Bondarenko I, Makhson A et al (2009) Fluorouracil, leucovorin, and oxaliplatin with and without cetuximab in the first-line treatment of metastatic colorectal cancer. J Clin Oncol 27(5):663–671

    Article  CAS  PubMed  Google Scholar 

  13. Van Cutsem E, Köhne CH, Hitre E et al (2009) Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med 360(14):1408–1417

    Article  PubMed  Google Scholar 

  14. Salazar R, Roepman P, Capella G et al (2011) Gene expression signature to improve prognosis prediction of stage II and III colorectal cancer. J Clin Oncol 29(1):17–24

    Article  PubMed  Google Scholar 

  15. van ‘t Veer LJ, Dai H, van de Vijver MJ et al (2002) Gene expression profiling predicts clinical outcome of breast cancer. Nature 415(6871):530–536

    Article  Google Scholar 

  16. Khambata-Ford S, Garrett CR, Meropol NJ et al (2007) Expression of epiregulin and amphiregulin and K-ras mutation status predict disease control in metastatic colorectal cancer patients treated with cetuximab. J Clin Oncol 25(22):3230–3237

    Article  CAS  PubMed  Google Scholar 

  17. Felipe De Sousa EM, Wang X, Jansen M et al (2013) Poor-prognosis colon cancer is defined by a molecularly distinct subtype and develops from serrated precursor lesions. Nat Med 19(5):614–618

    Article  Google Scholar 

  18. Soeda H, Shimodaira H, Watanabe M et al (2013) Clinical usefulness of KRAS, BRAF, and PIK3CA mutations as predictive markers of cetuximab efficacy in irinotecan-and oxaliplatin-refractory Japanese patients with metastatic colorectal cancer. Int J Clin Oncol 18(4):670–677

    Article  CAS  PubMed  Google Scholar 

  19. Takahashi S, Moriya T, Ishida T et al (2008) Prediction of breast cancer prognosis by gene expression profile of TP53 status. Cancer Sci 99(2):324–332

    Article  CAS  PubMed  Google Scholar 

  20. International Agency for Research on Cancer (IARC). IARC TP53 Mutation Database: Database Statistics: R17 November 2013. http://www-p53.iarc.fr. Accessed date 28 Jan 2015

  21. Calistri D, Rengucci C, Seymour I et al (2005) Mutation analysis of p53, K-ras, and BRAF genes in colorectal cancer progression. J Cell Physiol 204(2):484–488

    Article  CAS  PubMed  Google Scholar 

  22. Roth AD, Tejpar S, Delorenzi M et al (2010) Prognostic role of KRAS and BRAF in stage II and III resected colon cancer: results of the translational study on the PETACC-3, EORTC 40993, SAKK 60-00 trial. J Clin Oncol 28:466–474

    Article  CAS  PubMed  Google Scholar 

  23. Samowitz WS, Curtin K, Ma KN et al (2001) Microsatellite instability in sporadic colon cancer is associated with an improved prognosis at the population level. Cancer Epidemiol Biomarkers Prev 10(9):917–923

    CAS  PubMed  Google Scholar 

  24. Dienstmann R, Guinney J, Delorenzi M et al (2014) Colorectal Cancer Subtyping Consortium (CRCSC) identification of a consensus of molecular subtypes. J Clin Oncol 32(5s suppl; abstr):3511

    Google Scholar 

  25. Frattini M, Saletti P, Romagnani E et al (2007) PTEN loss of expression predicts cetuximab efficacy in metastatic colorectal cancer patients. Br J Cancer 97(8):1139–1145

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  26. Khambata-Ford S, Garrett CR, Meropol NJ et al (2007) Expression of epiregulin and amphiregulin and K-ras mutation status predict disease control in metastatic colorectal cancer patients treated with cetuximab. J Clin Oncol 25(22):3230–3237

    Article  CAS  PubMed  Google Scholar 

  27. Jacobs B, De Roock W, Piessevaux H et al (2009) Amphiregulin and epiregulin mRNA expression in primary tumors predicts outcome in metastatic colorectal cancer treated with cetuximab. J Clin Oncol 27(30):5068–5074

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

We thank Satoko Aoki for her technical assistance. This work was partially supported by a grant from Project for Development of Innovative Research on Cancer Therapeutics (P-DIRECT).

Conflict of interest

Dr Ishioka reports receipt of research grants from Chugai, Yakult, Daiichi-Sankyo, and Merk Serono; Dr Kato reports receipt of lecture fees and a research grant from Chugai; Dr Inoue, Dr Takahashi, Dr Soeda, Dr Watanabe, Dr Miura, and Dr Sasaki have no conflict of interest.

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    Authors and Affiliations

    1. Department of Clinical Oncology, Institute of Development, Aging and Cancer Tohoku University, 4-1 Seiryo-machi, Aobaku, Sendai, 980-8575, Japan

      Masahiro Inoue, Shin Takahashi, Hiroshi Soeda, Hideki Shimodaira, Shunsuke Kato & Chikashi Ishioka

    2. Department of Clinical Oncology, Tohoku University Hospital, 1-1 Seiryo-machi, Aobaku, Sendai, 980-8575, Japan

      Masahiro Inoue, Shin Takahashi, Hiroshi Soeda, Hideki Shimodaira, Shunsuke Kato & Chikashi Ishioka

    3. Department of Pathology, Tohoku University Hospital, 1-1 Seiryo-machi, Aobaku, Sendai, 980-8575, Japan

      Mika Watanabe

    4. Department of Gastroenterological Surgery, Tohoku University Hospital, 1-1 Seiryo-machi, Aobaku, Sendai, 980-8575, Japan

      Koh Miura & Iwao Sasaki

    Authors
    1. Masahiro Inoue
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    2. Shin Takahashi
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    Correspondence to Chikashi Ishioka.

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    M. Inoue, and S. Takahashi are contributed equally to this work.

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    Inoue, M., Takahashi, S., Soeda, H. et al. Gene-expression profiles correlate with the efficacy of anti-EGFR therapy and chemotherapy for colorectal cancer. Int J Clin Oncol 20, 1147–1155 (2015). https://doi.org/10.1007/s10147-015-0841-4

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    • DOI: https://doi.org/10.1007/s10147-015-0841-4

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