Spandidos Publications Logo
  • About
    • About Spandidos
    • Aims and Scopes
    • Abstracting and Indexing
    • Editorial Policies
    • Reprints and Permissions
    • Job Opportunities
    • Terms and Conditions
    • Contact
  • Journals
    • All Journals
    • Oncology Letters
      • Oncology Letters
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Oncology
      • International Journal of Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular and Clinical Oncology
      • Molecular and Clinical Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Experimental and Therapeutic Medicine
      • Experimental and Therapeutic Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Molecular Medicine
      • International Journal of Molecular Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Biomedical Reports
      • Biomedical Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Oncology Reports
      • Oncology Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular Medicine Reports
      • Molecular Medicine Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • World Academy of Sciences Journal
      • World Academy of Sciences Journal
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Functional Nutrition
      • International Journal of Functional Nutrition
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Epigenetics
      • International Journal of Epigenetics
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Medicine International
      • Medicine International
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
  • Articles
  • Information
    • Information for Authors
    • Information for Reviewers
    • Information for Librarians
    • Information for Advertisers
    • Conferences
  • Language Editing
Spandidos Publications Logo
  • About
    • About Spandidos
    • Aims and Scopes
    • Abstracting and Indexing
    • Editorial Policies
    • Reprints and Permissions
    • Job Opportunities
    • Terms and Conditions
    • Contact
  • Journals
    • All Journals
    • Biomedical Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Experimental and Therapeutic Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Epigenetics
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Functional Nutrition
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Molecular Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Medicine International
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular and Clinical Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular Medicine Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Oncology Letters
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Oncology Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • World Academy of Sciences Journal
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
  • Articles
  • Information
    • For Authors
    • For Reviewers
    • For Librarians
    • For Advertisers
    • Conferences
  • Language Editing
Login Register Submit
  • This site uses cookies
  • You can change your cookie settings at any time by following the instructions in our Cookie Policy. To find out more, you may read our Privacy Policy.

    I agree
Search articles by DOI, keyword, author or affiliation
Search
Advanced Search
presentation
Oncology Reports
Join Editorial Board Propose a Special Issue
Print ISSN: 1021-335X Online ISSN: 1791-2431
Journal Cover
July-2014 Volume 32 Issue 1

Full Size Image

Sign up for eToc alerts
Recommend to Library

Journals

International Journal of Molecular Medicine

International Journal of Molecular Medicine

International Journal of Molecular Medicine is an international journal devoted to molecular mechanisms of human disease.

International Journal of Oncology

International Journal of Oncology

International Journal of Oncology is an international journal devoted to oncology research and cancer treatment.

Molecular Medicine Reports

Molecular Medicine Reports

Covers molecular medicine topics such as pharmacology, pathology, genetics, neuroscience, infectious diseases, molecular cardiology, and molecular surgery.

Oncology Reports

Oncology Reports

Oncology Reports is an international journal devoted to fundamental and applied research in Oncology.

Experimental and Therapeutic Medicine

Experimental and Therapeutic Medicine

Experimental and Therapeutic Medicine is an international journal devoted to laboratory and clinical medicine.

Oncology Letters

Oncology Letters

Oncology Letters is an international journal devoted to Experimental and Clinical Oncology.

Biomedical Reports

Biomedical Reports

Explores a wide range of biological and medical fields, including pharmacology, genetics, microbiology, neuroscience, and molecular cardiology.

Molecular and Clinical Oncology

Molecular and Clinical Oncology

International journal addressing all aspects of oncology research, from tumorigenesis and oncogenes to chemotherapy and metastasis.

World Academy of Sciences Journal

World Academy of Sciences Journal

Multidisciplinary open-access journal spanning biochemistry, genetics, neuroscience, environmental health, and synthetic biology.

International Journal of Functional Nutrition

International Journal of Functional Nutrition

Open-access journal combining biochemistry, pharmacology, immunology, and genetics to advance health through functional nutrition.

International Journal of Epigenetics

International Journal of Epigenetics

Publishes open-access research on using epigenetics to advance understanding and treatment of human disease.

Medicine International

Medicine International

An International Open Access Journal Devoted to General Medicine.

