Excision Repair Cross-Complementing Group 1 May Predict the Efficacy of Chemoradiation Therapy for Muscle-Invasive Bladder Cancer

Abstract

Purpose: Chemoradiation therapy (CRT) is now widely recognized as bladder-preserving therapy for muscle-invasive bladder cancer (MIBC). However, some patients who fail CRT may miss the chance to be cured by cystectomy. Therefore, it is important to select patients with MIBC who are expected to have a good response to CRT. Several reports indicate that the excision repair cross-complementing group 1 (ERCC1) gene is associated with resistance to cisplatin and radiation therapy. In this study, we examined the correlation between ERCC1 and CRT in vitro and in vivo in bladder cancer.Experimental Design: Bladder cancer cell lines T24, 5637, Cl8-2 (multidrug-resistant subline of T24), and CDDP10-3 (cisplatin-resistant subline of T24) were used for in vitro assays to measure ERCC1 expression level and growth inhibition with cisplatin or ionizing radiation (IR). We then examined by immunohistochemistry that whether ERCC1 nuclear staining correlates with the efficacy of CRT using cisplatin in 22 patients with MIBC.Results: Cl8-2 cells expressed ERCC1 mRNA 5.96-fold higher than did T24. Cl8-2 and CDDP10-3 were more resistant to cisplatin or IR than was T24. Resistance to IR, but not to cisplatin, was removed by suppressing ERCC1 using siRNA in both Cl8-2 and CDDP10-3 cells. In immunohistochemistry with ERCC1, 6 of 8 positive cases did not have complete response to CRT, whereas 12 of 14 negative cases had complete response. Sensitivity and specificity were 75% and 85.7%, respectively (P ¼ 0.008).Conclusion: Although further study is needed, ERCC1 expression level may predict the efficacy of CRT for MIBC.

Expression of ribonucleoside reductase subunit M1, but not excision repair cross-complementation group 1, is predictive in muscle-invasive bladder cancer treated with chemotherapy and radiation

“…There are several available clinical and preclinical studies on the association of ERCC1 expression with resistance to platinum agents (11,12,17,(27)(28)(29) and radiosensitivity (15,18,30). The ERCC1 gene has 10 exons and generates 4 isoforms by alternative splicing; however, only 1 of these 4 isoforms is actively involved in the repair of platinum-DNA adducts.…”

“…Kawashima et al (15) previously evaluated ERCC1 expression in a small and heterogeneous group of 22 patients treated with radiation and platinum agents. To the best of our knowledge, our study is the first to evaluate RRM1 expression in patients undergoing chemoradiotherapy.…”

“…Excision repair cross-complementation group 1 (ERCC1) is a key part of the nucleotide-excision repair pathway that removes platinum-DNA adducts and counteracts the cytotoxic effects of platinum agents (12). ERCC1 expression was reported to confer resistance to platinum derivatives and has been evaluated as a predictive and prognostic marker in various tumors, where platinum is the cornerstone of chemotherapy (12)(13)(14)(15)(16)(17). ERCC1 was also implicated in repairing DNA double-strand breaks and conferring resistance to ionizing radiation, which may help identify the patients that are most suitable to undergo radical cystectomy compared to trimodality therapy (15,18).…”

Meta-analysis of Excision Repair Cross-complementation Group 1 (ERCC1) Association with Response to Platinum-based Chemotherapy in Ovarian Cancer

“…The similar mete-analysis was performed by Chen and the same conclusion was gained (Chen et al, 2010). In addition, many papers evaluated the relation between ERCC1 status and response to chemotherapy have been reported in various human cancers including Colorectal Cancer, bladder cancer, cervical cancer, Head and Neck Cancer, and most of studies showed ERCC1 expression was a predictor of response to chemotherapy (Handra-Luca et al, 2007;Braun et al, 2008;Kim et al, 2009;Ishibashi et al, 2010;Kim et al, 2010;Hayes et al, 2011;Kawashima et al, 2011;Park et al, 2011;Sun et al, 2012). In 2008, Lin et al performed a cohort study to evaluate the difference of ERCC1 protein expression levels between 36 sensitive cases and 27 resistant cases of serous ovarian cancer receiving neoadjuvant chemotherapy and demonstrated that ERCC1 protein expression levels in resistance group of serous ovarian cancer were significantly higher than those of sensitivity group, and Lin et al's study was in accordance with our meta-analysis (Lin et al, 2008).…”

“…In fact, much clinical studies also showed that negative/low expression of ERCC1 was associated with good response to chemotherapy. Among these clinical studies, a great deal of them have been conducted and focused on ERCC1 expression and response to chemotherapy in lung cancer patients (Ren et al, 2010;Wang et al, 2010;Hayes et al, 2011;Joerger et al, 2011;Kawashima et al, 2011;Su et al, 2011;Zhang et al, 2011;Sereno et al, 2012;Simon et al, 2012;Yu et al, 2012;Zhang et al, 2012). In 2011, Hubner et al performed a meta-analysis to investigate the correlation mentioned above and concluded that high ERCC1 may adversely influence response in platinumtreated NSCLC patients (Hubner et al, 2011).…”