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A clinical trial is underway in the UK to investigate whether treatment for muscle-invasive bladder cancer (MIBC) can be tailored to genetic subtypes of the disease.
The GUSTO study requires the laboratory team to deliver rapid gene expression subtype results to teams across twenty UK centers with a target turnaround of less than 7 days. To achieve this, the team has optimized new laboratory processes in collaboration with biomedical scientists, pathologists, National Health Service (NHS) laboratory management, and a commercial partner.
In recognition of its innovative approach, the GUSTO Trial Lab Team was recently honored by the Royal College of Pathologists, gaining one of its 2025 Achievement Awards.
We spoke with Jim Catto, Honorary Consultant Urological Surgeon at Sheffield Teaching Hospitals NHS Foundation Trust, Professor of Urology at the University of Sheffield, and Chief Investigator of GUSTO, to find out more about the study.
What inspired the GUSTO trial?
On a personal level, it is always individual patients who inspire our research. Some of our patients with MIBC achieved remarkable responses to chemotherapy, which led us to question whether removing the bladder was truly necessary in their cases. Others progressed during treatment, leaving us to wonder whether they might have been better served by immediate cystectomy instead.
We know that some patients with MIBC benefit from neoadjuvant chemotherapy given prior to radical cystectomy – but there are others who may not. Advances in molecular profiling have improved our understanding of genomic subtypes in bladder cancer, and several retrospective cohorts have suggested that responses to neoadjuvant therapy may differ depending on these molecular subtypes.
Who's involved, and what are the goals?
There is a huge team involved in GUSTO and all parts are equally vital. The Leeds Cancer Research UK Clinical Trials Unit, at the University of Leeds, runs the trial on a day-to-day basis. The sponsors (Sheffield Teaching Hospitals NHS Foundation Trust) and funders (NIHR and MRC) oversee safe implementation, patient safety, value of the trial, and delivery.
On the clinical side, we have the histopathology team in Sheffield that runs the pathological and genomics aspects, and a medical oncology team who developed the stratified care regimens and oversee safe delivery of the agents. There is also a surgical team of urologists that meets to discuss recruitment, standardize surgery, and review patient events.
Finally, we work closely with our industry partners: Veracyte, who developed the gene profiling test, and AstraZeneca, who supply the study drugs.
How is gene expression subtyping used to guide treatment decisions in bladder cancer?
In the randomized controlled trial, the control arm receives neoadjuvant chemotherapy prior to radical cystectomy. The experimental arm is divided into three according to subtyping. Luminal papillary and luminal tumors have immediate cystectomy, without neoadjuvant treatment. Luminal infiltrated tumors receive neoadjuvant durvalumab and tremelumimab plus adjuvant durvalumab. Basal and neuronal subtypes receive neoadjuvant chemo and immunotherapy, and adjuvant durvalumab.
What were the key considerations for optimizing turnaround times for gene expression subtyping?
We need to deliver diagnoses within usual NHS timelines, so timing is key. We had to work out how to deliver samples of invasive cancers from consented patients to Sheffield, extract RNA, run profiling, and allocate subtypes – all before patients arrive at their oncology clinics to discuss treatments.
What are the implications of the GUSTO trial results for patients with bladder cancer?
This is a phase 2 trial and so the immediate implications from GUSTO will be about design of a phase 3 definitive trial. However, we have shown that you can deliver a genomic study in real-time NHS timelines.
Overall, we are seeing some exciting results suggesting the individualized care for patients with MIBC is possible. And, as new treatments are coming very quickly, GUSTO has set a paradigm for genomic stratification of patients.
Why are academic and clinical partnerships so important in advancing diagnostics?
As the GUSTO team membership reflects, trials like this would not be possible without strong and close academic and clinical partnerships. Both bring different aspects to the study and different strengths to deliver clinical improvements.
This Article is included in the Johnson&Johnson Editor's Series on genitourinary pathology.
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