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

What Else is on the Horizon? Novel Investigational Urinary Biomarkers for Bladder Cancer

Gene-based Biomarkers

Aurora A Kinase. Aurora A Kinase (AURKA) is an encouraging serine/threonine kinase based on the FISH or RT-PCR biomarker assay. The enzyme is responsible for gene stability regulation during mitosis. The FISH assay for the recognition of bladder cancer identifies an overexpression of the AURKA gene with sensitivity of 87%, specificity of 97%, and AUC of 94%.[25] AURKA has been shown to be more precise than cytology in detecting low-grade tumors with predictive accuracy of 73 versus 59%.[26] The future of AURKA holds potential in the setting of these outcomes (Table 2).

Fibroblast Growth Factor 3 Receptor

Another promising biomarker for detection and monitoring of bladder cancer is fibroblast growth factor 3 (FGF-3) receptor assay. Mutations of FGF-3 are seen in approximately half of bladder cancer patients and in about 60–70% of the low-grade tumors.[27,28] In the surveillance setting, the sensitivity outperforms urine cytology, and when combined, it increases to 76%.[29] Recent studies have validated that partial replacement of cystoscopy with FGF-3 urinary biomarker during surveillance can be safe and cost effective.[30] The authors compared modified surveillance in 70 patients on surveillance with FGFR-3 mutation analysis of voided urine samples every 3 months with cystoscopies at 3, 12, and 24 months to a protocol of standard surveillance performed with cystoscopy every 3 months. Sensitivity analysis for assessment of influence of variations in cost, sensitivity, and specificity were carried out with higher no-recurrence probability for modified surveillance compared to standard surveillance (95.7 versus 95%, respectively). The total cost of modified surveillance was greater than half of the standard surveillance protocol (2558£ versus 5861£).[30]

Epigenetic based.DNA methylation/loss of heterozygosity/microsatellites/miRNAs: More than 25 sets of genes have been studied for DNA methylation changes for the purpose of both detection and surveillance of bladder cancer. The sensitivity ranged from 77 to 100% in detection setting, whereas the specificity ranged between 65 and 100%.[31] In the surveillance setting, however, Reinert et al.[31] reported a sensitivity of 82–89% and specificity of 94–100% when studying a panel of 6 genes.[31] An added value of methylation biomarkers is as a target of epigenetic modifiers that can boost other therapies. Microsatellites are polymorphic short-tandem DNA repeats in the genomic sequence that result from failure of DNA mismatch repair and can be used for detection of tumorigenesis. The accuracy in surveillance setting is very low, but in the detection setting, it has shown a good correlation with DNA extracts of tumor.[32]

RT-PCR can be used to measure miRNAs like urinary TWIST 1 and NID2 which are small noncoding RNAs that regulate the posttranscription of genes responsible for carcinogenesis. A specific miRNA signature is generated and shed in urine which may be analyzed. Fantony et al. evaluated 209 study participants with 40% for hematuria evaluation and 60% for bladder cancer surveillance. Cystoscopy was used as the gold standard and it was determined that the AUC for urinary TWIST 1 was 0.67, for urinary NID 2 was 0.64, and for a combined TWIST1 and NID2 was 0.66.[33]

368 urine sediment samples were serially collected in 90 patients with NMIBC. A three-marker DNA methylation test accurately predicted recurrence of tumor in 80% of patients and was greater than cytology (35%) and cystoscopy (15%). The panel discriminated between patients with and without recurrence with the AUC of 0.90 (95% CI, 0.86–0.92) and 0.95 (95% CI, 0.90–1.00), sensitivity of 86 and 89% (95% CI, 74–99% and 81–97%). The authors concluded that considering the higher sensitivity and specificity, a combination of hyper and hypomethylated markers may help avoid unnecessary invasive examinations like cystoscopy.[34]

Inflammatory markers. The host response to tumor may predict response to intravesical immune therapy. Kamat et al. developed a nomogram that may predict response to intravesical BCG.[34] They studied the change in the level of twelve urinary cytokines [interleukin (IL)-6, IL-1ra, IL-2, IL-1b, IL-8, IL-10, IL-12 (p40), IL-12 (p70), IL-18, interferon (IFN)-γ, tumor necrosis factor (TNF)-α, and TNF-related apoptosis-inducing ligand (TRAIL)] at multiple time points during BCG treatment.[12] The change in the level of nine cytokines (IL-6, IL-1ra, IL-2, IL-8, IL-12 (p70), IL-18, IFN-γ, TNF-α, and TRAIL), measured before and 4 h after, the sixth session of BCG induction, was predictive of recurrence. These cytokines were incorporated into a nomogram cytokine panel for response to intravesical therapy (CyPRIT) that predicted the likelihood of recurrence with 85.5% accuracy (95% CI, 77.9–93.1%).[35] Vascular endothelial growth factor (VEGF) is secreted by the bladder cancer cells and can be measured by ELISA. The levels of VEGF have been shown to correlate with the tumor stage.[36] The sensitivity and sensitivity were approximately 75% each. Similarly, IL-8 was assayed with ELISA for bladder cancer and also correlated with tumor stage in the detection setting.[37] Urinary levels of IL-8 correlated closely with those who had recurrent disease in the post-BCG surveillance. IL-6 also correlates with BCG response.[38] The ratio of the IL6/IL10 correlates with BCG response and recurrence in patients.[39] Both angiogenesis and inflammation being nonspecific events with overlap with benign processes; thus, the accuracy for detection of cancer with these assays is limited.

Telomerase. The enzyme telomerase is responsible for ensuring genetic stability by synthesizing telomeres at the end of chromosomes. Telomerase reverse transcriptase (TERT) maintains the integrity of telomeres and mutations in the TERT promoter are frequent in bladder cancer. Descotes et al.[40] recently demonstrated that an assay analyzing TERT promoter mutation in the urine had an overall sensitivity of 80.5% and specificity of 89.8% for detecting bladder cancer. In addition, TERT mutations were predictive of recurrence in NMIBC (P < 0.0001).

Metabolomic based. The evaluation of metabolites in the urine to identify the biological signature of cancer cells is designated metabolomics. Bladder cancer has unique metabolic characteristics that may be analyzed by liquid chromatography and mass spectrophotometry. Cheng et al. assessed the role of a urinary metabolite panel as a biomarker for NMIBC in 284 patients (117 healthy adults, 80 NMIBC without hematuria, and 87 NMIBC patients with hematuria). Using the metabolite panel, the authors were able to distinguish NMIBC patients from controls with an AUC of 0.838. Furthermore, they found a sensitivity and specificity for NMIBC detection of 0.881 and 0.786, respectively.[41]

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