EGFR EXPRESSION IN RECTAL CANCER, RELATION TO THE FREAQUENCY OF LYMPH NODE METASTASIS

The processes of vital activity of cancer cells mainly depend on the production of growth factors and their receptors. The epidermal growth factor receptor (EGFR) is a member of the ErbB family of receptor tyrosine kinases. Normally, binding of EGFR ligands and transforming growth factor alpha (TGFα) induces receptor activation, which triggers erk and PI3K signaling pathways that control cell proliferation, migration, invasion and many other processes. A number of studies have shown that a high percentage of EGFR expression is observed in 25–82 % of cases with rectal cancer. Thus, the expression and mutation of the EGFR gene is associated with various variants of tumor progression and an unfavorable prognosis for malignant tumors of various localizations.

The purpose of the study was to investigate the EGFR expression in cancer tissue and evaluate the relationship between EGFR expression and parameters of lymphogenous metastasis in patients with rectal cancer. 

Material And Methods. Surgical specimens of 149 patients with stage T1–4N0–2M0_, rectal adenocarcinoma, who were treated at the Cancer Research Institute of Tomsk National Research Medical Center, were studied using histological and immunohistochemical analyses. Positive EGFR expression was found in 88 (59.1 %) patients. Diagnosis was made according to WHO classification (2010).

Results. When studying the EGFR expression in tumor cells on different depth of invasion, it was found that the positive expression of this marker was observed in cases with and without lymph node metastases. The analysis of the EGFR expression in various structures of the parenchymatous component of the tumor located in different layers of the intestinal wall showed that in the solid structures of the mucosa, the positive expression of EGFR was detected more often in cases without lymph node metastases. In patients with lymph node metastases, the percentage of the EGFR expression was lower.  A similar pattern was observed in discrete groups of tumor cells.

Conclusion. The study showed the presence of heterogeneity of the expression characteristics of the epidermal growth factor in various tumor structures located at different depths of infestation. The relationship between the parameters of lymphogenous metastasis and the positive EGFR expression indicates the prognostic significance of this marker.

1. Korytova L.I. Short-term results of combination therapy for locally recurrent rectal cancer. Problems in oncology. 2015; 61 (1): 52–56. [in Russian]

2. Lescut N., Lepinoy A., Schipman B., Cerda T., Guimas V., Bednarek C., Bosset J.F. Preoperative chemoradiotherapy for rectal cancer: experience from one centre. Cancer Radiother. 2015; 19 (2): 98–105. doi: 10.1016/j.canrad.2014.11.011.

3. Berdov B.А. Multimodality treatment of patients with locally advanced rectal cancer. Problems in oncology. 2014; 4: 497–503. [in Russian]

4. Han W., Lo H.W. Landscape of EGFR signaling network in human cancers: biology and herapeutic response in relation to receptor subcellular locations. Cancer Lett. 2012 May 28; 318 (2): 124–34. doi: 10.1016/j.canlet.2012.01.011.

5. Minder P., Zajac E., Quigley J.P., Deryugina E.I. EGFR Regulates the Development and Microarchitecture of Intratumoral Angiogenic Vasculature Capable of Sustaining Cancer Cell Intravasation. Neoplasia. 2015 Aug; 17 (8): 634–49. doi: 10.1016/j.neo.2015.08.002.

6. Citri A., Yarden Y. EGF-ERBB signalling: towards the systems level. Nat Rev Mol Cell Biol. 2006 Jul; 7 (7): 505–16.

7. Van Emburgh B.O., Sartore-Bianchi A., Di Nicolantonio F., Siena S., Bardelli A. Acquired resistance to EGFR-targeted therapies in colorectal cancer. Mol Oncol. 2014 Sep 12; 8 (6): 1084–94. doi: 10.1016/j.molonc.2014.05.003.

8. Jeong W.J., Cha P.H., Choi K.Y. Strategies to overcome resistance to epidermal growth factor receptor monoclonal antibody therapy in metastatic colorectal cancer. World J Gastroenterol. 2014 Aug 7; 20 (29): 9862–71. doi: 10.3748/wjg.v20.i29.9862.

9. Rego R.L., Foster N.R., Smyrk T.C., Le M., O’Connell M.J., Sargent D.J., Windschitl H., Sinicrope F.A. Prognostic effect of activated EGFR expression in human colon carcinomas: comparison with EGFR status. Br J Cancer. 2010 Jan 5; 102 (1): 165–72. doi: 10.1038/sj.bjc.6605473.

10. Giralt J., de las Heras M., Cerezo L., Eraso A., Hermosilla E., Velez D., Benavente S. The expression of epidermal growth factor receptor results in a worse prognosis for patients with rectal cancer treated with preoperative radiotherapy: a multicenter, retrospective analysis. Radiother Oncol. 2005 Feb; 74 (2): 101–8.

