Clinical outcomes associated with expression of aurora kinase and p53 family members in muscle-invasive bladder cancer.

Abstract

Biomarkers are needed in muscle-invasive bladder cancer (MIBC). We previously reported that high tumor aurora kinase (AURK) A expression identifies patients with MIBC with poor prognosis. Aberrant p53 expression has also been associated with poor outcomes in MIBC, though to the best of our knowledge, co-expression rates of p53 and aurora kinases have not been previously described in MIBC. As aurora kinase and p53 family members may co-regulate each other, the present study investigated whether tumor p53 or p63 protein expression influenced the prognostic value of AURKA in a pilot study of 50 patients with MIBC treated with curative intent. Immunohistochemistry for AURKA, AURKB, p53 and p63 were performed on archival pre-treatment tumor specimens and correlated with clinical outcomes in patients with MIBC who received neoadjuvant chemotherapy (NAC) prior to cystectomy. Baseline p53 [hazard ratio (HR) 1.46; 95% confidence interval (CI)=0.55-3.9; P=0.448) and p63 (HR 2.02; 95% CI=0.51-8.1; P=0.313) protein expression did not predict for overall survival (OS). Low p53 protein expression did not correlate with high AURKA (φ=0.190) or AURKB (φ=0.075) expression. However, in tumors with low p53 expression (n=17), the presence of either high AURKA or AURKB expression levels predicted an increased risk for relapse (HR 27.1; 95% CI=2.7-270.1; P=0.005) and mortality (HR 14.9; 95% CI=2.3-95.6; P=0.004) compared to tumors with both low AURKA and AURKB levels. The relationship between p63 and AURKA/B expression levels was not tested due to the prevalence (80%) of high p63 expression in the present cohort. In tumors with low AURKA expression, p53 status did not predict for OS (HR 0.62; 95% CI 0.2-3.2; P=0.572). In multivariable analysis, only high baseline AURKA expression predicted for inferior OS (HR 4.9; 95% CI 1.7-14.1; P=0.003). To the best of our knowledge, the present study was the first to report co-expression of p53 and aurora kinase family members in MIBC, and although wild-type p53 may regulate the aurora kinases in preclinical models, the adverse prognostic value of tumor AURKA overexpression was independent from baseline tumor p53 protein expression in the present cohort. AURKA remains an important prognostic biomarker in patients with MIBC and warrants further evaluation in prospective studies to validate whether baseline AURKA can identify patients that are unlikely to benefit from standard of care with NAC.