The GALEAS™ Bladder genomic urine test for de-escalating surveillance in bladder cancer patients

RESEARCH QUESTIONS - Can the GALEAS Bladder urine test replace some cystoscopies in the follow-up of high-risk non-muscle-invasive bladder cancer (HR-NMIBC) patients? - Can gene expression profiles predict response to BCG and/or radiotherapy to enable personalised therapy? BACKGROUND HR-NMIBC patients undergo intensive cystoscopic surveillance during and after treatment. Cystoscopy is invasive, costly, morbid, and operator-dependent (sensitivity ?85%, specificity ?87%). With Nonacus Ltd, we have developed the GALEAS Bladder (GB) urine test for bladder cancer detection. Urine DNA is deep-sequenced to identify mutations in bladder cancer (BC) associated genes; sensitivity is >92% for incident BC (89% specificity) with >98% sensitivity for HR-NMIBC detection. For recurrence detection in NMIBC follow-up, sensitivity is 86% (all HR-NMIBCs detected). Cystoscopy-negative/GB-negative patients have half the risk of subsequent recurrence than GB ‘false-positive’ patients and it may be possible to de-escalate their surveillance. Transcriptomic profiling of index tumours will determine if NMIBC subtypes or other signatures predict response to BCG or radiotherapy. AIMS AND OBJECTIVES Primary objectives: to quantify recurrence-free intervals in cystoscopy-negative/GB-negative (‘double-negative’) patients and to consider alternative surveillance strategies. Secondary objectives: to assess the predictive accuracy of molecular subtypes/signatures, the prognostic value of double-negative status following treatment, and to observe events in cystoscopy-negative/GB-positive patients. METHODS We will partner the TRAIN trial (NIHR163351), a phase 3 RCT of radiotherapy with radiosensitisation versus intravesical BCG for HR-NMIBC. Our proposal, TRAIN-gen, is arranged into four Work Packages. WP1: Urine collection (1-30m). We will collect pre-cystoscopy urine samples every 3-months until recurrence or 24-months for 320 TRAIN participants. WP2: Urine analysis (1-30m). Samples will undergo Nonacus GB testing (readouts: test-positive/negative, mutations with variant allele frequencies). We will estimate the proportion of double-negative patients who remain event-free at each follow-up, supported by Kaplan-Meier plots and 95%CIs. WP3: Health economics (30-36m). A decision-analytic model will assess the cost-effectiveness of replacing some cystoscopies with GB and/or longer intervals between surveillance for double-negative patients, including costs and consequences of recurrence over a 10yr period. WP4: Transcriptomics (1-36m). Subtypes and signatures from Veracyte whole-transcriptome array analysis of FFPE tumours will be associated with therapy responses. TIMELINES FOR DELIVERY 36-months KNOWLEDGE MOBILISATION, DISSEMINATION AND IMPACT Key stakeholders are NMIBC patients, carers, and healthcare professionals/service providers/commissioners. With PPI contributors, results will be publicised via consumer groups and charities, TRAIN webpages, blogs, podcasts, and social media. Results will be published in peer-reviewed journals and presented at national/international meetings. We will engage with NICE, NHS and professional groups. Results will be shared with patients, clinicians and commissioners at individual sites. RESEARCH INCLUSION BC incidence increases with smoking and industrial exposure in jobs associated with less-affluent socioeconomic groups. Participants will be recruited from centres and regions that include under-served populations.