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Chakravarti A , Winter K , Wu CL , Kaufman D , Hammond E , Parliament M , Tester W , Hagan M , Grignon D , Heney N , Pollack A , Sandler H , Shipley W
Expression of the epidermal growth factor receptor and Her-2 are predictors of favorable outcome and reduced complete response rates, respectively, in patients with muscle-invading bladder cancers treated by concurrent radiation and cisplatin-based chemotherapy: A report from the Radiation Therapy Oncology Group
International Journal of Radiation Oncology Biology Physics. 2005 ;62(2) :309-317
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Abstract
Purpose: Erb-1 (epidermal growth factor receptor, EGFR) and Erb-2 (Her-2) are two of the best characterized members in the EGFR pathway. In many tumor types, overexpression of these proteins is associated with enhanced malignant potential. Our objective in this study was to investigate the clinical relevance of EGFR and Her-2 expression in bladder cancer cases from four prospective Radiation Therapy Oncology Group (RTOG) bladder preservation trials using cisplatin-containing chemoradiation (RTOG 8802, 8903, 9506, and 9706). Methods and Materials: Tumors from 73 cases from patients with muscle-invading T2-T4a bladder cancers had slides interpretable for EGFR staining; 55 cases had slides interpretable for Her-2 staining. Additionally, the respective prognostic values of p53, pRB, and p16 immunostaining were concomitantly examined. Staining and interpretation of staining were done in a blinded manner, without knowledge of clinical outcome. Staining was judged as positive or negative. Subsequently, staining was correlated with clinical outcome. Results: On univariate analysis, EGFR positivity was significantly associated with improved overall survival (p = 0.044); disease-specific survival (DSS) (p = 0.042); and DSS with intact bladder (p = 0.021). There was also a trend for association between EGFR expression and reduced frequency of distant metastasis (p = 0.06). On multivariate analysis adding tumor stage, tumor grade, whether a visibly complete transurethral resection of bladder tumor (TURBT) was done or not, and patient age to the model, EGFR positivity was significantly associated with improved DSS. On univariate analysis, Her-2 positivity was significantly associated with reduced complete response (CR) rates (50% vs. 81%, p = 0.026) after chemoradiation which remained significant on multivariate analysis. The other markers examined in this study were not found to have any prognostic value in this setting. Conclusion: Epidermal growth factor receptor expression appears to correlate significantly with improved outcome in bladder cancer, whereas Her-2 expression is significantly associated only with reduced CR rates after chemoradiation. Further investigations are warranted into how EGFR family members regulate response to chemoradiation in bladder cancer and their potential therapeutic implications. © 2005 Elsevier Inc.
Notes
03603016 (ISSN) Cited By: 1; Export Date: 25 May 2006; Source: Scopus CODEN: IOBPD; DOI: 10.1016/j.ijrobp.2004.09.047 Language of Original Document: English Correspondence Address: Chakravarti, A.; Massachusetts General Hospital; Department of Radiation Oncology; Founders House; 100 Blossom Street Boston, MA 02114, United States; email: achakravarti@partners.org Chemicals/CAS: cisplatin, 15663-27-1, 26035-31-4, 96081-74-2; epidermal growth factor receptor 2, 137632-09-8; fluorouracil, 51-21-8; methotrexate, 15475-56-6, 59-05-2, 7413-34-5; vinblastine, 865-21-4, Antineoplastic Agents; Cisplatin, 15663-27-1; Protein p16; Protein p53; Receptor, Epidermal Growth Factor, EC 2.7.1.112; Receptor, erbB-2, EC 2.7.1.112; Retinoblastoma Protein References: Baselga, J., Mendelsohn, J., The epidermal growth factor receptor as a target for therapy in breast carcinoma (1994) Breast Cancer Res Treat, 29, pp. 127-138; Baselga, J., The EGFR as a target for anticancer therapy--focus on cetuximab (2001) Eur J Cancer, 37 (4 SUPPL.), pp. 16-S22; Bianco, C., Bianco, R., Tortora, G., Antitumor activity of combined treatment of human cancer cells with ionizing radiation and anti-epidermal growth factor receptor monoclonal antibody C225 plus type I protein kinase a antisense oligonucleotide (2000) Clin Cancer Res, 6, pp. 4343-4350; Ciardielllo, F., Bianco, R., Damiano, V., Antitumor activity of sequential treatment with topotecan and anti-epidermal growth factor receptor monoclonal antibody C225 (1999) Clin Cancer Res, 5, pp. 909-916; Abdul-Manan, N., Aghazadeh, B., Liu, G.A., Structure of Cdc42 in complex with the GTPase-binding domain of the Wiskott-Aldrich syndrome' protein (1999) Nature, 399, pp. 379-383; Grandis, J.R., Chakraborty, A., Melhem, M.F., Inhibition of epidermal growth factor receptor gene expression and function decreases proliferation of head and neck squamous cell carcinoma but not normal mucosal epithelial cells (1997) Oncogene, 15, pp. 409-416; Esteller, M., Garcia-Foncillas, J., Andion, E., Inactivation of the DNA-repair gene MGMT and the clinical response of gliomas to alkylating agents (2000) N Engl J Med, 343, pp. 1350-1354; Hidalgo, A., Sanz-Rodriguez, F., Rodriguez-Fernandez, J.L., Chemokine stromal cell-derived factor-1alpha modulates VLA-4 integrin-dependent adhesion to fibronectin and VCAM-1 on bone marrow hematopoietic progenitor cells (2001) Exp Hematol, 29, pp. 345-355; Beenken, S.W., Sellers, M.T., Huang, P., Transforming growth factor alpha (TGF-alpha) expression in dysplastic oral leukoplakia: Modulation by 13-cis retinoic acid (1999) Head Neck, 21, pp. 566-573; Endo, S., Zeng, Q., Burke, N.A., TGF-alpha antisense gene therapy inhibits head and neck squamous cell carcinoma growth in vivo (2000) Gene Ther, 7, pp. 1906-1914; Milas, L., Mason, K., Hunter, N., In vivo enhancement of tumor radioresponse by C225 antiepidermal growth factor receptor antibody (2000) Clin Cancer Res, 6, pp. 701-708; Chakravarti, A., Chakladar, A., Delaney, M.A., The epidermal growth factor receptor pathway mediates resistance to sequential administration of radiation and chemotherapy in primary human glioblastoma cells in a ras-dependent manner (2002) Cancer Res, 62, pp. 4307-4315; Chakravarti, A., Loeffler, J.S., Dyson, N.J., 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 (2002) Cancer Res, 62, pp. 200-207; O'Rourke, D., Kao, G.D., Singh, N., Conversion of a radio-resistant phenotype to a more sensitive one by disabling erbB receptor signaling in human cancer cells (1998) Proc Natl Acad Sci USA, 95, pp. 10842-10847; Altiok, S., Batt, D., Altiok, N., Heregulin induces phosphorylation of BRCA1 through phosphatidylinositol 3-Kinase/AKT in breast cancer cells (1999) J Biol Chem, 274, pp. 32274-32278; Harari, P.M., Huang, S.-M., Combining EGFR inhibitors with radiation or chemotherapy: Will pre-clinical studies predict clinical results? 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