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Emmprin and Survivin Predict Response and Survival following Cisplatin-Containing Chemotherapy in Patients with Advanced Bladder Cancer

Authors' Affiliations: ¹ Department of Oncology, ² Molecular Diagnostics Laboratory, Department of Clinical Biochemistry, ³ Department of Pathology, and ⁴ Department of Urology, Aarhus University Hospital; ⁵ Department of Theoretical Statistics, Department of Mathematical Sciences, Aarhus University, Aarhus, Denmark; ⁶ Department of Oncology, Copenhagen University Hospital, Rigshospitalet, Denmark; and ⁷ Department of Oncology, Copenhagen University Hospital, Herlev, Denmark

Requests for reprints: Torben F. Ørntoft, Molecular Diagnostic Laboratory, Department of Clinical Biochemistry, Aarhus University Hospital, Skejby, Brendstrupgaardsvej 100, 8200 Aarhus North, Denmark. Phone: 45-89-49-51-00; Fax: 45-89-49-60-18; E-mail: orntoft{at}ki.au.dk.

Purpose: Cisplatin-containing chemotherapy is the standard of care for patients with locally advanced and metastatic transitional cell carcinoma of the urothelium. The response rate is 50% and tumor-derived molecular prognostic markers are desirable for improved estimation of response and survival.

Experimental Design: Affymetrix GeneChip expression profiling was carried out using tumor material from 30 patients. A set of genes with an expression highly correlated to survival time after chemotherapy was identified. Two genes were selected for validation by immunohistochemistry in an independent material of 124 patients receiving cisplatin-containing therapy.

Results: Fifty-five differentially expressed genes correlated significantly to survival time. Two of the protein products (emmprin and survivin) were validated using immunohistochemistry. Multivariate analysis identified emmprin expression (hazard ratio, 2.23; P < 0.0001) and survivin expression (hazard ratio, 2.46; P < 0.0001) as independent prognostic markers for poor outcome, together with the presence of visceral metastases (hazard ratio, 2.62; P < 0.0001). In the clinical good prognostic group of patients without visceral metastases, both markers showed significant discriminating power as supplemental risk factors (P < 0.0001). Within this group of patients, the subgroups of patients with no positive, one positive, or two positive immunohistochemistry scores (emmprin and survivin) had estimated 5-year survival rates of 44.0%, 21.1%, and 0%, respectively. Response to chemotherapy could also be predicted with an odds ratio of 4.41 (95% confidence interval, 1.91-10.1) and 2.48 (95% confidence interval, 1.1-5.5) for emmprin and survivin, respectively.

Conclusions: Emmprin and survivin proteins were identified as strong independent prognostic factors for response and survival after cisplatin-containing chemotherapy in patients with advanced bladder cancer.

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