Journal Cover
July-2014 Volume 32 Issue 1

Full Size Image

Sign up for eToc alerts
Recommend to Library

  • Article
  • Citations
    • Cite This Article
    • Download Citation
    • Create Citation Alert
    • Remove Citation Alert
    • Cited By
  • Similar Articles
    • Related Articles (in Spandidos Publications)
    • Similar Articles (Google Scholar)
    • Similar Articles (PubMed)
  • Download PDF
  • Download XML
  • View XML
Article

Impact of genetic profiles on the efficacy of anti-EGFR antibodies in metastatic colorectal cancer with KRAS mutation

  • Authors:
    • Tomokazu Kishiki
    • Hiroaki Ohnishi
    • Tadahiko Masaki
    • Kouki Ohtsuka
    • Yasuo Ohkura
    • Jyunji Furuse
    • Masanori Sugiyama
    • Takashi Watanabe
  • View Affiliations / Copyright

    Affiliations: Department of Surgery, Kyorin University School of Medicine, Mitaka, Tokyo 181-8611, Japan, Department of Laboratory Medicine, Kyorin University School of Medicine, Mitaka, Tokyo 181-8611, Japan, Department of Pathology, Kyorin University School of Medicine, Mitaka, Tokyo 181-8611, Japan, Department of Medical Oncology, Kyorin University School of Medicine, Mitaka, Tokyo 181-8611, Japan
  • Pages: 57-64
    |
    Published online on: May 15, 2014
       https://doi.org/10.3892/or.2014.3179
  • Expand metrics +
Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )
Cited By (CrossRef): 0 citations Loading Articles...

This article is mentioned in:



Abstract

Reports indicate that, even in KRAS-mutated colon cancer, there are subsets of patients who benefit from anti-EGFR monoclonal antibody (MoAb) treatment. The aim of the present study was to identify genetic profiles that contribute to the responsiveness of metastatic colorectal cancer (mCRC) to anti-EGFR MoAb. We retrospectively evaluated the efficacy of anti-EGFR MoAb in mCRC patients with KRAS mutations according to KRAS mutational subtypes, BRAF and PIK3CA mutational status and PTEN and MET expression. Among 21 patients with KRAS-mutant tumors, 8 (38%) harbored p.G13D, 7 (33%) harbored p.G12V, 5 (24%) harbored p.G12D, and 1 (5%) harbored p.G12C mutation. Patients with the p.G13D mutation exhibited a significantly higher disease control rate than patients with other KRAS mutations (P=0.042), and tended to show a longer progression-free survival (PFS) than patients with other KRAS mutations with marginal significance (P=0.074). Patients with loss of PTEN had significantly shorter PFS than those with normal PTEN expression in patients with KRAS mutations (P=0.044). MET overexpression was significantly associated with shorter PFS compared to normal MET expression in patients with KRAS mutations (P=0.016). Our data demonstrated the potential utility of alterations in PTEN and MET expression as predictive markers for response to anti-EGFR MoAbs in mCRC patients with KRAS mutations. In addition, we confirmed the predictive value of the KRAS p.G13D mutation for better response to anti-EGFR therapies in comparison with other KRAS mutations.
View Figures

Figure 1

Figure 2

Figure 3

View References

1 

Linardou H, Dahabreh IJ, Kanaloupiti D, et al: Assessment of somatic k-RAS mutations as a mechanism associated with resistance to EGFR-targeted agents: a systematic review and meta-analysis of studies in advanced non-small-cell lung cancer and metastatic colorectal cancer. Lancet Oncol. 9:962–972. 2008. View Article : Google Scholar

2 

Normanno N, Tejpar S, Morgillo F, De Luca A, Van Cutsem E and Ciardiello F: Implications for KRAS status and EGFR-targeted therapies in metastatic CRC. Nat Rev Clin Oncol. 6:519–527. 2009.

