Development of the UroMark assay. A non-invasive test for the detection of bladder cancer in urinary sediment cells

Lead Research Organisation: University College London
Department Name: Surgery

Abstract

Investigation for bladder cancer in patients with blood in their urine (haematuria) is important and incurs a cost to UK healthcare estimated at £55.39 million per year ranking bladder as one of the most expensive cancers to manage. Although haematuria is a sign of bladder cancer only 10% of patients with haematuria will be found to have cancer. In the majority of instances a non cancer cause and frequently no cause is found. The assessment of haematuria involves passing an instrument along the urethra, or water pipe, to view the lining of the bladder wall. The assessment known as cystoscopy is uncomfortable, carries a low but significant risk of infection and requires referral from a GP to hospital. We have developed a test which uses cutting edge technology known as highly multiplexed targeted sequencing to detect cancer specific changes known as epigenetic alterations in cells which can be collected from urine. A urine sample for testing can be provided at home and sent to our lab using the postal system. The test, UroMark, utilises a platform known as RainDrop BS-Seq to analyse a panel of 150 epigenetic alterations which accurately discriminate between bladder cancer and normal. In proof of concept studies the test performs with high sensitivity and specificity for the detection of bladder cancer.

The incorporation of a highly sensitive and specific assay will revolutionise bladder cancer pathways, have a profound impact on the requirement for cystoscopy and on patient wellbeing and, reduce the healthcare costs associated with investigation of haematuria and surveillance for disease recurrence.

Technical Summary

Cystoscopic investigation for bladder cancer in patients with haematuria and in patients requiring surveillance for recurrent disease incurs a cost to UK healthcare estimated at £55.39 million per year ranking bladder as one of the most expensive cancers to manage. We have developed a highly multiplexed targeted sequencing assay (UroMark) to detect cancer specific epigenetic alterations in urinary sediment, along with a home collection kit allowing the collection of urine through the postal system. The UroMark assay utilises a micro-droplet PCR platform (RainDance Technology) which allows the analysis of a panel of 150 epigenetically altered loci which accurately discriminate between tumour and normal urothelium. Proof of concept testing has shown the potential utility of this assay for the detection of bladder cancer in urinary sediment cells. The aim this project is to validate the UroMark assay through two non-IMP clinical trials. DETECT I, will determine if the assay can rule out bladder cancer in patients with haematuria and DETECT II will validate the diagnostic accuracy of the test in a cohort trial enriched for low grade cancer. Our aim is to show sufficient diagnostic precision to replace cystoscopy in the evaluation of patients with haematuria. The incorporation of a highly sensitive and specific assay will revolutionise bladder cancer pathways, have a profound impact on the requirement for cystoscopy and on patient well being and, reduce the healthcare costs associated with investigation of haematuria and surveillance for disease recurrence.

Planned Impact

Worldwide cancer affects around 14 million people each year. Approximately 22 million people are living with cancer and nearly 7 million people die each year. With around 450,000 new cases per year worldwide and almost 11,000 each year in the UK, bladder cancer is the 4th most frequent cancer in the UK in men. Despite recent therapeutic advances the disease still causes more than 165,100 deaths worldwide each year (5,242 in UK) according to the World Health Organization. While at early stages surgery is curative, the prognosis for patients with advanced disease and metastatic spread remains bleak with five-year survival rates of only 15%.

The accurate and timely diagnosis of bladder, particularly for females, is a key issue in increasing the long term survival of bladder cancer patients. The most common sign of bladder cancer is blood in the urine, known as haematuria, which is usually identified in the primary care setting. Patients are then referred to hospital, for visual inspection of the bladder by cystoscopy to rule out the presence of bladder cancer. At present approximately 100,000 patients a year are referred from primary care for cystoscopy in the UK, however only 10,000 cancers will be diagnosed. This means that of the patients who of undergo cystoscopy, an invasive, uncomfortable procedure requiring hospital attendance and associated with a low, but significant risk of infection, 90% will not have cancer and this cysotoscopy may ultimately be uneccesary. Not only does this have a major impact on patient wellbeing, it also results in a considerable cost to the health service. Cystoscopy to investigate haematuria costs the UK healthcare an estimated £55 million per year, which makes bladder one of the most expensive cancers to manage. There is therefore an urgent need for a non-invasive test which can rule out the presence of bladder cancer and accurately direct patients to cystoscopy if necessary. We have developed a non-invasive assay which has the potential to replace the need for cystoscopy for the detection of bladder cancer from urinary sediment cells.

