Bladder Cancer Test: Does GALEAS Bladder aid in the early detection of bladder cancers? Prof. Bryan Dr. Ward
Bladder Cancer Test: Does GALEAS Bladder aid in the early detection of bladder cancers? Prof. Bryan Dr. Ward
Professor Richard Bryan and Doug Ward, PhD, Institute of Cancer and Genomic Sciences, University of Birmingham
GALEAS Bladder is a DNA based diagnostic urine test for bladder cancer, and it relies upon the targeted deep sequencing of mutations in the most commonly mutated genes in bladder cancer, 23 genes, and in total, within those genes, the test is seeking to identify up to 451 single nucleotide variants. A positive test is signified by any one (or more) of those single nucleotide variants being above what we deem is the threshold.
How accurate is the GALEAS Bladder test compared to current methods of detecting bladder cancer?
The current method for detecting bladder cancer in most developed countries is outpatient flexible cystoscopy under local a aesthetic. The data that we have for flexible cystoscopy would indicate that it has a sensitivity of around 85% and a specificity of around 85%. Flexible cystoscopy is operator dependent, and so experienced operators may well have higher sensitivity and specificity than 85%, and less experienced operators may well have a lower sensitivity in specificity.
What is the significance of a non-invasive method for detecting bladder cancer?
Flexible cystoscopy is obviously an invasive procedure and is uncomfortable for patients, and it's not without its side effects, including urine tract infections and bleeding (a haematuria). It would be considered by most patients as an unpleasant investigation. It's also an expensive test to implement and here in the UK we associate a tariff with flexible cystoscopy, and that tariff is around £450 - somewhere in the region of maybe about $500. And obviously, a flexible cystoscopy requires a trained urologist to undertake the investigation. And so it can also be associated with a delay for investigation. So the ability to detect bladder cancer accurately by a urine test, by a non-invasive method, means that you are sparing patients an invasive investigation.
You may well be able to investigate them more quickly, and although the GALEAS bladder test pricing will vary from territory to territory, Its current projected pricing for the UK would mean that it's also slightly cheaper than flexible cystoscopy. So there are a number of potential advantages of non-invasive detection of bladder cancer.
How was the GALEAS Bladder test developed, and what research went into creating it?
The huge amount of sequencing of tumors that's been done over the last decade of or so has really increased our knowledge of what genes are mutated in bladder cancer. So we were able to pick a panel of genes, which we initially sequenced individually to see how frequently they were mutated in a collection of bladder cancers collected here in the UK, and we honed this panel until we had a panel that was small, comprising less than 30 genes, but was big enough that we would find at least one mutation in at least 96% of tumors. And on average, a bladder tumor actually has three mutations within the panel.
So we started working on tissue, so we knew the panel worked if we used tumor DNA, and we then went and validated it on urine from bladder cancer patients and patients who were undergoing investigation because they had symptoms suggestive of bladder cancer, but ultimately they were diagnosed with other conditions. So ultimately we took the test from something that we developed on tissue DNA through to something that was really, pretty thoroughly validated on urine DNA.
I think, as Doug alluded to, it’s very important to use real world patient cohorts such that you can genuinely evaluate how accurate your test is: the sensitivity and the specificity. And certainly in the initial clinical setting that GALEAS Bladder has shown potential utility and value, patients being investigated for symptoms suspicious of bladder cancer (or what we frequently call in the UK hematuria clinic patients), we know that about 80% of patients who are investigated in hematuria clinic turn out to either have no abnormalities whatsoever or non-malignant conditions.
And equally, a number of patients who appear to have lesions in their bladders will undergo a removal of those lesions under anesthetic with a resectoscope. And those lesions sometimes turn out to be benign lesions. And so having urine samples representative of patients who have confirmed bladder cancer, patients who had a lesion in their bladder that was not bladder cancer, and also urine samples from patients who've been investigated for hematuria but who don't have any abnormalities detected, having those cohorts is crucial in being able to develop a test such as this and to be able to generate real world data on sensitivity and specificity.
What is the potential impact of the GALEAS Bladder test on the diagnosis and treatment of bladder cancer?
So in terms of impact, each year worldwide, millions of patients will be investigated for symptoms that are suspicious for bladder cancer and 80% or more of those patients will undergo flexible cystoscopy alongside a suite of other investigations, which may well include imaging of the upper urine tract, either by CT or ultrasound scanning, and may also include a urine cytology test. And we propose that in the first instance, our urine test could be used alongside upper tract imaging and possibly urine cytology, and be used as a triage test, for flexible cystoscopy, which is the invasive and expensive component of hematuria clinic investigations. And so in the first instance, we're keen to suggest that our urine test could be used as a triage tool such that if you are negative for your upper tract imaging, you're negative for urine cytology, and you are negative on our urine tests, then you may not need to undergo flexible cystoscopy.