3 

Messner I, Cadeddu G, Huckenbeck W, Knowles HJ, Gabbert HE, Baldus SE and Schaefer KL: KRAS p. G13D mutations are associated with sensitivity to anti-EGFR antibody treatment in colorectal cancer cell lines. J Cancer Res Clin Oncol. 139:201–209. 2013. View Article : Google Scholar

4 

Loupakis F, Pollina L, Stasi I, et al: PTEN expression and KRAS mutations on primary tumors and metastases in the prediction of benefit from cetuximab plus irinotecan for patients with metastatic colorectal cancer. J Clin Oncol. 27:2622–2629. 2009.PubMed/NCBI

5 

Saridaki Z, Tzardi M, Papadaki C, et al: Impact of KRAS, BRAF, PIK3CA mutations, PTEN, AREG, EREG expression and skin rash in ≥ 2 line cetuximab-based therapy of colorectal cancer patients. PLoS One. 6:e159802011.

6 

O’Neil BH: Systemic therapy for colorectal cancer: focus on newer chemotherapy and novel agents. Semin Radiat Oncol. 13:441–453. 2003.PubMed/NCBI

7 

Adlard JW, Richman SD, Seymour MT and Quirke P: Prediction of the response of colorectal cancer to systemic therapy. Lancet Oncol. 3:75–82. 2002. View Article : Google Scholar : PubMed/NCBI

8 

Benvenuti S, Sartore-Bianchi A, Di Nicolantonio F, et al: Oncogenic activation of the RAS/RAF signaling pathway impairs the response of metastatic colorectal cancers to anti-epidermal growth factor receptor antibody therapies. Cancer Res. 67:2643–2648. 2007. View Article : Google Scholar

9 

Bando H, Yoshino T, Yuki S, et al: Clinical outcome of Japanese metastatic colorectal cancer patients harbouring the KRAS p. G13D mutation treated with cetuximab + irinotecan. Jpn J Clin Oncol. 42:1146–1151. 2012. View Article : Google Scholar : PubMed/NCBI

10 

Tejpar S, Celik I, Schlichting M, Sartorius U, Bokemeyer C and Van Cutsem E: Association of KRAS G13D tumor mutations with outcome in patients with metastatic colorectal cancer treated with first-line chemotherapy with or without cetuximab. J Clin Oncol. 30:3570–3577. 2012.PubMed/NCBI

11 

Guerrero S, Casanova I, Farré L, Mazo A, Capellà G and Mangues R: K-ras codon 12 mutation induces higher level of resistance to apoptosis and predisposition to anchorage-independent growth than codon 13 mutation or proto-oncogene overexpression. Cancer Res. 60:6750–6756. 2000.

12 

De Roock W, Jonker DJ, Di Nicolantonio F, et al: Association of KRAS p. G13D mutation with outcome in patients with chemotherapy-refractory metastatic colorectal cancer treated with cetuximab. JAMA. 304:1812–1820. 2010.

13 

Peeters M, Douillard JY, Van Cutsem E, Siena S, Zhang K, Williams R and Wiezorek J: Mutant KRAS codon 12 and 13 alleles in patients with metastatic colorectal cancer: assessment as prognostic and predictive biomarkers of response to panitumumab. J Clin Oncol. 31:759–765. 2013.

14 

Gajate P, Sastre J, Bando I, et al: Influence of KRAS p. G13D mutation in patients with metastatic colorectal cancer treated with cetuximab. Clin Colorectal Cancer. 11:291–296. 2012.

15 

Di Nicolantonio F, Martini M, Molinari F, et al: Wild-type BRAF is required for response to panitumumab or cetuximab in metastatic colorectal cancer. J Clin Oncol. 26:5705–5712. 2008.

