Abstract 2693: MDR1 and ERCC1 expression predict outcome in patients with locally advanced bladder cancer and adjuvant chemotherapy
Authors: Hoffmann Andreas C. , Bertz Simone , Stöhr Robert , Wild Peter J. , Lehmann Jan , Danenberg Kathleen D. , Danenberg Peter V. , Schuler Martin , Hartmann Arndt 
Published: February 2011

Abstract
Aims: Patients with locally advanced bladder cancer show a poor prognosis and can benefit from adjuvant chemotherapy. It was previously shown that expression of MDR1 and ERCC1 is linked to resistance against platinum-based chemotherapy in several cancer types. The aim of the present study was to evaluate the impact of classical histological, new immunohistochemical and molecular markers on prognosis of patients with locally advanced bladder cancer undergoing cystectomy (pT3a-4a and/or pN+) and response to chemotherapy within a randomized, multicenter, phase III trial (AUO-AB 05/95).
Methods: Clinico-pathological parameters were assessed retrospectively after histopathological review in 204 patients randomized to adjuvant systemic chemotherapy with cisplatin and methotrexate (CM) vs. methotrexate, vinblastine, epirubicin, and cisplatin (M-VEC) after radical cystectomy. Tissue microarrays were constructed to study the immunohistochemical expression of ERCC1, BSG (Emmprin/CD147) CAV1, phospho-CAV1 (Y14), RRM1, BRCA1, BRCA2, BIRC5 (Survivin), and KISS1. Tumor samples from 108 patients were analyzed for MDR1 and ERCC1 mRNA expression by quantitative real-time RT-PCR using formalin-fixed and paraffin embedded tumor tissue.
Results: Expression of MDR1 and ERCC1 were independently associated with overall and progression-free survival (p=0.001, 2.9 exp[b]; p=0.01, 2.24 exp[b]). In contrast to ERCC1 expression, MDR1 separated patients receiving M-VEC with higher sensitivity and specificity than those receiving CM (ROC Analysis p=0.008; [AUC]=0.71). These results could be partially confirmed by immunohistochemical analysis of 204 patients. ERCC1 and RRM1 expression correlated significantly with shorter overall survival in both therapy arms by univariate analysis. Multivariate analysis showed that ERCC1 expression was an independent prognostic factor for shorter overall survival (HR=2.3, 95%CI=1.18-4.43, p=0.014). Positive nodal status (pN1-3), histologic blood vessel invasion (V1), and positive BIRC5 immunoreactivity were significant as well.
Conclusion: Our results suggest a predictive value of ERCC1 and MDR1 expression levels for therapy response and outcome in patients with locally advanced bladder cancer which allows the identification of patients who are likely to benefit from adjuvant platinum-based chemotherapy. The qPCR analysis is feasible in studying paraffin-embedded material from clinical bladder cancer trials. In addition, standard histopathological variables in combination with immunohistochemical and molecular prognostic markers can be used to predict therapy outcome in bladder cancer, irrespective of the mode of chemotherapy. Prospective studies are warranted to define a role for MDR1, ERCC1 and RRM1 in individualizing multimodality treatment in locally advanced bladder cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2693.