Improving the outcomes from bladder cancer through genomic stratification and novel agents

Research questions: Does the use of genomic stratification improve survival, quality of life and reduce the cost of managing Bladder Cancer? Can genomic targeting be used to test novel agents in the window prior to Cystectomy? Background: Survival rates from BC have not improved for 30 years. Despite being the 3rd most prevalent cancer, BC receives relatively little research funding. Current treatments combine radical treatment with systemic chemotherapy and may include immunotherapy. Individual responses to multimodal approaches vary widely; around 30% of BCs respond completely to neoadjuvant chemotherapy, whilst 40% are locally advanced at cystectomy. Molecular advances have identified genomic subgroups that differ in treatment sensitivity. However, the ability to genotype in realtime and prospective evidence of personalised genomic outcomes are lacking. Aims and objectives: I will evaluate the feasibility of genomic stratification in BC and compare a stratified approach with generic (histology based) approach. I will complement on-going trials and obtain necessary information to plan future studies. I will test novel targeted agents for proof of efficacy using the window from diagnosis to cystectomy. My objectives are to deliver genomic stratification within the NHS BC pathway, examine response rates from stratified treatment approaches, and to test the feasibility of targeted novel agents. Methods: I propose five work packages (WPs) to complement and design studies of genomic stratification in invasive BC and low risk BC, to model its application in NHS care and to test personalised treatments in a window of opportunity study prior to Radical Cystectomy. In particular, I will detail genomic events in the 100,000 genomes BC cohort (cohort already collected), undertake exome sequencing of tumours within an RCT of genome stratified care and explore Quality of Life of genome-stratified care. Timelines for delivery: Within 12 months, I will detail the molecular profile of the 100,000 genomes BC cases (WP1). This will inform other work packages and help researchers in the field. By 2.5 years, I will have completed (WP3) the modelling analysis of the potential economic impact of genome stratified BC and have designed a Low risk BC RCT (WP4). This will need economic and quality of life outcomes, and so will need data from an ongoing PROMs studies, modelling data and PPI engagement. I will undertake the sequencing of BCs from GUSTO at 24-54 months and annotate with response rates (pT0) in the final 6 months (WP2). The window of opportunity work (WP5) will run throughout the 5 years. We will complete regulatory approvals within 6 months and start with Karonudib, before moving to intravesical immunotherapies. Anticipated impact and dissemination: The key impact from this work will be the introduction of genomic stratification in the BC pathway. I hypothesise that, as with breast cancer, stratification will allow personalised treatment to improve survival, reduce treatment intensity, cost and morbidity. This work will deliver trials that test this hypothesis and collaboration with a commercial partner to deliver this within the NHS. I will disseminate findings through publication, social media and the commencement of new trials.