905 Hypoxia is independently associated with poor outcome in urothelial bladder cancer patients treated with radical cystectomy

Abstract

INTRODUCTION AND OBJECTIVES: Cisplatin-based chemotherapy is the first-line standard treatment in metastatic bladder cancer (BC), with response rates of only 50% but significant toxicity. Clinical and pathological parameters are unable to distinguish between cisplatin sensitive and resistant BCs. Therefore, predictive markers are urgently needed to avoid unnecessary toxicity. Cisplatin-based chemotherapeutic agents exhibit their cytotoxic effect by cross-linking DNA preventing DNA-duplication for mitosis in dividing cells. This process leads ultimately to apoptosis of these cells. ERCC1 has been suggested to be involved in the elimination of cisplatin-DNA adducts decreasing efficacy of the therapy. More recently, in vitro studies in various tumors demonstrated that MMP-7 plays a causal role in the development of cisplatin resistance by inhibiting chemotherapy-induced apoptosis. However, its chemotherapy predicting value in BC has not been evaluated yet. Therefore, we assessed the predictive value of MMP-7 and ERCC1 expressions in patients with metastatic BC treated with cisplatin-based chemotherapy. METHODS: Protein expressions of ERCC1 and MMP-7 were analyzed by immunostaining in chemo-naive tumor specimens of 72 patients treated with cisplatin-based chemotherapy (GC or MVAC) because of a metastatic BC. The expression levels were correlated with the clinical follow-up data. RESULTS: High ERCC1 and MMP-7 levels were associated with significantly shorter patientsâ€TM survival (p 0.025 and p 0.026 respectively). The highest predictive significance (p 0.017) could be reached when ERCC1 and MMP-7 were combined; the median survival time was 13.6 months in cases where both ERCC1 and MMP-7 levels were low, 10.2 months if one of these marker level were high and 5.7 months when both ERCC1 and MMP-7 levels were elevated. CONCLUSIONS: Our data reveals for the first time MMP-7 as a predictive factor in BC patients treated with cisplatin-based chemotherapy. The combination of MMP-7 with ERCC1 provides the highest predictive accuracy in this patient group. These data together suggest that ERCC1 and MMP-7 may help to select patients who will not benefit from a cisplatin-based therapy. These patients might be optimal candidates for studies with new chemotherapeutic agents. Furthermore, specific inhibition of these molecular factors may help to overcome chemotherapy resistance.