Gül KANYILMAZ, Meryem AKTAN, Mehmet KOÇ, Sümeyye KOZACIOĞLU, Berrin BENLİ YAVUZ

Prognostic importance of PTEN, EGFR, HER-2, and IGF-1R in gastric cancer patients treated with postoperative chemoradiation

Background/aim: This study aimed to describe the prognostic importance of epidermal growth factor (EGFR), phosphatase and tensinhomolog (PTEN), human EGF receptor-2 (HER-2), and insulin-like growth factor 1 receptor (IGF-1R) in gastric cancer patients treatedwith postoperative chemoradiation therapy.Materials and methods: Sixty-nine patients treated with adjuvant chemoradiation therapy were retrospectively evaluated. Tumorsamples were stained immunohistochemically.Results: All patients were treated with 3D conformal radiation therapy with concomitant and adjuvant chemotherapy. Perineuralinvasion (PNI) (P = 0.042), prechemoradiation therapy albumin levels below 3.5 mg/dL (P = 0.011), and EGFR positivity (P = 0.008) hadnegative effects on overall survival (OS). The median OS was 26 months for patients with PNI (+), 34.9 months for those with PNI (–),19.5 months for those with albumin levels below 3.5 mg/dL, and 33.2 months for those with albumin levels above 3.5 mg/dL. IGF-1R (+)(P = 0.035) and history of cigarette smoking (P = 0.033) were observed to have a statistically significantly negative effect on disease-freesurvival (DFS). The median DFS was 29.2 months for IGF-1R (+) patients, 37.9 months for those with IGF-1R (-), and 26.3 and 40.59months for smokers and nonsmokers, respectively.Conclusion: IGF-1R and EGFR may be used for patient selection in future prospective studies that evaluate the prognostic importanceof these receptors.