16 

Ulivi P, Capelli L, Valgiusti M, et al: Predictive role of multiple gene alterations in response to cetuximab in metastatic colorectal cancer: a single center study. J Transl Med. 10:872012. View Article : Google Scholar : PubMed/NCBI

17 

Kato S, Iida S, Higuchi T, et al: PIK3CA mutation is predictive of poor survival in patients with colorectal cancer. Int J Cancer. 121:1771–1778. 2007. View Article : Google Scholar

18 

Inno A, Di Salvatore M, Cenci T, et al: Is there a role for IGF1R and c-MET pathways in resistance to cetuximab in metastatic colorectal cancer? Clin Colorectal Cancer. 10:325–332. 2011. View Article : Google Scholar

19 

Guo A, Villén J, Kornhauser J, et al: Signaling networks assembled by oncogenic EGFR and c-Met. Proc Natl Acad Sci USA. 105:692–697. 2008. View Article : Google Scholar : PubMed/NCBI

20 

Sattler M, Reddy MM, Hasina R, Gangadhar T and Salgia R: The role of the c-Met pathway in lung cancer and the potential for targeted therapy. Ther Adv Med Oncol. 3:171–184. 2011. View Article : Google Scholar : PubMed/NCBI

21 

Therasse P, Arbuck SG, Eisenhauer EA, et al: New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst. 92:205–216. 2000. View Article : Google Scholar

22 

Ohnishi H, Ohtsuka K, Ooide A, Matsushima S, Goya T and Watanabe T: A simple and sensitive method for detecting major mutations within the tyrosine kinase domain of the epidermal growth factor receptor gene in non-small-cell lung carcinoma. Diagn Mol Pathol. 15:101–108. 2006. View Article : Google Scholar

23 

Torres J, Navarro S, Roglá I, et al: Heterogeneous lack of expression of the tumour suppressor PTEN protein in human neoplastic tissues. Eur J Cancer. 37:114–121. 2001. View Article : Google Scholar : PubMed/NCBI

24 

Dua R, Zhang J, Parry G and Penuel E: Detection of hepatocyte growth factor (HGF) ligand-c-MET receptor activation in formalin-fixed paraffin embedded specimens by a novel proximity assay. PLoS One. 6:e159322011. View Article : Google Scholar : PubMed/NCBI

25 

Murray S, Karavasilis V, Bobos M, et al: Molecular predictors of response to tyrosine kinase inhibitors in patients with non-small-cell lung cancer. J Exp Clin Cancer Res. 31:772012. View Article : Google Scholar : PubMed/NCBI

26 

Lin B, Utleg AG, Gravdal K, et al: WDR19 expression is increased in prostate cancer compared with normal cells, but low-intensity expression in cancers is associated with shorter time to biochemical failures and local recurrence. Clin Cancer Res. 14:1397–1406. 2008. View Article : Google Scholar

27 

Halvorsen OJ, Rostad K, Øyan AM, et al: Increased expression of SIM2-s protein is a novel marker of aggressive prostate cancer. Clin Cancer Res. 13:892–897. 2007. View Article : Google Scholar : PubMed/NCBI

28 

Zeng ZL, Wu WJ, Yang J, et al: Prognostic relevance of melanoma antigen D1 expression in colorectal carcinoma. J Transl Med. 10:1812012. View Article : Google Scholar : PubMed/NCBI

29 

Pandolfi PP: Breast cancer - loss of PTEN predicts resistance to treatment. N Engl J Med. 351:2337–2338. 2004. View Article : Google Scholar : PubMed/NCBI

30 

Jo M, Stolz DB, Esplen JE, Dorko K, Michalopoulos GK and Strom SC: Cross-talk between epidermal growth factor receptor and c-Met signal pathways in transformed cells. J Biol Chem. 275:8806–8811. 2000. View Article : Google Scholar : PubMed/NCBI

31 

Takeuchi H, Bilchik A, Saha S, et al: c-MET expression level in primary colon cancer: a predictor of tumor invasion and lymph node metastases. Clin Cancer Res. 9:1480–1488. 2003.

32 

Trusolino L and Comoglio PM: Scatter-factor and semaphorin receptors: cell signalling for invasive growth. Nat Rev Cancer. 2:289–300. 2002. View Article : Google Scholar : PubMed/NCBI

33 

Kiaris H and Spandidos DA: Mutations of ras genes in human tumours (Review). Int J Oncol. 7:413–421. 1995.