This project has the potential to have a significant benefit on patients with haematuria, by reducing the need for invasive procedures, which are in the majority of cases unnecessary. It will also impact on their quality of life, reducing the number of hospital visits and the associated anxiety which often accompanies them. It may also lead to a more timely diagnosis, which would ultimately help improve survival rates, particularly among female patients. As bladder cancer is a major problem worldwide, once completed the UroMark assay also has the potential to benefit patient wellbeing internationally.
Ultimately a clinically useful non-invasive diagnostic test which can accurately rule out the presence of bladder cancer will also have significant benefit to the health services. Not only will it have to potential to significantly reduce the cost of the managing bladder cancer, by reducing the number of cystoscopies necessary. It also has a potential impact on the NHS resources, by reducing the number of hospital attendances freeing up both clinical and administrative resources, which will potentially allow for a more effective service delivery.
Furthermore, epigenetic alterations are highly cell type specific, the research proposed in this project will also provide the basis for others to examine the clinical utility of non-invasive epigenetic biomarkers for other disease, for example blood based markers of cancer or common diseases such as diabetes and heart disease. Finally, if proven useful, ultimately this research will also be of interest to molecular diagnostics companies or venture capitalists for commercialisation. As the IP is held by UCL/UCLH, potential revenue raised form the licensing will be put back into further research and development.

Publications

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Chakravarthy A (2016) Human Papillomavirus Drives Tumor Development Throughout the Head and Neck: Improved Prognosis Is Associated With an Immune Response Largely Restricted to the Oropharynx. in Journal of clinical oncology : official journal of the American Society of Clinical Oncology

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Chakravarthy A (2018) Pan-cancer deconvolution of tumour composition using DNA methylation. in Nature communications

 
Description Our data has been use to validate national guidlines for investigation of haematuria in the USA.
Geographic Reach North America 
Policy Influence Type Contribution to new or improved professional practice
Impact Improved guidelines for the assessment of haematuria resulting in fewer unnecessary investigations for patients. Woldu SL, Ng CK, Loo RK, Slezak JM, Jacobsen SJ, Tan WS, Kelly JD, Lough T, Darling D, van Kessel KEM, de Jong JJ, van Criekinge W, Shariat SF, Hiar A, Brown S, Boorjian SA, Barocas DA, Svatek RS, Lotan Y. Evaluation of the New American Urological Association Guidelines Risk Classification for Hematuria. J Urol. 2021 May;205(5):1387-1393. doi: 10.1097/JU.0000000000001550. Epub 2020 Dec 24. PMID: 33356483.
URL https://www.auajournals.org/doi/10.1097/JU.0000000000001550
 
Title Development and validation of a haematuria cancer risk score to identify patients at risk of harbouring cancer 
Description Background: A lack of consensus exists amongst national guidelines regarding who should be investigated for haematuria. Type of haematuria and age-specific thresholds are frequently used to guide referral for the investigation of haematuria. Objectives: To develop and externally validate the haematuria cancer risk score (HCRS) to improve patient selection for the investigation of haematuria. Methods: Development cohort comprise of 3539 prospectively recruited patients recruited at 40 UK hospitals (DETECT 1; ClinicalTrials.gov: NCT02676180) and validation cohort comprise of 656 Swiss patients. All patients were aged >18 years and referred to hospital for the evaluation of visible and nonvisible haematuria. Sensitivity and specificity of the HCRS in the validation cohort were derived from a cut-off identified from the discovery cohort. Results: Patient age, gender, type of haematuria and smoking history were used to develop the HCRS. HCRS validation achieves good discrimination (AUC 0.835; 95% CI: 0.789-0.880) and calibration (calibration slope = 1.215) with no significant overfitting (P = 0.151). The HCRS detected 11.4% (n = 8) more cancers which would be missed by UK National Institute for Health and Clinical Excellence guidelines. The American Urological Association guidelines would identify all cancers with a specificity of 12.6% compared to 30.5% achieved by the HCRS. All patients with upper tract cancers would have been identified. Conclusion: The HCRS offers good discriminatory accuracy which is superior to existing guidelines. The simplicity of the model would facilitate adoption and improve patient and physician decision-making. 
Type Of Material Model of mechanisms or symptoms - human 
Year Produced 2019 
Provided To Others? Yes  
Impact As a result we are collaborating with a team at University of Texas to validate a cancer risk score which may be used in future guidelines. 
URL https://onlinelibrary.wiley.com/doi/10.1111/joim.12868
 