We are just in the process of, recruiting participants to a prospective study funded by Cancer Research UK, which will formally evaluate that potential. And so in the haematuria clinic, if our data suggests that we can use GALEAS bladder as a triage tool, then millions of patients would be spared an unnecessary, flexible cystoscopy.
And that should also reduce waiting times for cystoscopies. And so it's not just easier - it could lead to faster diagnosis.
Now, the other setting where we frequently use cystoscopy is in the surveillance of patients who have non-muscle invasive bladder cancer, so patients who've already been through the diagnostic process, most commonly through a hematuria clinic, they've had initial surgery then to remove the tumor, transurethral resection of the bladder tumor with a resectoscope. And they may well then have undergone a course of adjuvant therapy directly into their bladder, intravesical therapy. Those, those patients then go on to a program of surveillance with regular outpatient flexible cystoscopy. In the UK each year, there's about 50,000 flexible cystoscopies undertaken for patients for surveillance.
And we also feel that the GALEAS Bladder test would be able to replace some of those flexible cystoscopies, such that the number of invasive procedures that non-muscle invasive bladder cancer patients experience could be halved. And again, when we look at the sensitivity of our test for patients undergoing surveillance, we can see that it's there at around 86% sensitivity. So rivalling the sensitivity of flexible cystoscopy. Now interestingly, in the setting of non-muscle invasive bladder cancer surveillance, GALEAS bladder has a lower specificity, so there are more false positives than we see in the hematuria clinic patients. But when we look in detail at those false positives, we see that a substantial proportion of those patients actually are diagnosed with a recurrence of their disease at the next cystoscopy, or perhaps the cystoscopy after that. So there's also an element of pre-emptive diagnosis of visible disease. So the patient will have had a positive urine tests around the time of their cystoscopy, but when the bladder was inspected, there was no evidence of a tumor having recurred. But 3 or 6 months or even 12 months later, a tumor has been seen, and it may well be that GALEAS Bladder is pre-emptively detecting recurrence before it can be visibly identified at cystoscopy.
How long does the GALEAS Bladder test take to provide results, and how widely available is it?
Just to reiterate, the GALEAS Bladder urine test for hematuria clinic patients has a sensitivity of 87% at a specificity of 85%. So it's very similar, if not marginally better, than flexible cystoscopy. And, we anticipate that in clinical use, that a patient will actually be sent a urine collection kit in the post. They will give their urine sample at home. It'll be returned by post to the GALEAS Bladder laboratory and results would be provided within 10 days.
What are the next steps for the GALEAS Bladder test in terms of clinical trials and regulatory approval?
So at the moment we are just starting to recruit participants to our assessment of GALEAS Bladder in the hematuria clinic setting. So, clearly here in the UK if we want to implement GALEAS bladder widely through our National Health Service, then that would need to be approved here in the UK by the NICE organization, the National Institute for Health and Care Excellence, and they would need to approve the test. Our future studies now are being devised very much with regulatory approval in mind. Clearly, similar approvals and guideline recommendations would be required in other territories around the world - Europe, North America, et cetera.
Our next study, which we call BC-Recon, reconfiguring Bladder Cancer Diagnostic Pathways is funded by Cancer Research UK, and we've just started to recruit participants, and we're aiming to recruit over 3000 participants from hematuria clinics around the UK in order for us to formally evaluate the ability of GALEAS bladder to act as a triage test for flexible cystoscopy. In parallel with that, we're also working with Nonacus to investigate a very large cohort of patients who were recruited into a previous non-muscle invasive bladder cancer surveillance study. So again, several thousand urine samples for us to evaluate in the non-muscle invasive bladder cancer surveillance setting.
And what we're very actively working on at the moment is using the same panel of mutations (451 variants across 23 genes) and the same Nonacus capture approach (which is one of the unique components of GALEAS bladder) to identify circulating tumor DNA - our work in this area so far has been very promising and that clearly has great relevance for patients who are being managed with muscle-invasive bladder cancer.
Are there any limitations or potential drawbacks to using the GALEAS Bladder test for detecting bladder cancer?
We've devised a panel that potentially detects 96% of all bladder cancers. So 96% of all bladder cancers will have one or more of the 451 single nucleotide variants that are in the panel, and one or more above the threshold for a positive test is enough to be a positive test. However, that does mean that around 4% of bladder cancers do not necessarily have those mutations. And although that's a relatively small number, it still is a potential limitation of the test. And clearly it's a test that relies heavily on next generation sequencing technologies and for the time being that means that it's going to have to be a laboratory based test. So even if a patient gives their urine sample in the hospital setting, it is going to have to then be analyzed by a genomics laboratory. So at the moment point of care testing is not possible. However, we've seen amazing advancements of sequencing technologies over the last two decades.
