Co-expression of ERCC1 and Snail is a prognostic but not predictive factor of cisplatin-based neoadjuvant chemotherapy for bladder cancer

Abstract

Abstract. Neoadjuvant chemotherapy (NC) for bladder cancer has been reported to significantly improve the 5-year survival rate. The aim of the present study was to examine the roles of ERCC1 and Snail in determining the response to chemotherapy in bladder cancer treated with NC and radical cystectomy (RC). The expression of the Snail and ERCC1 proteins was determined by immunohistochemical staining of specimens obtained from 58 patients with bladder tumors treated with NC and RC. The correlation between clinical response and the expression of Snail and ERCC1 was investigated. Snail and ERCC1 were co-expressed in 24 (41.4%) of the 58 patients. A marked correlation was found between the expression of Snail and ERCC1 (P=0.001). The co-expression of Snail and ERCC1 was not able to predict pathological complete response (P=0.202). Results of the univariate analysis revealed that the co-expression of Snail and ERCC1 predicted shorter diseasefree survival (DFS) and overall survival (OS) than the negative expression of Snail and/or ERCC1. Moreover, the co-expression of ERCC1 and Snail was the only predictive factor for both DFS (P=0.029) and OS (P=0.040). The expression of Snail was correlated with that of ERCC1 and the co-expression of Snail and ERCC1 was the only significant predictive factor of shorter DFS and OS in patients with bladder cancer treated with NC and RC. IntroductionBladder cancer is the fourth most common cancer in males in the USA (1). For muscle-invasive bladder cancer, radical cystectomy (RC) and urinary diversion are the gold standard of therapy in many parts of the world (1-3). Neoadjuvant chemotherapy (NC) with cisplatin-based combination chemotherapy significantly improved the 5-year survival rate in two meta-analysis studies (4,5) and pathological complete response (pCR) with NC was correlated with survival (6,7). Although a number of studies have discussed factors which predict pCR or a favorable survival rate (8-10), none of the factors has been proven in a clinical study.The excision repair cross-complementing group 1 (ERCC1) gene is located on chromosome 19q13.2-q13.3. The ERCC1 protein is crucial in the nucleotide excision repair pathway (11,12). In a previous study, we reported that ERCC1 may predict the prognosis of chemoradiotherapy for bladder cancer and that it was correlated with radiation rather than cisplatin resistance in an in vitro study (13). A correlation between ERCC1 and bladder cancer has been reported (14-17), but whether ERCC1 is capable of predicting a favorable survival rate in patients with advanced bladder cancer treated with cisplatin-based chemotherapy is controversial.The endothelial-mesenchymal transition (EMT) is significant in invasive bladder cancer (18,19). Mesenchymal markers, including N-cadherin, Zeb1, Snail and Slug, suppress the expression of E-cadherin and are correlated with radiation and cisplatin resistance in numerous types of cancer (20)(21)(22). In their study, Hsu et al reported that Snail regulated the expression of ERCC1 and that the co-expressi...

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“…Third, we observed co-expression of Smad4, Snail and Ercc1 proteins in human skin SCCs and precancerous AKs. Similar expression patterns of Snail and Ercc1 have also been observed in head and neck cancer, and bladder cancer (Hsu et al , 2010; Kawashima et al , 2012). Thus, Snail regulated Ercc1 expression may occur broadly in human cancers.…”

Prognostic and Predictive Factors in Patients Treated with Chemotherapy for Advanced Urothelial Cancer: Where Do We Stand?

“…Moreover, the coexpression of Snail and ERCC1 seems to be associated with poor prognosis in head and neck tumors treated with cisplatinbased chemotherapy [79]. Similarly, the coexpression of Snail and ERCC1 in bladder cancer represents a significant predictive factor for OS and disease-free survival (DFS) in patients treated with cisplatin-based neoadjuvant chemotherapy and cystectomy [46].…”

Emerging concepts on drug resistance in bladder cancer: Implications for future strategies

“…Snail can regulate the expression of ERCC1, and their co-expression seems to be a significant predictive factor for OS and disease free survival (DFS) in patients treated with cisplatin-based neoadjuvant chemotherapy and cystectomy [38]. Therefore, EMT may represent a potential target to overcome the cisplatin resistance.…”