Cyclooxygenase-2 Expression in Bladder Cancer and Patient Prognosis: Results from a Large Clinical Cohort and Meta-Analysis

Abstract

Aberrant overexpression of cyclooxygenase-2 (COX2) is observed in urothelial carcinoma of the bladder (UCB). Studies evaluating COX2 as a prognostic marker in UCB report contradictory results. We determined the prognostic potential of COX2 expression in UCB and quantitatively summarize the results with those of the literature through a meta-analysis. Newly diagnosed UCB patients recruited between 1998–2001 in 18 Spanish hospitals were prospectively included in the study and followed-up (median, 70.7 months). Diagnostic slides were reviewed and uniformly classified by expert pathologists. Clinical data was retrieved from hospital charts. Tissue microarrays containing non-muscle invasive (n = 557) and muscle invasive (n = 216) tumours were analyzed by immunohistochemistry using quantitative image analysis. Expression was evaluated in Cox regression models to assess the risk of recurrence, progression and disease-specific mortality. Meta-hazard ratios were estimated using our results and those from 11 additional evaluable studies. COX2 expression was observed in 38% (211/557) of non-muscle invasive and 63% (137/216) of muscle invasive tumors. Expression was associated with advanced pathological stage and grade (p<0.0001). In the univariable analyses, COX2 expression - as a categorical variable - was not associated with any of the outcomes analyzed. As a continuous variable, a weak association with recurrence in non-muscle invasive tumors was observed (p-value = 0.048). In the multivariable analyses, COX2 expression did not independently predict any of the considered outcomes. The meta-analysis confirmed these results. We did not find evidence that COX2 expression is an independent prognostic marker of recurrence, progression or survival in patients with UCB.

Is Overexpression of Ki-67 a Prognostic Biomarker of Upper Tract Urinary Carcinoma? A Retrospective Cohort Study and Meta-Analysis

“…When the individual HR together with its variance were not reported in the selected articles, we performed, when possible, a calculation from the survival comparison statistics and its variance. The estimated HR may be less reliable than the one obtained directly from published statistics [52]. Finally, when defining Ki-67 overexpression, the cut-off values for IHC varied from 6% to 30% among these studies [23,29,31,35].…”

A Review of the Application of Inflammatory Biomarkers in Epidemiologic Cancer Research

“…In an investigation of COX-2 expression in bladder cancer, a weak association with recurrence in non-muscle invasive bladder tumors was observed (p-value = 0.048). In the multivariable analyses, COX2 expression did not independently predict any of the considered outcomes (248). …”

Developing proteomic biomarkers for bladder cancer: towards clinical application

“…Among these were apoptosis regulatory proteins Bcl-2 and Bax, 99 inhibitors of apoptosis such as survivin 97 , proliferation associated proteins such as TP53, cyclin-dependent kin ase inhibitor 1 (also known as p21), cyclin-dependent kinase inhibitor 1B (also known as p27), retinoblastomaassociated protein, 100 galectin-8, 101 serpin B5, 102 cyclin D1, 103 double-strand break repair protein MRE11A, DNA repair protein RAD50, Nibrin, serine-protein kinase ATM, histone H2AX, 104 PLK1, 97 carbonic anhydrase 9 105 and prostaglandin G/H synthase 2. 106 These proteins were assessed either as prognostic markers or for prediction of the outcomes of radiotherapy and/or chemotherapy in patients with bladder cancer ( Table 4). The number of samples analysed in these studies, either using immuno histochemistry or tissue microarrays, ranges from h undreds to thousands.…”