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

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.The work was partially supported by the Fondo de Investigaciones Sanitarias, Instituto de Salud Carlos III, Ministry of Science and Innovation, Spain (G03/174, 00/0745, PI051436, PI061614 and G03/174); Red Temática de Investigación Cooperativa en Cáncer- RD06/0020-RTICC; Consolider ONCOBIO; EU-FP6-STREP-37739-DRoP-ToP; EU-FP7-HEALTH-F2-2008-201663-UROMOL; EU-FP7-HEALTH-F2-2008-201333-DECanBio; USA-NIH-RO1-CA089715; and a PhD fellowship awarded to MJC from the ‘‘la Caixa’’ foundation, Spain, and a postdoctoral fellowship awarded to AFSA from the Fundación Científica de la AEC

Cyclooxygenase-2 expression in bladder cancer and patient prognosis: results from a large clinical cohort and meta-analysis

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.The work was partially supported by the Fondo de Investigaciones Sanitarias, Instituto de Salud Carlos III, Ministry of Science and Innovation, Spain (G03/174, 00/0745, PI051436, PI061614 and G03/174); Red Temática de Investigación Cooperativa en Cáncer- RD06/0020-RTICC; Consolider ONCOBIO; EU-FP6-STREP-37739-DRoP-ToP; EU-FP7-HEALTH-F2-2008-201663-UROMOL; EU-FP7-HEALTH-F2-2008-201333-DECanBio; USA-NIH-RO1-CA089715; and a PhD fellowship awarded to MJC from the ‘‘la Caixa’’ foundation, Spain, and a postdoctoral fellowship awarded to AFSA from the Fundación Científica de la AEC

Distribution of characteristics of patients with MIBCs by COX2 expression.

*<p>COX2 expression score dichotomised at the threshold of positivity (0,340 au).</p>†<p>Fisher’s exact test comparing distribution of patients with negative or positive COX-2 expression; missing, Nx and Mx values excluded from analysis where applicable.</p>‡<p>Chem.: Systemic chemotherapy; RT: Radiation therapy.</p

Distribution of characteristics of patients with NMIBCs by COX2 expression.

*<p>COX2 expression score dichotomised at the threshold of positivitiy (0,340 au).</p>†<p>Fisher’s exact test comparing distribution of COX-2 negative versus positive patients; missing values excluded from analysis where applicable.</p>‡<p>TUR: transurethral resection; BCG: Bacillus Calmette-Guerin instillation; Chem.: chemotherapy via endovesical instillation.</p

Kaplan-Meier survival curves corresponding to failures in superficial (A, B) and invasive (C, D) tumors for specified prognostic endpoints.

<p>Dashed curves: patients with tumors positive for COX2 protein staining; solid curves: patients with tumors negative for COX2 protein staining. Significance values from two-sided logrank test.</p

Forest plots from selected univariable studies indicating the risk of reaching the indicated prognostic endpoints in non-muscle invasive (NMIBC; two upper panels), and muscle invasive (MIBC; two lower panels) UCBs in the presence of urothelial COX2 expression.

<p>Forest plots from selected univariable studies indicating the risk of reaching the indicated prognostic endpoints in non-muscle invasive (NMIBC; two upper panels), and muscle invasive (MIBC; two lower panels) UCBs in the presence of urothelial COX2 expression.</p

Analysis of COX2 expression in NMIBCs and MIBCs; univariable and multivariable analyses.

*<p>Expression cut-points used for categorical variables: "Neg. vs. Pos." - NMIBC/MIBC: 0.340; "Median" - NMIBC: 0.121, MIBC: 0.760; "Extreme tertiles" - NMIBC: (<0.0239, >0.586), MIBC: (<0.270, >2.149).</p>†<p>Multivariate models adjusted for established bladder cancer prognostic factors as follows: NMIBC Recurrence adjusted by region, gender, tumour stage and grade, # tumours, size of tumours, and treatment; NMIBC Progression adjusted by region, # recurrences, age, tumour stage and grade, # tumours, and treatment; MIBC Progression adjusted by region, tumour stage, treatment, and presence of nodes; MIBC Survival adjusted by region, tumour stage, treatment, presence of nodes, and metastases.</p>‡<p>Cox proportional hazards analysis.</p>§<p>One patient excluded due to incomplete follow-up record.</p

Forest plots from selected multivariable studies indicating the risk of reaching the indicated prognostic endpoints in non-muscle invasive (NMIBC; two upper panels), and muscle invasive (MIBC; two lower panels) UCBs in the presence of urothelial COX2 expression.

<p>Forest plots from selected multivariable studies indicating the risk of reaching the indicated prognostic endpoints in non-muscle invasive (NMIBC; two upper panels), and muscle invasive (MIBC; two lower panels) UCBs in the presence of urothelial COX2 expression.</p