Medical technologist holding urine tube test in medical laboratory

Back in July last year, we announced that The University of Birmingham had partnered with Nonacus, a provider of genetic testing products for precision medicine and liquid biopsy, to produce a urine test for bladder cancer.

Now, less than a year later, the first results from the partnership are in.

The test will use highly sensitive liquid biopsy technology developed by Nonacus in conjunction with a panel of biomarkers developed and validated by Dr 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.

Together, the team, funded by us and the Medical Research Council, has found that the urine test they have developed for bladder cancer could reduce the need for invasive and time-consuming procedures currently used to diagnose the disease.

The need for a new test

Invasive bladder cancer is the 11th most common cancer in the UK, accounting for 3% of all new cancer cases, between 2016 and 2018. And each year, over300,000 people in England are referred to hospital clinics for cytoscopies, usually after seeing blood in their urine (haematuria).

“So firstly, in the diagnosis of new cases of disease, most patients diagnosed with bladder cancer will have developed haematuria or blood in their urine. And in about 80 to 90% of those patients it will be blood that they have seen themselves when going to the toilet,” says Mr Richard Bryan, director of the University of Birmingham’s Bladder Cancer Research Centre.

If referred, the first stage of investigation is usually a cystoscopy, an invasive and costly procedure which involves inserting a camera into the bladder.

“If you’re diagnosed with bladder cancer, then the vast majority of patients are diagnosed with early disease, what we call non-muscle-invasive bladder cancer,” explains Bryan. “And although it’s generally not immediately life threatening, it needs appropriate early treatment and long term follow up. And the long term follow up for those patients involves regular outpatient flexible cystoscopy – that can be every as often as every three months, and for as long as for the rest of your life.”

However, haematuria is often a symptom of other conditions, such as a bladder infection or urinary tract stones, and of the 300,000 patients referred, around 80% of patients with haematuria who’ve had cystoscopy are found to have no cancers or abnormalities. Those who are diagnosed with bladder cancer are normally after a second invasive procedure to extract a biopsy.

For years, researchers have been looking for a way to detect bladder cancer that is less invasive, but just as effective as cystoscopy.

Bryan said that while blood visible in the urine should always be investigated, there is a pressing need for a highly sensitive and specific, non-invasive test that can rapidly determine those who need a cystoscopy and those who do not, and a urine test is the obvious place to start.

Janine’s story

Janine from Ipswich was diagnosed with bladder cancer when she was 5 months pregnant with her son, Jonty.

Janine with her son, Jonti.

“I had a cystoscopy in 2006 after a growth was found during my routine 20-week foetal ultrasound, that indicated that I might have bladder cancer,” says Janine. “I had a six week wait for my appointment, which was a pretty anxious time and I had to go into my local hospital. They numbed me with local anaesthetic but it’s still uncomfortable and it was sore afterwards, let alone the worry about how it may affect my unborn child.”

Fortunately, Janine’s son Jonty was born a healthy 7lb 14oz before she started treatment, which eventually proved successful.

“I’ve had a few cystoscopies since then as part of my ongoing monitoring and they’re not something I look forward to. If instead of that I just had to give a urine sample that would be a massive, positive change. I really hope this test becomes part of standard treatment soon.”

How does the test work?

“The rationale is clear that if you have a tumour in the bladder, urine is in contact with the tumour for hours on end in between your visits to the toilet. And there must be something cancer-specific that passes from the tumour into the urine and that can then be detected,” says Bryan.

And that ‘something cancer-specific’ is tumour DNA.

Detecting cancer DNA in urine can be tricky because there’s a lot of other DNA from normal tissues that it needs to be differentiated from. This requires highly sensitive tests that can accurately detect small amounts of specific pieces of DNA.

This is what Nonacus is providing, having developed ways of accurately detecting specific DNA for various scenarios, such as pre-natal blood tests.

The test analyses urine for the DNA from cells shed by bladder cancer tumours, looking for the most common mutations found in bladder cancer. The new test analyses 443 specific changes in 23 genes from up to 50ml urine sample.

The latest findings

The latest results found that the urine test was able to successfully detect 144 out of the 165 people with bladder cancer that had experience haematuria. The test showed an overall sensitivity of 87.3% – a measure of how often a test correctly generates a positive result for people who had bladder cancer – and a specificity of 84.8% – a measure of the test’s ability to correctly generate a negative result for people who didn’t have bladder cancer.

The team also looked at using the test in patients 293 patients who were already being 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, suggesting that the test could help detect recurrent disease before it is visible by cystoscopy.

There’s still a way to go

The next step for the team, in order to get the test closer to the clinic, is to figure out how many patients could avoid having a cystoscopy by taking the urine test.

The researchers believe that using the urine test in haematuria clinic could reduce the number of patients requiring a cystoscopy by at least 45%.

“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,” says Bryan.

“We are now going to prospectively evaluate how powerful our test can be in reducing the number of patients who have cystoscopy for the investigation of haematuria. That’s our next study, which is funded by CRUK Early Detection and Diagnosis.”

Iain Foulkes, Executive Director of Research and Innovation at Cancer Research UK, said: “These findings show that this urine test could help the NHS 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.”

It’s time to put this test to the test and we’ll be keeping our eyes peeled for the next results to come in.


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