Urine tests
Many companies and researchers have been working to develop non-invasive tests which could be used for both initial diagnosis of bladder cancer, and in follow up – to catch recurrences early.
A non-invasive test, used alongside cystoscopies, is something patients have been asking for; having one accurate enough to reduce the number of cystoscopies would represent a significant improvement for patients and great progress has been made towards that goal.
Urinary biomarkers – what are they?
Urinary biomarkers are natural substances from cancer cells that show up in your urine. If these are found in your pee, it could mean cancer is present. Researchers and companies are working to make these tests accurate enough to help spot bladder cancer early or to check if it has returned after treatment.
Types of urinary biomarkers (The technical bits)
Many chemicals are present in the pee of people with bladder cancer. These include particular proteins, as well as traces of DNA and mRNA. These chemicals are generally more plentiful in high-grade cancers and less plentiful in lower-grade cancers (Jur, RE et al, Urologic Oncology, 39(3))
Proteins: Proteins are complex molecules comprised of peptides, which are in turn comprised of amino acids. Proteins are involved in many functions including metabolism, movement, defence, cellular communication and molecular recognition.
DNA: DNA is an organic molecule found in the cell nucleus that codes the genetic information required for the transmission of inheritable traits.
mRNA: mRNA (messenger RNA) is a molecule that transfers information from DNA to the cell machinery that makes proteins.
How are urinary biomarkers tested for?
Urinary biomarkers are collected in samples of pee. The sample is then sent to a laboratory to be processed; it may take several days to get the result back. The result may be presented as a score or as a positive or negative result.
Some tests may be completed in the clinic (this is called near patient testing) with the result being rapidly available.
Sensitivity relates to how likely the test is to be positive in people with cancer. If the sensitivity is high, there will be very few negative tests in cancer patients, and this test can help to ‘rule out’ disease. If the sensitivity is low there will be many false negative tests.
Specificity: if the test is positive, this relates to how likely you are to have cancer. If the specificity is high, a positive test likely means that cancer is present. If the specificity is low, there will be many false positive tests.
A helpful example is urinary cytology, where a urine sample is examined in a laboratory for the presence of abnormal cells. If abnormal cells are present, then this is very likely to indicate the presence of bladder cancer and the test is said to have high specificity. However, the test is often negative in people with bladder cancer, and so the test is said to have low sensitivity. The low sensitivity limits the value of this test in ‘ruling out’ disease.
Another term which can be used to describe the accuracy and usefulness of a test is Negative Predictive Value (NPV). This is the probability that a person with a negative screening test truly does not have cancer.
A perfect test (which does not exist) would have 100% sensitivity and 100% specificity but real-world tests never achieve this goal. Evaluating whether or not a urinary biomarker test is appropriate for you is personal to each bladder cancer patient and should be discussed with your urologist.
What are the advantages of urinary biomarkers?
One advantage of urine biomarker tests is the fact that they are non-invasive and have no side effects.
In general, urinary biomarkers have a high sensitivity and a high Negative Predictive Value. This means that a negative test very likely indicates no cancer present. This feature is helpful in the follow-up of non-muscle-invasive bladder cancer, when checking for early recurrences of the cancer.
Using urinary biomarkers raises the prospect of reducing the number of cystoscopies required during follow-up. Although this benefit has yet to be demonstrated in large clinical trials, it has been estimated that there could be between 500-740 fewer cystoscopies needed per 1,000 people with cancer (Laukhtina et al., 2021).
Some urinary biomarkers can potentially indicate the presence of upper urinary tract cancers in addition to bladder cancer.
Urinary biomarkers are typically unaffected by the presence of blood in pee.
Are there disadvantages of urinary biomarkers?
All bladder cancer tests, including both cystoscopies and urinary biomarkers, might miss cancer by giving a “false negative” result, meaning the test shows no cancer when cancer is actually present. For urinary biomarkers, this happens in about 10 to 80 out of every 1,000 people with cancer. Similarly, tests can also give a “false positive” result, where the test indicates cancer, but no cancer is actually found. For urinary biomarkers, this occurs in about 120 to 340 out of every 1,000 people (Laukhtina et al., 2021).
These tests can cost between £110 and £450. Despite these potential downsides, urinary biomarkers may help reduce the need for cystoscopies, potentially offering savings by avoiding a more expensive and uncomfortable procedure.
What is the current state of play?
Doctors in the UK look to various bodies for guidelines on clinical practice. In general, NHS England guidelines are followed by physicians in England, Wales and Northern Ireland whereas NHS Scotland issues guidelines for Scotland. Physicians also often consult the European Association of Urology (EAU) guidelines for bladder cancer.
Screening (in undiagnosed, symptom-free people)
Biomarker screening for bladder cancer in undiagnosed, symptom-free people is currently not recommended by NHS England, NHS Scotland or the European Association of Urology.
Diagnosis and follow-up of bladder cancer
The NHS England guidelines for bladder cancer (written in 2015) state, ‘Offer white-light-guided Trans Urethral Removal of Bladder Tumour (TURBT) with one of photodynamic diagnosis, narrow-band imaging, cytology or a urinary biomarker test (such as UroVysion using in-situ fluorescence hybridisation [FISH], ImmunoCyt or a nuclear matrix protein 2022 [NMP22] test to people with suspected bladder cancer. This should be carried out or supervised by a urologist experienced in TURBT’.
