Non-invasive genomic profiling of bladder cancer using urinary cfDNA

Abstract: Urothelial bladder cancer (UBC) is the 7th most common cancer in Western societies with a rising global incidence. Disease management currently poses numerous challenges because of the variable risk of progression to Muscle Invasive Bladder Cancer (MIBC) and the propensity of Non-Muscle-Invasive Bladder Cancer (NMIBC) to recur, necessitating long-term surveillance at high cost to the NHS. UBCs are thus highly heterogenous in their clinical characteristics and this is mirrored in their genomics, features of which traverse conventional grade and stage groupings. Current detection and monitoring of bladder cancer is by cystoscopy, which is both expensive for the NHS and also burdensome for the patient. Following any subsequent biopsy or resection procedure, tumours are typically characterised by conventional histopathology using formalin-fixed paraffin-embedded (FFPE) tumour tissue to allow grading and staging of the tumour. Despite the genomic heterogeneity of UBCs and uncertainties in management across NMIBC risk categories, the potentially informative data from genomic characterisation is not routinely utilised outside of the research setting. Within our current IUK-funded project 'Developing a Robust, Reliable Multiplex Clinical Tool for Guiding Tumour Therapy' we have reported utilisation of the Affymetrix OncoScan® FFPE Assay Kit for genomic profiling of UBC using cell-free DNA (cfDNA) from urine. Further, we have demonstrated that the informative genomic aberrations evident in FFPE tumour material are echoed in urinary cfDNA, even for very early stage NMIBCs down to 0.5cm in diameter. Identifying such genomic complexity in a non-invasive fashion would likely be highly advantageous for facilitation of the diagnosis, management and surveillance of patients with NMIBC or MIBC, with significant cost-savings for the NHS. This proposal, in response to Part I of the IUK competition 'Stratified Medicine: connecting the UK infrastructure', is to collaborate with a network of specialists and infrastructure available in the UK to report on specific health and economic benefits of applying the OncoScan assay to non-invasive detection, characterisation and monitoring of UBC as compared to current procedures and workflows. Within this project phase we also plan to generate further evidence of the value of genomic grading of UBC with OncoScan. We will also work with the NIHR and bladder cancer CIs/PIs to generate a detailed plan for Phase II of the competition where we would trial this platform within the NHS to assess the utility and health-economic benefit compared to current practices.