Correlation of Metastasis Related Gene Expression and Relapse-Free Survival in Patients With Locally Advanced Bladder Cancer Treated With Cystectomy and Chemotherapy

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Abstract
Patients with locally advanced (ie clinically extravesical) transitional cell carcinoma are at high risk for recurrence after cystectomy. Although randomized trials have established an incremental benefit from the addition of chemotherapy in this setting, many patients still have disease relapse, and therefore it is necessary to determine patient and tumor characteristics that correlate with outcome in this setting. We investigated the tumor expression of several metastasis related genes and the association of gene expression with disease specific survival of patients with locally advanced transitional cell carcinoma treated randomized to either neoadjuvant or adjuvant chemotherapy and radical cystectomy. Archival paraffin embedded specimens were available for 64 patients enrolled in a clinical trial of the methotrexate, vinblastine, doxorubicin and ciplatin regimen and cystectomy. Only samples obtained before exposure to chemotherapy were studied. The expression of several metastasis related genes, including basic fibroblast growth factor, vascular endothelial growth factor (VEGF), interleukin-8, matrix metalloproteinase (MMP)-9, and E-cadherin were assayed on paraffin sections using a colorimetric in situ hybridization assay. Expression of basic fibroblast growth factor, interleukin-8 and MMP-9 did not correlate with outcome. Expression of VEGF and E-cadherin were strongly related to disease specific survival. In addition, the ratio of MMP-9-to-E-cadherin was strongly prognostic for disease specific survival. These data advance the hypotheses that VEGF expression and an “invasive phenotype” characterized by the ratio of MMP-9-to-E-cadherin expression are mechanistically relevant to clinically aggressive locally advanced bladder cancers that are not cured by currently available combined modality treatment. Thus, in our view there is a compelling rationale to target these aspects of the malignant phenotype in this patient population.