34 

Mao C, Huang YF, Yang ZY, Zheng DY, Chen JZ and Tang JL: KRAS p. G13D mutation and codon 12 mutations are not created equal in predicting clinical outcomes of cetuximab in metastatic colorectal cancer: A systematic review and meta-analysis. Cancer. 119:714–721. 2013. View Article : Google Scholar

35 

Strumberg D, Scheulen ME, Schultheis B, et al: Regorafenib (BAY 73-4506) in advanced colorectal cancer: a phase I study. Br J Cancer. 106:1722–1727. 2012. View Article : Google Scholar : PubMed/NCBI

36 

Van Cutsem E, Tabernero J, Lakomy R, et al: Addition of aflibercept to fluorouracil, leucovorin, and irinotecan improves survival in a phase III randomized trial in patients with metastatic colorectal cancer previously treated with an oxaliplatin-based regimen. J Clin Oncol. 30:3499–3506. 2012.

Related Articles

  • Abstract
  • View
  • Download
  • Twitter
Copy and paste a formatted citation
Spandidos Publications style
Kishiki T, Ohnishi H, Masaki T, Ohtsuka K, Ohkura Y, Furuse J, Sugiyama M and Watanabe T: Impact of genetic profiles on the efficacy of anti-EGFR antibodies in metastatic colorectal cancer with KRAS mutation. Oncol Rep 32: 57-64, 2014.
APA
Kishiki, T., Ohnishi, H., Masaki, T., Ohtsuka, K., Ohkura, Y., Furuse, J. ... Watanabe, T. (2014). Impact of genetic profiles on the efficacy of anti-EGFR antibodies in metastatic colorectal cancer with KRAS mutation. Oncology Reports, 32, 57-64. https://doi.org/10.3892/or.2014.3179
MLA
Kishiki, T., Ohnishi, H., Masaki, T., Ohtsuka, K., Ohkura, Y., Furuse, J., Sugiyama, M., Watanabe, T."Impact of genetic profiles on the efficacy of anti-EGFR antibodies in metastatic colorectal cancer with KRAS mutation". Oncology Reports 32.1 (2014): 57-64.
Chicago
Kishiki, T., Ohnishi, H., Masaki, T., Ohtsuka, K., Ohkura, Y., Furuse, J., Sugiyama, M., Watanabe, T."Impact of genetic profiles on the efficacy of anti-EGFR antibodies in metastatic colorectal cancer with KRAS mutation". Oncology Reports 32, no. 1 (2014): 57-64. https://doi.org/10.3892/or.2014.3179
Copy and paste a formatted citation
x
Spandidos Publications style
Kishiki T, Ohnishi H, Masaki T, Ohtsuka K, Ohkura Y, Furuse J, Sugiyama M and Watanabe T: Impact of genetic profiles on the efficacy of anti-EGFR antibodies in metastatic colorectal cancer with KRAS mutation. Oncol Rep 32: 57-64, 2014.
APA
Kishiki, T., Ohnishi, H., Masaki, T., Ohtsuka, K., Ohkura, Y., Furuse, J. ... Watanabe, T. (2014). Impact of genetic profiles on the efficacy of anti-EGFR antibodies in metastatic colorectal cancer with KRAS mutation. Oncology Reports, 32, 57-64. https://doi.org/10.3892/or.2014.3179
MLA
Kishiki, T., Ohnishi, H., Masaki, T., Ohtsuka, K., Ohkura, Y., Furuse, J., Sugiyama, M., Watanabe, T."Impact of genetic profiles on the efficacy of anti-EGFR antibodies in metastatic colorectal cancer with KRAS mutation". Oncology Reports 32.1 (2014): 57-64.
Chicago
Kishiki, T., Ohnishi, H., Masaki, T., Ohtsuka, K., Ohkura, Y., Furuse, J., Sugiyama, M., Watanabe, T."Impact of genetic profiles on the efficacy of anti-EGFR antibodies in metastatic colorectal cancer with KRAS mutation". Oncology Reports 32, no. 1 (2014): 57-64. https://doi.org/10.3892/or.2014.3179
Follow us
  • Twitter
  • LinkedIn
  • Facebook
About
  • Spandidos Publications
  • Careers
  • Cookie Policy
  • Privacy Policy
How can we help?
  • Help
  • Live Chat
  • Contact
  • Email to our Support Team