Prediction of Muscle-invasive Bladder Cancer Using Urinary Proteomics

Purpose: Minimally invasive methods of predicting the risk of muscle-invasive urothelial bladder carcinoma may expedite appropriate therapy and reduce morbidity and cost. Experimental Design: Here, capillary electrophoresis coupled mass spectrometry was used to identify urinary polypeptide bladder cancer biomarkers in 127 patients. These markers were used to construct a panel discriminating muscle-invasive from noninvasive disease, which was refined in 297 additional samples from healthy volunteers, patients with malignant and nonmalignant genitourinary conditions. Sequencing of panel polypeptides was then done. Finally, the ability of the panel to predict muscle-invasive disease was evaluated prospectively in 130 bladder carcinoma patients. Four sequenced polypeptides formed a panel predictive of muscle-invasive disease. Results: Prospective evaluation of this panel revealed a sensitivity of 81% [95% confidence interval (CI), 69-90] and specificity of 57% (95% CI, 45-69) for muscle-invasive disease. Multivariate analysis revealed the panel (P < 0.0001) and tumor grade (P = 0.0001), but not urine cytology, predict muscle invasion. A model including grade and panel polypeptide levels improved sensitivity [92% (95% CI, 82-97)] and specificity [68% (95% CI, 55-79)] for muscle-invasive disease. A model score of >0.88 provided a negative predictive value of 77% and positive predictive value of 90% for muscle invasion. Conclusions: Use of urinary peptides seems promising in estimating the probability a patient harbors muscle-invasive urothelial bladder cancer. These peptides may also shed novel insights into the biology of bladder tumor progression not obtainable by other methods. Clinical trials seem warranted to evaluate the effect of this approach on practice.