Objectives: The present study evaluated the prognostic implications of insulin-like growth factor-1 receptor (IGF-1R), epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor (HER)-2 in patients with colorectal cancer (CRC). Methods: Our subjects were 91 patients who underwent surgery and subsequently received fluoropyrimidines. Expressions of IGF-1R, EGFR and HER-2 in primary lesions were analyzed immunohistochemically to determine the prognostic significance of these biomarkers. Results: Overexpression was found for IGF-1R in 48 tumors (53%), EGFR in 57 (63%) and HER-2 in 2 (2%). Overexpression of IGF-1R was significantly correlated with shorter survival from the start of first-line chemotherapy (p = 0.033). Overexpression of EGFR was a significant predictor of clinical response to fluoropyrimidines (p = 0.032). Multivariate analysis of potential prognostic factors showed that IGF-1R expression and worsened performance status were independent predictors of poor outcomes. Conclusions: Our results suggest that anti-IGF-1R strategies may offer a useful approach in molecular therapy for CRC, which has the potential to improve outcomes.

Keywords:
Insulin-like growth factor-1 receptor, Epidermal growth factor receptor, Colorectal cancer
1.
Editorial Board of Cancer Statistics in Japan: Cancer Statistics in Japan 2005 (in Japanese). Tokyo, Foundation for Promotion of Cancer Research, 2005.
2.
LeRoith D, Roberts CT Jr: The insulin-like growth factor system and cancer. Cancer Lett 2003;195:127–137.
3.
Baselga J, Arteaga CL: Clinical update and emerging trends in epidermal growth factor receptor targeting in cancer. J Clin Oncol 2005;23:2445–2459.
4.
Nielsen TO, Andrews HN, Cheang M, et al: Expression of the insulin-like growth factor-I receptor and urokinase plasminogen activator in breast cancer is associated with poor survival: potential for intervention with 17-allylamino geldanamysin. Cancer Res 2004;64:286–291.
5.
Railo MJ, von Smitten K, Pekonen F: The prognostic value of insulin-like growth factor receptor-I in breast cancer patients: results of a follow-up study on 126 patients. Eur J Cancer 1994;30A:307–311.
6.
Mitsiades CS, Mitsiades NS, McMullan CJ, et al: Inhibition of the insulin-like growth factor receptor-1 tyrosine kinase activity as a therapeutic strategy for multiple myeloma, other hematologic malignancies, and solid tumors. Cancer Cell 2004;5:221–230.
7.
Hailey J, Maxwell E, Koukouras K, Bishop WR, Pachter JA, Wang Y: Neutralizing anti-insulin-like growth factor receptor 1 antibodies inhibit receptor function and induce receptor degradation in tumor cells. Mol Cancer Ther 2002;1:1349–1353.
8.
Vallböhmer D, Iqbal S, Yang DY, et al: Molecular determinants of irinotecan efficacy. Int J Cancer 2006;119:2435–2442.
9.
Takaoka M, Harada H, Andl CD, et al: Epidermal growth factor receptor regulates aberrant expression of insulin-like growth factor-binding protein 3. Cancer Res 2004;64:7711–7723.
10.
Caminard A, Lu Y, Pollak M: Co-targeting HER-2/ErbB2 and insulin-like growth factor-I receptors causes synergistic inhibition of growth on HER-2 overexpressing breast cancer cells. Med Sci Monit 2002;8:521–526.
11.
Goetsch L, Gonzalez A, Leger O, et al: A recombinant humanized anti-insulin-like growth factor receptor type I antibody (h7C10) enhances the antitumor activity of vinorelbine and anti-epidermal growth factor receptor therapy against human cancer xenografts. Int J Cancer 2005;113:316–328.
12.
Cohen BD, Baker BA, Soderstrom C, et al: Combination therapy enhances the inhibition of tumor growth with the fully human anti-type 1 insulin-like growth factor receptor monoclonal antibody CP-751,871. Clin Cancer Res 2005;11:2063–2073.
13.
