Title: Improving the outcomes from bladder cancer through genomic stratification and novel agents
Funder: Department of Health and Social Care

Abstract: 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.

Lay abstract: My clinical and research work to date has focused on improving the health of patients with bladder cancer. I believe that we can improve the survival rate of patients with this cancer by tailoring treatments to individual cancers. To be able to predict how best to treat individual cancers, we first need to examine the characteristics and responses to treatments of individual cancers.Bladder cancer is a common disease with 10,000 new cases each year in the UK and nearly 400,000 people living with the disease worldwide. Across Europe, we spend nearly 5 Billion Euros each year on this cancer. Treatments vary from minor surgery to removal of the entire bladder, radiotherapy to the pelvis or chemotherapy. In the future, immune treatments will also be used. Patients with aggressive cancers receive multiple treatments, involving numerous hospital visits and affecting their quality of life for many months. Most bladder cancers look similar under the microscope and so are treated the same. However, some cancers are very sensitive to chemotherapy and do not need surgery, whilst others need immune therapy instead of or as well as chemotherapy. Some cancers do not respond to chemotherapy at all and so need surgery quickly.Current methods of treatment choice are unpredictable. However, recent scientific discoveries have found genetic differences between cancers can predict which treatment is best for an individual person. In this project, I will examine NHS bladder cancers to understand how genetic differences affect their response to treatment. I will then introduce genetic testing into patient care and use it to choose treatments. I will run a study of patients, from 10 hospitals across the UK, to see if changing treatment using genetic information is similar or better to current treatments. I will use computer models to map out how these cancers behave and how much it would cost to bring gene testing into the NHS. These models will tell us how best to test new pathways. In the long term, I aim to show that some cancers need faster treatment, some cancers do best with chemotherapy and radiotherapy, and that some cancers can be managed in the community. I will also test new treatments for bladder cancer using the 6 week window from diagnosis to bladder removal. This is safer than current ways of testing and allows us to examine how an individual's cancer responds to treatment. I presented my research ideas to 14 patients from Sheffield and a national patient support charity. They felt my plans addressed important areas for further research because of the need to avoid unnecessary treatment and to improve survival rates. When this work is completed I will report back to these patients and charities, to show how their concerns have helped improve outcomes for future patients. I will work with patient groups and charities to ensure that the information produced from this work is accessible to them. I will publicise the results through medical meetings and publications in journals read by doctors who look after bladder cancer. I will use social media to spread the findings to national newspapers, patients and their families. I will use the findings to influence NHS care through my experience with NICE and my contacts with the commissioners who pay for NHS bladder cancer services.

Research activity codes: 6.1 PHARMACEUTICALS;6.4 SURGERY;6.5 RADIOTHERAPY AND OTHER NON-INVASIVE THERAPIES
Health categories: CANCER AND NEOPLASMS