11. Ohashi K., Maruvka Y.E., Michor F., Pao W. Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor–Resistant Disease. J Clin Oncol. 2013 Mar 10; 31 (8): 1070–80. doi: 10.1200/JCO.2012.43.3912.

12. Richter I., Dvořák J., Urbanec M., Bluml A., Čermáková E., Bartoš J., Petera J. The prognostic significance of tumor epidermal growth factor receptor (EGFR) expression change after neoadjuvant chemoradiation in patients with rectal adenocarcinoma. Contemp Oncol (Pozn). 2015; 19 (1): 48–53. doi: 10.5114/wo.2015.50013.

13. Du C., Zhao J., Xue W., Dou F., Gu J. Prognostic value of microsatellite instability in sporadic locally advanced rectal cancer following neoadjuvant radiotherapy. Histopathology. 2013 Apr; 62 (5): 723–30. doi: 10.1111/his.12069.

14. McCollum A.D., Kocs D.M., Chadha P., Monticelli M.A., Boyd T.E., Fain J.D., Thummala A. Randomized phase II trial of preoperative chemoradiotherapy with or without cetuximab in locally advanced rectal adenocarcinoma. J. Clin. Oncol. 2014; 32 (suppl 3): abstr 537.

15. Ott K., Blank S., Becker K., Langer R., Weichert W., Roth W., Sisic L., Stange A., Jäger D., Büchler M., Siewert J.R., Lordick F. Factors predicting prognosis and recurrence in patients with esophago-gastric adenocarcinoma and histopathological response with less than 10% residual tumor. Langenbecks Arch Surg. 2013 Feb; 398 (2): 239–49. doi: 10.1007/s00423-012-1039-0.

16. Kim S.Y., Shim E.K., Yeo H.Y., Baek J.Y., Hong Y.S., Kim D.Y., Kim T.W., Kim J.H., Im S.A., Jung K.H., Chang H.J. KRAS mutation status and clinical outcome of preoperative chemoradiation with cetuximab in locally advanced rectal cancer: a pooled analysis of 2 phase II trials. Int J Radiat Oncol Biol Phys. 2013 Jan 1; 85 (1): 201–7. doi: 10.1016/j.ijrobp.2012.03.048.

17. Kurt A., Yanar F., Asoglu O., Balik E., Olgac V., Karanlik H., Kucuk S.T., Ademoglu E., Yegen G., Bugra D. Low Mmp 9 and VEGF levels predict good oncologic outcome in mid and low rectal cancer patients with neoadjuvant Chemoradiation. BMC Clin Pathol. 2012 Dec 31; 12: 27. doi: 10.1186/1472-6890-12-27.

18. Yasuda H., Tanaka K., Saigusa S., Toiyama Y., Koike Y., Okugawa Y., Kusunoki M. Elevated CD133, but not VEGF or EGFR, as a predictive marker of distant recurrence after preoperative chemoradiotherapy in rectal cancer. Oncol Rep. 2009 Oct; 22 (4): 709–17.

19. Hainsworth J.D., Waterhouse D.M., Penley W.C., Shipley D.L., Thompson D.S., Webb C.D., Anthony Greco F. Sorafenib and everolimus in advanced clear cell renal carcinoma: a phase I/II trial of the SCRI Oncology Research Consortium. Cancer Invest. 2013 Jun; 31 (5): 323–9. doi: 10.3109/07357907.2013.789900.

20. Ng K., Tabernero J., Hwang J., Bajetta E., Sharma S., Del Prete S.A., Arrowsmith E.R., Ryan D.P., Sedova M., Jin J., Malek K., Fuchs C.S. Phase II study of everolimus in patients with metastatic colorectal adenocarcinoma previously treated with bevacizumab-, fluoropyrimidine-, oxaliplatin-, and irinotecan-based regimens. Clin Cancer Res. 2013; 19: 3987–3995.

21. Bardelli A., Siena S. Molecular mechanisms of resistance to cetuximab and panitumumab in colorectal cancer. J Clin Oncol. 2010 Mar 1; 28 (7): 1254–61. doi: 10.1200/JCO.2009.24.6116.

22. Van Cutsem E., Köhne C.H., Láng I., Folprecht G., Nowacki M.P., Cascinu S., Shchepotin I., Maurel J., Cunningham D., Tejpar S., Schlichting M., Zubel A., Celik I., Rougier P., Ciardiello F. Cetuximab plus irinotecan, fluorouracil, and leucovorin as first-line treatment for metastatic colorectal cancer: updated analysis of overall survival according to tumor KRAS and BRAF mutation status. J Clin Oncol. 2011 May 20; 29 (15): 2011–9. doi: 10.1200/JCO.2010.33.5091.

23. Usova A.V., Frolova I.G., Afanasyev S.G., Tarasova A.S. Potential role of magnetic resonance imaging in diadnosis and assessment of treatment response in patients with rectal cancer. Siberian Journal of Oncology. 2012; 5: 74–80. [in Russian]