The European Association of Urology’s guidelines for non-muscle-invasive bladder cancer state:
“Several urinary biomarkers, assessing multiple targets, have been tested in prospective multicentre studies. Four of the commercially available urine biomarkers, Cx-Bladder, ADX-Bladder, Xpert Bladder® and EpiCheck, although not tested in Randomised Controlled Trialss, have such high sensitivities and negative predictive values in the referenced studies for High Grade disease that these biomarkers may approach the sensitivity of cystoscopy. These 4 tests might be used in the initial diagnostic workup to avoid/implement cystoscopy, or in follow-up to replace or postpone cystoscopy”
NHS England is continually reviewing the evidence for urinary biomarkers. ADXBLADDER was evaluated in 2019, URO17 was evaluated in 2021, and Bladder EpiCheck was reviewed in 2022. NHS England concluded that, while promising, these tests need additional research to confirm their value before they can be widely adopted by the NHS. Updated guidelines are expected to provide more guidance on how these tests could be used in the future.
What does this mean?
There is increasing interest in the potential role of urinary biomarkers in the management of bladder cancer:
Screening: There is ongoing research into using urinary biomarkers in routine screening for bladder cancer. However, NHS England and the European Association of Urology note that routine bladder cancer screening is not recommended.
Diagnosis: Both NHS England and the European Association of Urology agree that cystoscopy remains the key test in the diagnosis of bladder cancer. NHS England have identified some biomarkers that could be used alongside cystoscopy to assist in the diagnosis of bladder cancer and the European Association of Urology agrees, noting that urinary biomarkers may help to identify missed tumours.
Surveillance/ follow-up: The European Association of Urology have identified some urinary biomarker tests with high Negative Predictive Values and high sensitivities. They have stated that these tests might be used to replace and/or postpone cystoscopy as they may identify the rare High-Grade recurrences occurring in low/intermediate non-muscle-invasive bladder cancer.
Potential use of urinary biomarkers to delay or replace cystoscopy in low/intermediate risk bladder cancer surveillance
While NHS England and the European Association of Urology have not yet recommended using urinary biomarkers to replace or delay cystoscopy in monitoring low to intermediate-risk non-muscle-invasive bladder cancer, these tests hold promise for reducing the frequency of cystoscopy in some cases.
If a biomarker test result is positive, a follow-up cystoscopy will confirm the presence or absence of cancer. While this may mean undergoing a cystoscopy that the test didn’t eliminate, it ensures thorough follow-up. These tests currently require out-of-pocket payment as they’re not covered by the NHS, but many people find the added reassurance valuable.
False negatives, where the test misses a recurrence, are uncommon and tend to happen more with low-grade recurrences, which generally present a lower immediate risk. High-grade recurrences, which require more urgent attention, are typically detected reliably. Weighing the small chance of missing a low-grade recurrence against the comfort of reducing invasive procedures may help you decide if this option suits your care approach.
Availability
Table 2: Urinary biomarker tests for bladder cancer detection
| Product | Company | Technology | Availability | Estimated Cost | Contact |
|---|---|---|---|---|---|
| Bladder EpiCheck® | Nucleix | DNA | Private clinics, online providers, NHS trials underway | £190-£300 | camclinlabs.co.uk/bladder-epicheck |
| Cxbladder™ | Pacific Edge | mRNA | Not available in the UK | Not available in the UK | cxbladder.com |
| GALEAS™ Bladder Cancer Test | Nonacus | DNA | Available for at-home use in the UK | £449 (Bupa reimbursement for policyholders) | fgih.co.uk/product/bladder-cancer-test |
| URO17™ | KDx Diagnostics | Protein | Available at Lister Hospital; selected labs; NHS evaluation | £110 | MCT Lifesciences |
| Uromonitor | Uromonitor | DNA | Unknown | Unknown | uromonitor.com |
| Xpert® Bladder Cancer Monitor | Cepheid | mRNA | Available privately; limited NHS availability* | Unknown | cepheid.com |
* Addenbrookes Hospital, Cambridge. James Cook University Hospital, Middlesbrough. New Cross Hospital, Wolverhampton. Ninewells Hospital, Dundee. Royal Bolton Hospital, Bolton. Royal Liverpool University, Liverpool. Royal Surrey County Hospital, Guilford. Information provided by the companies and deemed correct as at May 2023
Additionally, urinary biomarker tests may be offered to people in clinical trials. Recent trials have looked at blood markers (circulating cancer DNA) and urinary tests (the UroX and BladderPath studies). Details of current clinical trials in the UK can be found at: https://www.fightbladdercancer.co.uk/research-trials/
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Summary
Urinary biomarkers present a promising option for bladder cancer follow-up. Current guidance from the European Association of Urology suggests they may support surveillance in individuals with low- to intermediate-risk non-muscle-invasive bladder cancer, potentially reducing the need for follow-up cystoscopies.
Each individual’s case is different. We encourage discussing your specific needs and preferences with your healthcare team to determine whether urinary biomarkers may be suitable within your care plan.
More information
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What are urine tests
Low and intermediate risk bladder cancer