Higano C, Yu E, Whiting S, et al: A phase I, first in man study of weekly IMC-A12, a fully human insulin like growth factor-I receptor IgG1 monoclonal antibody, in patients with advanced solid tumors. J Clin Oncol 2007, ASCO Annu Meet Proc 2007;25:3505.
14.
Ryan CJ, Haqq CM, Simko J, et al: Expression of insulin-like growth factor-1 receptor in local and metastatic prostate cancer. Urol Oncol 2007;25:134–140.
15.
de Alava E, Panizo A, Antonescu CR, et al: Association of EWS-FLI1 type 1 fusion with lower proliferative rate in Ewing’s sarcoma. Am J Pathol 2000;156:849–855.
16.
Burrow S, Andrulis IL, Pollak M, Bell RS: Expression of insulin-like growth factor receptor, IGF-1, and IGF-2 in primary and metastatic osteosarcoma. J Surg Oncol 1998;69:21–27.
17.
Chng WJ, Gualberto A, Fonseca R: IGF-1R is overexpressed in poor-prognostic subtypes of multiple myeloma. Leukemia 2006;20:174–176.
18.
Cunningham MP, Essapen S, Thomas H, et al: Coexpression of the IGF-1R, EGFR and HER-2 is common in colorectal cancer patients. Int J Oncol 2006;28:329–335.
19.
Koda M, Reszec J, Sulkowska M, Kanczuga-Koda L, Sulkowski S: Expression of insulin-like growth factor-I receptor and proadoptotic Bax and Bak proteins in human colorectal cancer. Ann NY Acad Sci 2004;1030:377–383.
20.
Peters G, Gongoll S, Langer C, et al: IGF-1R, IGF-1 and IGF-2 expression as potential prognostic and predictive markers in colorectal-cancer. Virchows Arch 2003;443:139–145.
21.
Goldstein NS, Armin M: Epidermal growth factor receptor immunohistochemical reactivity in patients with American Joint Committee on cancer stage IV colon adenocarcinoma. Cancer 2001;92:1331–1346.
22.
McKay JA, Murray LJ, Curran S, et al: Evaluation of the epidermal growth factor receptor (EGFR) in colorectal tumors and lymph node metastasis. Eur J Cancer 2002;38:2258–2264.
23.
Spano JP, Lagorce C, Atlan D, et al: Impact of EGFR expression on colorectal cancer patient prognosis and survival. Ann Oncol 2005;16:102–108.
24.
Barber TD, Vogelstein B, Kinzler KW, Velculescu VE: Somatic mutations of EGFR in colorectal cancers and glioblastomas. N Engl J Med 2004;351:2883.
25.
Lièvre A, Bachet JB, Boige V, et al: KRAS mutations as an independent prognostic factor in patients with advanced colorectal cancer treated with cetuximab. J Clin Oncol 2008;26:374–379.
26.
Khambata-Ford S, Garrett CR, Meropol NJ, et al: Expression of epiregulin and amphiregulin and K-ras mutation status predict disease control in metastatic colorectal cancer patients treated with cetuximab. J Clin Oncol 2007;25:3230–3237.
27.
Schuell B, Gruenberger T, Scheithauer W, Zielinski Ch, Wrba F: Her-2/neu protein expression in colorectal cancer. BMC Cancer 2006;6:123.
28.
Chakravarti A, Loeffler JS, Dyson NJ: Insulin-like growth factor receptor I mediates resistance to anti-epidermal growth factor receptor therapy in primary human glioblastoma cells through continued activation of phosphoinositide 3-kinase signaling. Cancer Res 2002;62:200–207.
29.
Adams TE, McKern NM, Ward CW: Signaling by the type I insulin-like growth factor receptor: interplay with the epidermal growth factor receptor. Growth Factors 2004;22:89–95.
30.
Lu Y, Zi X, Zhao Y, Mascarenhas D, Pollak M: Insulin-like growth factor-I receptor signaling and resistance to Trastuzumab (Herceptin). J Natl Cancer Inst 2001;93:1852–1857.
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2008
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