Skip to main content

Advertisement

SpringerLink
Log in

EGFR Protein Expression of KRAS Wild-Type Colorectal Cancer: Predictive Value of the Sidedness for Efficacy of Anti-EGFR Therapy

  • Original Article
  • Published:
Pathology & Oncology Research

Abstract

Right- and left-sided colorectal cancers (RSCRC and LSCRC, respectively) are different developmentally, genetically and prognostically. Clinical data also indicate that they respond differently to anti-EGFR therapies. The role of EGFR protein expression in KRAS wild type colorectal cancer is also controversial. Here we have used a cohort of anti-EGFR antibody treated KRAS-wild type colorectal cancer patients (n = 97) to analyse the prognostic role of EGFR protein expression in relation to sidedness. In our cohort EGFR copy number, determined by FISH, was not associated with the level of EGFR protein, assessed by immunohistochemistry and measured by H-scoring. There was a significantly higher EGFR H-score detected in RSCRC as compared to LSCRC in primary tumors (p = 0.04). Furthermore, in a proportion of cases (n = 31) metastatic tissues were also available and their analysis also found a significantly higher EGFR H-score in metastases of RSCRC compared to LSCRC (p = 0.018). Kaplan Meyer survival analysis demonstrated that anti-EGFR antibody therapies were more effective in case of LSCRC compared to RSCRC. Although in case of progression-free survival data just indicated a trend (p = 0.065), in case of overall survival the difference was significant favouring LSCRC (p = 0.047). These data demonstrated for the first time that the EGFR protein expression is significantly higher in KRAS wild type RSLCL as compared to LSCRC. Meanwhile it is somewhat unexpected that the lower EGFR protein expression was found to be associated with better efficacy of anti-EGFR antibody therapies of colorectal cancer, the finding of which must be further validated.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Petrelli F, Tomasello G, Borgonovo K, Ghidini M, Turati L, Dallera P, Passalacqua R, Sgroi G, Barni S (2017) Prognostic survival associated with left-sided vs right-sided colon cancer: a systematic review and meta-analysis. JAMA Oncol 3:211–219

    Article  Google Scholar 

  2. Warschkow R, Sulz MC, Marti L, Tarantino I, Schmied BM, Cerny T, Güller U (2016) Better survival in right-sided versus left-sided stage I - III colon cancer patients. BMC Cancer 16:554

    Article  Google Scholar 

  3. Baran B, Ozupek NM, Tetik YN, Acar E, Bekcioglu O, Baskin Y (2018) Difference between left-sided and right-sided colorectal cancer: a focused review of literature. Gastroenterol Res 11:264–273

    Article  CAS  Google Scholar 

  4. Loree JM, Pereira AAL, Lam M, Willauer AN, Raghav K, Dasari A, Morris VK, Advani S, Menter DG, Eng C, Shaw K, Broaddus R, Routbort MJ, Liu Y, Morris JS, Luthra R, Meric-Bernstam F, Overman MJ, Maru D, Kopetz S (2018) Classifying colorectal cancer by tumor location rather than sidedness highlights a continuum in mutation profiles and consensus molecular subtypes. Clin Cancer Res 24:1062–1072

    Article  CAS  Google Scholar 

  5. Dienstmann R, Vermeulen L, Guinney J, Kopetz S, Tejpar S, Tabernero J (2017) Consensus molecular subtypes and the evolution of precision medicine in colorectal cancer. Nat Rev Cancer 17:79–92

    Article  CAS  Google Scholar 

  6. Tejpar S, Stintzing S, Ciardiello F, Tabernero J, van Cutsem E, Beier F, Esser R, Lenz HJ, Heinemann V (2017) Prognostic and predictive relevance of primary tumor location in patients with RAS wild-type metastatic colorectal cancer: retrospective analyses of the CRYSTAL and FIRE-3 trials. JAMA Oncol 3:194–201

    Article  Google Scholar 

  7. Brule SY, Jonker DJ, Karapetis CS et al (2015) Location of colon cancer (right-sided versus left-sided) as a prognostic factor and a predictor of benefit from cetuximab in NCIC CO.17. Eur J Cancer 51:1405–1414

    Article  CAS  Google Scholar 

  8. Li D, Fu Q, Li M, Yin C, Zhao J, Li F (2017) Primary tumor site and anti-EGFR monoclonal antibody benefit in metastatic colorectal cancer: a meta-analysis. Future Oncol 13:1115–1127

