New urine test for bladder cancer


Birmingham researchers funded by Cancer Research UK and liquid biopsy company Nonacus have developed a new urine test for bladder cancer, which could reduce the need for invasive and time-consuming procedures to diagnose the disease.

The test will use highly sensitive liquid biopsy technology developed by Nonacus in conjunction with a panel of biomarkers developed and validated by Mr Rik Bryan and Dr Douglas Ward from the University of Birmingham’s Bladder Cancer Research Centre, to detect the presence of bladder cancer by finding DNA from tumour cells present in the urine.

The biomarker panel, which consists of 443 genetic mutations that are common in bladder cancer has been validated in a deep sequencing study recently published in European Urology Oncology.

In this study, which was funded by Cancer Research UK and the Medical Research Council, the researchers used the test to analyse urine from 165 people with bladder cancer that had experienced haematuria (blood in the urine), and successfully detected the disease in 144 of them (87%).

The researchers also looked at using the test in 293 patients who had already been treated for bladder cancer and were being monitored for the cancer returning. In this setting, the test returned a higher proportion of false positive results compared to when used in the haematuria clinic (37.5% vs 15.2%), with 99 positive urine tests without a tumour being seen by cystoscopy on the same day.

However, during their follow up monitoring, the patients who had those positive results had almost 3-times higher (11% vs 4%) rates of the cancer returning within 24 months indicating that the test could help detect recurrent disease before it is visible by cystoscopy (the camera inspection of the bladder). Further research is needed for the test to be used for surveillance.

Lead researcher Mr Richard Bryan said: “Even though cystoscopy is good at detecting bladder cancer, it’s invasive and time consuming for patients, so we need a better way to diagnose patients. In the future our test could be an easier way to get people with bladder cancer diagnosed faster and could mean that tens of thousands of cystoscopies on healthy patients can be avoided each year.”

Iain Foulkes, executive director of research and innovation at Cancer Research UK added: “These findings show that this urine test could help diagnose bladder cancer more easily. Early detection of cancer is key for improving patient outcomes and research like this could help identify the patients that need treatment soonest, while easing the pressures of diagnostic procedures on the NHS. We look forward to seeing how the test performs in the next clinical trial.”

The researchers are working in partnership with Nonacus, a provider of genetic testing products for precision medicine and liquid biopsy, to turn their approach into a clinical test for patients to be used within the NHS and will start a clinical study funded by Cancer Research UK and involving over 3000 patients to evaluate just how powerful the test is at reducing the number of cystoscopies.

Each year, over 300,000 cystoscopies are carried out in England, however, around 80% of patients with haematuria who’ve had cystoscopy are found to have no cancers or abnormalities. The researchers believe that using the urine test in haematuria clinic could reduce the number of patients requiring a cystoscopy by at least 45%.

Bladder cancer is the sixth most commonly diagnosed cancer in men and the tenth in both genders globally [1]. Nearly half of bladder cancer cases are attributed to tobacco smoking [2], followed by occupational exposure to chemicals such as aromatic amines and chlorinated hydrocarbons, which are responsible for 10% of bladder cancer cases [3].

It is not yet clear if family history plays a role in bladder cancer development. Research shows that the risk increases for first- and second-degree relatives, yet genetic predisposition is still under investigation [4,5,6]. Bladder cancer is usually presented with painless macrohematuria [7]. Bladder cystoscopy is the gold standard for diagnosis and follow-up [8].

Follow-up strategies involve repeated cystoscopies associated with the risk of infection and bleeding, and due to its high recurrence, they require patient compliance over a long period of time [7]. Currently, a noninvasive diagnostic tool such as urine cytology is used in clinical practice with variable sensitivity from 16% for low-grade tumors to about 84% for high-grade tumors [9]. Urine cytology has its drawbacks; negative cytology does not exclude malignancy; nonetheless, infections, stone disease, a low number of cells, and subjective interpretation of the test can affect the results drastically [10,11].

Current urine-based biomarkers approved by the US Food and Drug Administration (FDA) for diagnosis and follow-up include UroVysion, NMP22 BladderChek, and NMP22 enzyme-linked immunosorbent assay (ELISA). BTA-TRAK, immunocyte (UCyt+), and BTA-STAT are approved for follow-up only.

These markers show high false-positive rates, which limits their use in clinical settings [12]. Urine cytology and urine-based biomarkers do not replace the gold standard, cystoscopy; therefore, the search for reliable tests to use in screening, primary detection, and follow-up of nonmuscle invasive diseases continues.

Recent studies in the context of nonmuscle-invasive bladder cancer (NMIBC) have shown that inflammation markers would also be a useful indicator for patient stratification and monitoring, in particular owing to the high recurrence rate of NMIBCs and the role of chronic inflammation [13,14]. For example, studies using peripheral blood measuring the neutrophil-to-lymphocyte ratio have shown evidence of the potential use of the marker in bladder cancer prognostics [15,16].

Next-generation sequencing (NGS) of cell-free DNA (cfDNA) from blood plasma has become the focus of many studies and was recently proposed for the early detection of multiple cancer types. However, its sensitivity in detecting bladder cancer only reaches 35% [17]. Hence, there is growing interest in the utility of urine as a liquid biopsy in bladder cancer.

Particularly for a heterogeneous disease such as cancer, liquid biopsy may revolutionize management options for patients through comprehensive molecular characterization. It is also practical for clinical use due to its noninvasive nature and the ease of obtaining and handling the sample compared to traditional tumor biopsies, which can be limited in certain tumor cases. In the context of bladder cancer, urine liquid biopsy has the capability to provide in-depth information on the tumor.

In contrast to other tumors and their limited exposure to the blood circulation, urine is in constant contact with the tumor, resulting in the concentrated availability of tumor-related entities in the urine [18]. A recent study reached 52–68% sensitivity using a small NGS panel (10 genes) and could increase sensitivity to 68–83% by adding aneuploidy and telomerase reverse transcriptase gene (TERT) promoter mutation detection [19]. This set of three examinations may be too complex for some clinical studies or the clinical routine.

Here, we consider a single examination using just a large NGS panel (127 genes) and find that this simpler set-up gave a similar if not better sensitivity of 91%. Given the options of cfDNA or urothelial cell DNA as input for the panel sequencing, it has been shown that cfDNA amounts in urine are low and variable, making the cfDNA isolation almost as costly as the sequencing [20].

Therefore, we explored whether urothelial cell DNA isolation is more suitable for clinical practice. For this analysis, we included healthy probands to analyze whether (a) gender-based differences and (b) time-of-day variability also apply to urothelial cell DNA.

Our results indicate that urothelial cell DNA may be a promising avenue for analyzing various urothelial tumor entities at specific time points, such as before and after treatments for prognostic or monitoring purposes.

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