A Novel Approach to Using Matrix Metalloproteinases for Bladder Cancer

Purpose

Given the steadily growing cancer survivor population, increasing pressure has been placed on more effective clinical approaches and biomarker assays to manage care. For bladder cancer despite the high probability of recurrence the number of patients with recurrent disease is significantly lower than the number that remains cancer free at any monitoring interval. We developed a noninvasive urine assay using a novel approach to identify patients without recurrent cancer with extremely high confidence.

Materials and Methods

Previous studies show that matrix metalloproteinases are increased in the urine of patients with cancer compared to that in disease-free individuals. To determine the clinical usefulness of these markers as monitors for bladder cancer recurrence we measured and compared metalloproteinase-2, metalloproteinase-9 and metalloproteinase-9/neutrophil gelatinase-associated lipocalin by enzyme-linked immunosorbent assay and zymography in a set of 530 samples, including 84 samples from patients with bladder cancer.

Results

Initial studies using urine metalloproteinase to discriminate disease-free patients from those with bladder cancer resulted in 80% sensitivity (67 of 84) and 71% specificity (318 of 446) for metalloproteinase-9. By applying our novel Clinical Intervention Determining Diagnostic^™ clinical approach to metalloproteinase-9 we correctly identified 42% of cases that were cystoscopy negative with 98% negative predictive value.

Conclusions

A noninvasive urine diagnostic assay that uses metalloproteinases with the Clinical Intervention Determining Diagnostic could lead to more efficient treatment in bladder cancer survivors by decreasing the number of negative cystoscopies (42%), allowing physicians to more selectively monitor those at high risk.

Key Words: urinary bladder, urinary bladder neoplasms, neoplasm recurrence, local, matrix metalloproteinases, tumor markers, biological

Abbreviations and Acronyms: CIDD, Clinical Intervention Determining Diagnostic, ELISA, enzyme-linked immunosorbent assay, MMP, matrix metalloproteinase, NED, no disease evidence, NGAL, neutrophil gelatinase-associated lipocalin, NPV, negative predictive value, PPV, positive predictive value