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1. Terashima M, Kitada K, Ochiai A, Ichikawa W, Kurahashi I et al. Impact of expression of human epidermal growth factor receptors EGFR and ERBB2 on survival in stage II/III gastric cancer. Clinical Cancer Research 2012; 18 (21): 5992-6000. doi: 10.1158/1078-0432.CCR-12-1318
2. Gunderson L, Tepper J. Clinical Radiation Oncology. 4th ed. Philadelphia, PA, USA: Elsevier; 2016.
3. Kim TH, Park SR, Ryu KW, Kim YW, Bae JM et al. Phase 3 trial of postoperative chemotherapy alone versus chemoradiation therapy in stage III-IV gastric cancer treated with R0 gastrectomy and D2 lymph node dissection. International Journal of Radiation Oncology Biology Physics 2012; 84 (5): 585-592. doi: 10.1016/j.ijrobp.2012.07.2378
4. Macdonald JS, Smalley SR, Benedetti J, Hundahl SA, Estes NC et al. Chemotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophageal junction. New England Journal of Medicine 2001; 345 (10): 725-730. doi:10.1056/NEJMoa010187
5. Brady LW, Heilmann HP, Molls M, Nieder C. Radiation Oncology: An Evidence-Based Approach. Berlin, Germany: Springer; 2008.
6. Atmaca A, Werner D, Pauliqk C, Steinmetz K, Wirtz R et al. The prognostic impact of epidermal growth factor receptor in patients with metastatic gastric cancer. BMC Cancer 2012; 12: 524. doi: 10.1186/1471-2407-12-524
7. Oh HS, Eom DW, Kang GH, Ahn YC, Lee SJ et al. Prognostic implications of EGFR and HER-2 alteration assessed by immunohistochemistry and silver in situ hybridization in gastric cancer patients following curative resection. Gastric Cancer 2014; 17 (3): 402-411. doi: 10.1007/s10120-013-0288-0
8. Pathmanathan N, Geng JS, Li W, Nie X, Veleso J et al. Human epidermal growth factor receptor 2 status of gastric cancer patients in Asia: results from a large, multicountry study. AsiaPacific Journal of Clinical Oncology 2017; 13 (3): 249-260. doi: 10.1111/ajco.12653
9. Boku N. HER2–positive gastric cancer. Gastric Cancer 2014; 17 (1): 1-12. doi: 10.1007/s10120-013-0252-z
10. Bang YJ, Van Cutsem E, Feyereislova A, Chung HC, Shen L et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER-2 positive advanced gastric or gastrooesophageal junction cancer (TOGA): a phase 3, open-label, randomized controlled trial. Lancet 2010; 376 (9742): 687-697. doi: 10.1016/S0140-6736(10)61121-X
11. Matsubara J, Yamada Y, Hirashima Y, Takahari D, Okita NT et al. Impact of insulin-like growth factor type 1-receptor, epidermal growth factor receptor, and HER-2 expression on outcomes of patients with gastric cancer. Clinical Cancer Research 2008; 14 (10): 3022-3029. doi: 10.1158/1078-0432. CCR-07-1898
12. Zhang B, Zhang X, Jin M, Hu L, Zang M et al. CagA increases DNA methylation and decreases PTEN expression in human gastric cancer. Molecular Medicine Reports 2019; 19 (1): 309- 319. doi: 10.3892/mmr.2018.9654
13. Xu WT, Yang Z, Lu NH. Roles of PTEN (phosphatase and tensin homolog) in gastric cancer development and progression. Asian Pacific Journal of Cancer Prevention 2014;15 (1): 17-24. doi: 10.7314/APJCP.2014.15.1.17
14. Li Y, Cui J, Zhang CH, Yang DJ, Chen JH et al. High-expression of DJ-1 and loss of PTEN associated with tumor metastasis and correlated with poor prognosis of gastric carcinoma. International Journal of Medical Sciences 2013; 10 (12): 1689- 1697. doi: 10.7150/ijms.7292
15. Shimizu C, Hasegawa T, Tani Y, Takahashi F, Takeuchi M et al. Expression of insulin–like growth factor 1 receptor in primary breast cancer: Immunohistochemical analysis. Human Pathology 2004; 35 (12): 1537-1542. doi: 10.1016/j. humpath.2004.09.005
16. Gu MJ, Bae YK, Choi JH. Clinical significance of insulingrowth factor 1 and insulin-growth factor 1 receptor expression in gastrointestinal stromal tumors. Hepatogastroenterology 2013; 60 (126): 1383-1386. doi: 10.5754/hge13102
17. Deng J, You Q, Gao Y, Yu Q, Zhao P et al. Prognostic value of perineural invasion in gastric cancer: a systematic review and meta-analysis. PLoS One 2014; 9 (2): e88907. doi: 10.1371/ journal.pone.0088907
18. Matsubara J, Yamada Y, Nakajima TE, Kato K, Hamaguchi T et al. Clinical significance of insulin-like growth factor type-1 receptor and epidermal growth factor receptor in patients with advanced gastric cancer. Oncology 2008; 74 (1-2): 76-83. doi: 10.1159/000139127
19.
20. Inokuchi M, Murayama T, Hayashi M, Takagi Y, Kato K et al. Prognostic value of co-expression of STAT3, mTOR and EGFR in gastric cancer. Experimental and Therapeutic Medicine 2011; 2 (2): 251-256. doi: 10.3892/etm.2011.187
21. Zhang L, Yang J, Cai J, Song X, Deng J et al. A subset of gastric cancers with EGFR amplification and overexpression respond to cetuximab therapy. Scientific Reports 2013; 3: 2992. doi: 10.1038/srep02992
22. Lordick F, Kang YK, Chung HC, Salman P, Oh SC et al. Capecitabine and cisplatin with or without cetuximab for patients with previously untreated advanced gastric cancer (EXPAND): a randomised, open-label phase 3 trial. Lancet Oncology 2013; 14 (6): 490-499. doi: 10.1016/S1470- 2045(13)70102-5
23. Waddell T, Chau L, Cunningham D. Epirubicin, oxaliplatin and capecitabine with or without panitumumab for patients with previously untreated advanced oesophagogastric cancer (REAL-3), a randomised, open-label phase 3 trial. Lancet Oncology 2013; 14 (6): 481-489. doi: 10.1016/S1470- 2045(13)70096-2
24. Igbal N, Igbal N. Human epidermal growth factor receptor 2 (HER2) in cancers: overexpression and therapeutic implications. Molecular Biology International 2014; 2014: 852748. doi: 10.1155/2014/852748
25. Costa LB, d Farias LSD, d’Ávila NG, Araujo-Neto I, Pinheiro FI et al. Gastric cancer: biological markers as prognostic factor. Advanced Research in Gastroenterology & Hepatology 2018; 8 (4): 555745. doi: 10.19080/ARGH.2018.08.555745
26. Zhu X, Qin X, Fei M, Hou W, Greshock J et al. Loss and reduced expression of PTEN correlate with advanced-stage gastric carcinoma. Experimental and Therapeutic Medicine 2013; 5 (1): 57-64. doi: 10.382/etm.2012.749
27. Pasupathi P, Pichandi S, Subramaniyam B, Thimoolam A, Ponnusha B et al. Chronic tobacco smoking and gastric cancer: a review. International Journal of Current Biomedical and Pharmaceutical Research 2011; 1 (2): 48-66.
28. Han MA, Kim YW, Choi IJ, Oh MG, Kim CG et al. Association of smoking history with cancer recurrence and survival in stage III-IV male gastric cancer patients. Cancer Epidemiology, Biomarkers & Prevention 2013; 22 (10): 1805-1812. doi: 10.1158/1055-9965.EPI-13-0385
29. Rota M, Pelucchi C, Bertuccio P, Matsuo K, Zhang ZF et al. Alcohol consumption and gastric cancer risk – a pooled analysis within the StoP project consortium. International Journal of Cancer 2017; 141 (10): 1950-1962. doi: 10.1002/ ijc.30891
30. Zhou ZH, Xu GF, Zhang WJ, Zhao HB, Wu YY. Reevaluating significance of perineural invasion in gastric cancer based on double immunohistochemical staining. Archives of Pathology & Laboratory Medicine 2014; 138 (2): 229-233. doi: 10.5858/ arpa.2012-0669-OA
31. Duraker N, Sişman S, Can G. The significance of perineural invasion as a prognostic factor in patients with gastric carcinoma. Surgery Today 2003; 33 (2): 95-100. doi: 10.1007/ s005950300020
32. Bilici A, Seker M, Ustaalioglu BB, Kefeli U, Yildirim E et al. Prognostic significance of perineural invasion in patients with gastric cancer who underwent curative resection. Annals of Surgical Oncology 2010; 17 (8): 2037-2044. doi: 10.1245/ s10434-010-1027-y