Urinary Biomarkers in Bladder Cancer: Where Do We Stand?

Abhishek Bhat; Chad R. Ritch

Disclosures

Curr Opin Urol. 2019;29(3):203-209. 

In This Article

Where are we Today? Current FDA-approved Urinary Biomarkers

Fluorescent in Situ Hybridization: UroVysion

UroVysion (Abbott Laboratories, Abbott Park, Illinois, USA) fluorescent in situ hybridization (FISH) was devised for the detection of bladder cancer using the exfoliated urothelial cells and examining them for aneuploidy of chromosomes 3,7, and 17 and loss of 9p21 locus. UroVysion was found to have a sensitivity of 72% and specificity of 83%, respectively, in a pooled metanalysis of 2477 FISH tests.[3] The sensitivity for picking up low-grade cancer, however, continues to be low at around 41%.[3] Patients with an initial false-positive FISH test and a negative cystoscopy are more likely to experience disease recurrence within the year after the test; however, these results are yet to be validated on prospective analysis.[4] A positive UroVysion test therefore can be employed to anticipate disease recurrence while on surveillance.[4] Studies have also validated the usage of FISH with atypical cytology to monitor the recurrence patterns, which may reduce the number of unwanted biopsies.[5] Kim et al. observed that FISH results were significantly associated with risk of recurrence (<0.001). Further, on multivariate analysis, it was demonstrated that positive UroVysion FISH significantly increased the risk of recurrence compared to negative FISH (P = 0.001). FISH results were also significantly associated with increased risk of progression (P = 0.02).[5] The usage of FISH in monitoring response to Bacillus Calmette Guerin (BCG) has been described as well. In a study by Savic et al.,[6] 13 of 17 (77%) post-BCG-positive FISH results had a persistent or recurrent tumor, whereas only 13 of 51 patients had a negative FISH result. Compared to patients with negative results, the risk of cancer recurrence or persistence was 5.6 times higher in patients with positive FISH result (P < 0.001)[6] (Table 1).

Nuclear Matrix Protein 22

Nuclear matrix proteins (NMP 22) are a group of proteins required for structural composition of the nucleus and actively involved in most of the functions at the genetic level. The level of NMP22 in urine is considerably greater in bladder cancer patients.[7] Two NMP22 assays have been designed for bladder cancer purposes. The quantitative assay (NMP22 BC) uses two antibodies and is FDA approved for bladder cancer surveillance.[2] The NMP22 BladderChek test is a qualitative immunochromatic assay and is FDA approved for surveillance as well as detection of bladder cancer. Although the sensitivity outperformed cytology, the specificity was significantly lesser. The sensitivity incremental benefit was mainly because of increased detection of low-grade tumors as well.[8–10] Although the sensitivity and specificity is 50 and 87%, respectively, for surveillance purposes, the combination with cystoscopy increases the detection of recurrent tumors to 99% which is higher than cystoscopy alone.[11]

Bladder Tumor Antigen

Bladder tumor antigen (BTA) is a human complement factor H-related protein produced by cancerous cells and interferes with the complement cascade conferring a survival advantage to the tumor cells.[12] Two assays, similar to the NMP22, exist with BTA Trak being the quantitative and BTA Stat being the qualitative assay. The key difference lies in the fact that both tests have been approved only for surveillance purposes in combination with cystoscopy. The assays are limited by low sensitivity (68–77.5%) and specificity (50–75%) and hence not widely used in clinical practice.

Immunocyt

The Immunocyt (Diagnocure Inc, Quebec, Canada) assay employs the combination of cytology and immunofluorescence to detect three[3] antigens of bladder cancer cells: M344, LDQ10, and 19A11 using monoclonal antibodies. Cytopathologists are able to report a positive result only in the presence of a large number of exfoliated cells (>500 cells/slide) and it is approved only as an adjunct to cystoscopy. Being a cell-based assay, the influence of inflammatory conditions and hematuria is lesser compared to the other assays.[13] A large, multicenter trial established Immunocyt as a strong predictor of bladder cancer in painless hematuria.[14] In multivariate analysis adjusted for sex, age, smoking history, and gross hematuria, Immunocyt (P < 0.0001) and cytology (P < 0.0001) were independently associated with bladder cancer detection.[14] A recent meta-analysis demonstrated that Immunocyt had a lower specificity and area under curve (AUC) for detecting bladder cancer compared to urine cytology (Specificity of 65.7% compared to 90.6%).[15]

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