Description Evaluation of the New American Urological Association Guidelines Risk Classification for Hematuria 
Organisation University of Texas Southwestern Medical Center
Country United States 
Sector Academic/University 
PI Contribution We provided the DETECT patient cohorts who underwent cystoscopic evaluation of hematuria. And contributed to the analysys and drafting of the subsequent publication to validate novel National Guidelines for investigation of haematuria in the USA.
Collaborator Contribution Our partners wished to validate guidelines. It was necessary to invite research groups such as ours with high quality trials data.
Impact Woldu SL, Ng CK, Loo RK, Slezak JM, Jacobsen SJ, Tan WS, Kelly JD, Lough T, Darling D, van Kessel KEM, de Jong JJ, van Criekinge W, Shariat SF, Hiar A, Brown S, Boorjian SA, Barocas DA, Svatek RS, Lotan Y. Evaluation of the New American Urological Association Guidelines Risk Classification for Hematuria. J Urol. 2021 May;205(5):1387-1393. doi: 10.1097/JU.0000000000001550. Epub 2020 Dec 24. PMID: 33356483.
Start Year 2021
 
Title METHODS OF DIAGNOSING BLADDER CANCER 
Description The present invention relates to methods of diagnosing bladder cancer in a patient, involving determining the methylation status of Methylation Variable Positions (MVPs) in DNA from the patient and providing a diagnosis based on methylation status data. The invention also relates to methods of treating bladder cancer comprising providing a diagnosis of bladder cancer by the diagnostic methods defined herein followed by administering one or more anti-cancer agents to a patient. The invention also relates to methylation-discriminatory arrays comprising probes directed to the MVPs defined herein and kits comprising the arrays. 
IP Reference WO2016207656 
Protection Patent application published
Year Protection Granted 2016
Licensed No
Impact Intention to license to UCLB Spinout
 
Title UK00003130435: UroMark 
Description Epinostix have a registered trademark for its first product, UroMark(r) (UK00003130435), in the UK with plans of expanding protection to the US and Europe. 
IP Reference  
Protection Trade Mark
Year Protection Granted 2016
Licensed No
Impact Furthermore, Epinostix have a registered trademark for its first product, UroMark(r) (UK00003130435), in the UK with plans of expanding protection to the US and Europe.
 
Title UroMark 
Description The UroMark assay is a targeted next generation sequencing assay which detects the presence of bladder cancer specific epigenetic alterations in urinary sediment. This unique approach predicts the presence of bladder cancer from urinary DNA with high sensitivity (98%) whilst retaining cancer specificity (97%), and has similar performance characteristics to cystoscopy (cystoscopy sensitivity and specificity >97%) (Feber et al., Clinical Epigenetics 2017). The founding team from UCL have performed the clinical validation of the UroMark assay in two dedicated MRC funded clinical trials, DETECT I and DETECTII, these trials have recruited over 4500 patients. The read out of these trials in currently under analysis at UCL. 
Type Diagnostic Tool - Non-Imaging
Current Stage Of Development Late clinical evaluation
Year Development Stage Completed 2017
Development Status Actively seeking support
Clinical Trial? Yes
Impact Epinostix, a UCL spin-out has been set up to mange the tec transfer with the intention to license UroMark from UCLB 
URL https://clinicaltrials.gov/show/NCT02676180
 
Company Name EPINOSTIX LTD 
Description Epinostix, a spin-out SME from University College London (UCL) founded in 2017, has developed a highly accurate non-invasive diagnostic test to detect bladder cancer in urine, called UroMark. The UroMark test is the only non-invasive test with performance characteristics comparable to cystoscopy and represents the only viable non-invasive replacement to cystoscopy in development. Epinostix will operate a software as a service (SaaS) model, with established laboratory partners (partners have been identified in the UK and US), who have the existing infrastructure to deliver the UroMark test both within the UK. 
Year Established 2017 
Impact Epinostix (UCLB) has received Tec Funding to develop route to market strategy in the US. Epinostix is entering into a MOU with Poplar labs with the intention to develop a licensing agreement around UroMark