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

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.

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.

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.