And so there's no reason that, perhaps in the near future, it could actually become a near patient test with a much, much quicker turnaround time.
Alluding to the bad consequences of a false negative result when you miss a cancer. So two things we're doing - firstly, because it's a capture based library prep workflow, we get off target reads, which can in theory be used to give us genome-wide copy number data. We're looking at whether we can incorporate this into the test as a safety net to make sure that we don't miss any significant bladder cancers because aggressive high-grade bladder cancers are characterized by a lot of copy number changes. Secondly, in the BC-Recon study, which Rik has mentioned, we're not talking about relying solely on the biomarker test for cancer detection.
We're talking about, eventually, perhaps swapping it in for flexible cystoscopy, but keeping imaging and urine cytology there. So it will only be one of three tests which is used to detect bladder cancer. And what we hope that the BC-Recon study will show is that this can really simplify and make the investigations less burdensome, whilst actually never missing any significant bladder cancers. So I think we've got some safety and redundancy built into our trials.
I think it's also important to say that there are a number of other DNA and RNA based urine tests for bladder cancer. We think that the sensitivity and specificity that we have achieved so far with GALEAS Bladder is very competitive and as good, if not better, than other tests that are available. I think the analytical steps are very easy to understand, are very transparent. But with all such tests, DNA and RNA based, even protein-based urine tests for bladder cancer, they perform better in patients with higher grade and higher stage disease.
And clearly those are the most important cancers not to miss. When we look at the data from our latest study that was published in European Urology Oncology earlier this year, when we look at high grade tumors we have a one hundred percent detection rate for high grade Ta and for high grade T1, and so we're missing very few worrying or concerning cancers. If we also look at that same publication and the patients that were undergoing surveillance, we didn't miss any high grade non-muscle invasive cancers or any carcinoma in situ. So, although some of our future studies are building in elements of redundancy because GALEAS Bladder is not going to be the only test that's being used, we are very confident of the performance of GALEAS bladder.
Is there anything you would like to add in closing?
No, thank you very much for interviewing us over GALEAS Bladder, it's been a lot of work over a lot of years, and we're very happy with the result.
Yeah, I think that's right. It's taken us about eight years, maybe slightly more, to get from the starting point, to actually having a product that's available on the market. I think what really excites us, are the possibilities for this test being able to streamline the bladder cancer patient pathway, so various different indications for using the test throughout the bladder cancer, patient journey - various different indications that would both potentially streamline that journey, make it quicker, and also make it much less invasive.
And what really excites us is the ability to, in essence, use the same test to also identify circulating tumor DNA. So I suppose if you come back to us at some point in the not too distant future, we'll hopefully be able to tell you all about those data as well, such that you almost have a single test that has multiple uses throughout the patient pathway, and that can only be a good thing for patients.
What is the GALEAS Bladder tests for Bladder Cancer?
The University of Birmingham, in collaboration with Nonacus Ltd, has recently developed an innovative urine-based test for the non-invasive detection of bladder cancer known as the GALEAS Bladder test. This groundbreaking diagnostic tool offers a promising alternative to invasive procedures, such as cystoscopy, for identifying bladder cancer.
Bladder cancer is a prevalent form of cancer that affects the lining of the bladder. Early detection is crucial for successful treatment and improved patient outcomes. Traditional methods of diagnosing bladder cancer often involve uncomfortable and invasive procedures, such as the insertion of a thin tube with a camera into the bladder (cystoscopy). These methods can be distressing for patients and may result in complications.
The GALEAS Bladder test, however, provides a less invasive and more patient-friendly approach to detecting bladder cancer. The test is based on the analysis of specific genetic markers present in urine samples. These markers are indicative of the presence of bladder cancer cells (abnormal cells) and can be detected through advanced molecular techniques.
One of the key advantages of the GALEAS Bladder test is its non-invasive nature. Patients simply need to provide a urine sample, which can be collected easily and without discomfort. The sample is then analyzed in the laboratory, where the genetic markers associated with bladder cancer are assessed. This approach eliminates the need for invasive procedures and significantly reduces patient anxiety and discomfort.
Furthermore, the GALEAS Bladder test has demonstrated impressive accuracy in clinical trials. The test has shown a high sensitivity and specificity for detecting bladder cancer, meaning it can reliably identify the presence or absence of the disease. This accuracy is crucial for early detection and prompt initiation of appropriate treatment strategies.
The development of the GALEAS Bladder test is a result of the collaborative efforts between the University of Birmingham and Nonacus Ltd, a company specializing in molecular diagnostics. The expertise and resources from both entities have contributed to the successful translation of this innovative technology from the research laboratory to a practical clinical application.