    Article  CAS  Google Scholar 

  9. Cao DD, Xu HL, Xu XM, Ge W (2017) The impact of primary tumor location on efficacy of cetuximab in metastatic colorectal cancer patients with different KRAS status: a systematic review and meta-analysis. Oncotarget 8:53631–53641

    Article  Google Scholar 

  10. Salem ME, Weinberg BA, Xiu J et al (2017) Comparative molecular analyses of left-sided colon, right-sided colon, and rectal cancers. Oncotarget 8:86356–86368

    Article  Google Scholar 

  11. Cserepes M, Gy O, Lohinai Z et al (2014) Subtype-specific KRAS mutations in advanced lung adenocarcinoma: a retrospective study of patients treated with platinum-based chemotherapy. Eur J Cancer 50:1819–1828

    Article  CAS  Google Scholar 

  12. Hirsch FR, Varella-Garcia M, Bunn PA et al (2003) Epidermal growth factor receptor in nonsmall-cell lung carcinomas: correlation between gene copy number and protein expression and impact on prognosis. J Clin Oncol 21:3798–3807

    Article  CAS  Google Scholar 

  13. Snyder M, Bottiglieri S, Almhanna K (2018) Impact of primary tumor location on first-line bevacizumab or cetuximab in metastatic colorectal cancer. Rev Recent Clin Trials 13:139–149

    Article  CAS  Google Scholar 

  14. Yang Z-Y, Shen W-X, Hu X-F, Zheng DY, Wu XY, Huang YF, Chen JZ, Mao C, Tang JL (2012) EGFR gene copy number as a predictive biomarker for the treatment of metastatic colorectal cancer with anti-EGFR monoclonal antibodies: a meta-analysis. J Hematol Oncol 5:52–62

    Article  CAS  Google Scholar 

  15. Hecht JR, Mitchell E, Neubauer MA, Burris HA, Swanson P, Lopez T, Buchanan G, Reiner M, Gansert J, Berlin J (2010) Lack of correlation between epidermal growth factor receptor status and response to Panitumumab monotherapy in metastatic colorectal cancer. Clin Cancer Res 16:2205–2213

    Article  CAS  Google Scholar 

  16. Licitra L, Störkel S, Kerr KM, van Cutsem E, Pirker R, Hirsch FR, Vermorken JB, von Heydebreck A, Esser R, Celik I, Ciardiello F (2013) Predicitive value of epidermal growth factor receptor expression for first-line chenmotherapy plus cetuximab in patients with head and neck and colorectal cancer: analysis of data from the EXTREME and CRYSTAL studies. Eur J Cancer 49:1161–1168

    Article  CAS  Google Scholar 

  17. Chung KY, Shia J, Kemeny NE, Shah M, Schwartz GK, Tse A, Hamilton A, Pan D, Schrag D, Schwartz L, Klimstra DS, Fridman D, Kelsen DP, Saltz LB (2005) Cetuximab shows activity in colorectal cancer patients with tumors that do not express the epidermal growth factor receptor by immunohistochemistry. J Clin Oncol 23:1803–1810

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by MKOT (AU), NKFIH K-116151 (JT) and NVKP-16-1-2016-0004.

Author information

Authors and Affiliations

  1. Department of Oncology, Medical Center, Hungarian Defence Forces, Budapest, Hungary

    A. Uhlyarik, Zs Pápai, E. Lahm, E. Kiss, M. Sikter & J. Vachaja

  2. 2nd Department of Pathology, Semmelweis University, 93 Üllöi str, Budapest, 1091, Hungary

    V. Piurko, L. Vizkeleti, E. Rásó, I. Kenessey & József Tímár

Authors
  1. A. Uhlyarik
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. V. Piurko
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. L. Vizkeleti
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Zs Pápai
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. E. Rásó
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. E. Lahm
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. E. Kiss
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. M. Sikter
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. J. Vachaja
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. I. Kenessey
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. József Tímár
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to József Tímár.

Ethics declarations

Conflict of Interest

The authors do not report any conflict of interest concerning this manuscript.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Uhlyarik, A., Piurko, V., Vizkeleti, L. et al. EGFR Protein Expression of KRAS Wild-Type Colorectal Cancer: Predictive Value of the Sidedness for Efficacy of Anti-EGFR Therapy. Pathol. Oncol. Res. 26, 1429–1434 (2020). https://doi.org/10.1007/s12253-018-00572-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12253-018-00572-2

Keywords

Search

Navigation