Liquid Biopsies to Transform the Diagnosis and Treatment of Gut Cancers

Research question Can circulating tumour DNA (ctDNA) liquid biopsies support more accurate, faster diagnosis and precise treatment in gut cancers? Background Patients with advanced gut cancers have some of the worst outcomes accounting for over a third of all cancer-related deaths across the world. Whilst improving survival is vital, our patients contributors highlight that delayed diagnosis, poor access to new diagnostics for tailored treatments and debilitating short- and long-term side effects of chemotherapy, still prevalent for these conditions, are poorly recognised and under-researched. Liquid biopsies with simple blood tests detecting circulating tumour DNA (ctDNA) could revolutionise accurate, faster diagnosis and personalise treatments, reducing unnecessary chemotherapy. ctDNA will transform the whole cancer pathway from early detection, faster diagnosis, treatment after surgery, recurrence monitoring and advanced cancer treatment. This research proposes to generate the clinical validation and clinical utility evidence to translate ctDNA into the NHS. Aim 1: Faster diagnosis of pancreatic and bile duct cancers with liquid biopsies Objectives: 1.2 - To demonstrate the reduction in repeated biopsies and improved time to diagnosis and patient satisfaction 1.2 - To accelerate clinical implementation through the NHSE Network of Excellence in Circulating Biomarkers with The NIHR Health Research Centre 1.3 - To cross validate emerging ctDNA technologies from the large plasma biobank associated with the programme Aim 2: To develop the current/next generation of ctDNA assays for Minimal Residual Disease (MRD) detection after bowel cancer surgery Objectives: 2.1 - To complete recruitment to the TRACC studies assessing ctDNA-directed chemotherapy decision-making after surgery 2.2 - To further clinically validate the INFINITY ctDNA-assay based on the TRACC observational (N=800 patients) and TRACC interventional (N=1621) samples also defining ctDNA surrogacy as a new clinical endpoint 2.3 - To clinically validate new and emerging methods for MRD detection 2.4 - To integrate liquid biopsies, tissue analysis and immune surveillance to identify immune mechanisms underlying relapse Aim 3: To generate evidence to support clinical implementation of serial ctDNA assays for monitoring therapy response and adaptation including drug holidays Objectives 3.1 - To initiate and conduct two new chemotherapy-free clinical trials ZODIAC (immunotherapy in dMMR gastric cancer) and INTERCEPT (cetuximab with treatment holidays in bowel cancer) 3.2- To analyse serially collected plasma in SOLAR (olaparib targeted treatment in gastric cancer), ZODIAC and INTERCEPT to define ctDNA association with response Methods This programme will leverage 5 clinical trials (3 pre-dating and 2 during this award) and their associated blood biobanks to address each aim, with pre-defined statistical analyses (Royal Marsden CTU). We will collaborate with the NHSE genomic laboratory hubs/ctDNA network of excellence, health economists, patient contributors and global ctDNA collaboratives to support evidence generation and translation during the timeframe of this award. Anticipated impact/dissemination As a result of this research, by 10/2028 ctDNA will start to be implemented into gut diagnosis and treatment paradigms in the NHS. Next generation ctDNA assays will be identified with evidence to support ctDNA surrogacy and immune control of microscopic relapse. Dissemination is through conference presentation, publication, patient contributors, charities and various media outlets.