The introduction of the GALEAS Bladder test has the potential to revolutionize bladder cancer diagnosis by providing a non-invasive, accurate, and patient-friendly alternative to traditional methods. This novel approach not only improves patient experience, but also enables earlier detection, leading to better treatment outcomes and potentially saving lives.
In conclusion, the GALEAS Bladder test, developed by the University of Birmingham and Nonacus Ltd, represents a significant advancement in the field of bladder cancer diagnosis. By utilizing urine-based genetic markers, this non-invasive test offers an accurate and convenient means of detecting bladder cancer. With its potential to enhance patient care and outcomes, the GALEAS Bladder test holds great promise for the future of bladder cancer diagnostics.
10 Key Takeaways from the GALEAS Bladder Test for Bladder Cancer?
- Non-Invasive Detection: One of the most significant advantages of the GALEAS Bladder Test is its non-invasive nature. Unlike traditional diagnostic methods such as cystoscopy, which can be uncomfortable and invasive, the GALEAS test relies on urine samples (possibly detecting blood in the urine), making it a more patient-friendly option.
- Early Detection: Early detection is crucial for successful treatment of bladder cancer. The GALEAS Bladder Test is highly sensitive and can detect bladder cancer in its early stages, allowing for timely intervention and improved patient outcomes.
- High Accuracy: The GALEAS Bladder Test exhibits a high level of accuracy in diagnosing bladder cancer. Its advanced technology enables the identification of genetic alterations in the DNA of bladder cells, ensuring reliable results.
- Risk Stratification: Beyond mere detection, the GALEAS Bladder Test also provides valuable information for risk stratification (high risk). It can provide a signal of the likelihood of tumor recurrence and progression, aiding clinicians in developing personalized treatment plans for patients.
- Monitoring Disease Progression: The GALEAS Bladder Test is not only useful for initial diagnosis but also for monitoring disease progression over time. It may allow healthcare professionals to track changes in the genetic profile of bladder cells, enabling them to adapt treatment strategies where suitable alternatives exist.
- Reduction in Healthcare Costs: By offering a non-invasive alternative to invasive procedures like cystoscopy, the GALEAS Bladder Test can potentially reduce healthcare costs associated with bladder cancer diagnosis and surveillance. It minimizes the need for frequent invasive examinations, making it a cost-effective option.
- Enhanced Patient Comfort: The non-invasive nature of the GALEAS Bladder Test improves patient comfort and reduces anxiety related to bladder cancer screening. Patients can easily provide urine samples without experiencing the discomfort associated with invasive procedures causing blood in the urine.
- Potential for Population Screening: Due to its non-invasive and cost-effective nature, the GALEAS Bladder Test has the potential to be used for population screening. It could be implemented as a routine screening tool, allowing for the early detection of bladder cancer in a broader population.
- Complementary to Existing Diagnostics: The GALEAS Bladder Test can complement existing diagnostic methods for bladder cancer. It can be used in conjunction with cystoscopy and other imaging techniques to enhance accuracy and improve patient outcomes.
- Future Research and Development: The GALEAS Bladder Test represents a significant advancement in the field of bladder cancer diagnosis, but further research and development are essential. Continued studies will refine the test's sensitivity, specificity, and overall performance, leading to continuous improvements in bladder cancer management.
Professor Richard T. Bryan MBChB PhD MRCS FAcadTM - About The Author, Credentials, and Affiliations
Rik Bryan, a former clinical urologist, has transitioned into a distinguished career as a full-time academic focused on bladder cancer research. Currently, he holds multiple prestigious positions within the field. As the Chief Investigator of the Bladder Cancer Prognosis Programme (BCPP), the SELENIB clinical trial, and POUT-T, he plays a pivotal role in advancing the understanding and treatment of bladder cancer. Additionally, Rik Bryan serves as the Director of the Bladder Cancer Research Centre (BCRC), which is housed within the Institute of Cancer & Genomic Sciences.
The BCRC is at the forefront of investigating the intricacies of bladder cancer, particularly in the realms of proteomics, genomics, and epigenomics. The center is dedicated to uncovering valuable biomarkers associated with bladder cancer and exploring novel agents, technologies, and pathways that hold promise for improved diagnostics and therapies.
Doug Ward, PhD - About The Author, Credentials, and Affiliations
Dr. Doug Ward, PhD, holds the position of Senior Research Fellow and serves as the esteemed theme lead for Biomarkers and Proteomics at the Bladder Cancer Research Centre, affiliated with the University of Birmingham. Dr. Ward's primary focus lies in utilizing proteomic and genomic platforms to uncover vital prognostic and diagnostic biomarkers specifically tailored for bladder cancer. He also dedicates his efforts towards the crucial aspects of biomarker validation and facilitating their smooth transition into practical clinical applications.