National multi-centre study: a urine-based test for improved management of bladder cancer patients

This national multi-center study has been delayed due to Covid-19 and a resulting lock-down of the factory in France producing our equipment for sample collection and processing. The necessary equipment could not be delivered until autumn 2020, causing a significant delay in patient inclusion and in the overall progress of the clinical trial. We highly appreciate the prolongation of the project period granted by the Norwegian research council, including the adjusted timeline for milestones. The project reached its' first milestone end of 2020 when all 6 hospitals participating in the multicenter study started patient inclusion. Only patients with a histologically confirmed non-muscle invasive bladder cancer can be included in the study. However, since the first urine sample is a pre-treatment sample it needs to be collected prior to surgery and thereby prior to the pathological evaluation of tumor histology. Eligible patients will be surveilled for the study period. Patients with a negative histology result - where presence of bladder cancer tumor cells can not be confirmed - are excluded. So far, >560 eligible patients have been diagnosed with a histologically confirmed non-muscle-invasive bladder cancer. Our recent pilot study indicates that 80% of the patients will be qualified for monitoring with the urine test (positive test at inclusion). In order to reach the goal of following 500 patients longitudinally, we have increased the inclusion goal from 500 to 600 patients. With the current inclusion rate, we expect to reach the goal in 2023, in line with the project milestones, indicating that the study has a good progression. Included patients will be followed for 2 years with urine samples collected during their standard clinical examination (cystoscopy). In addition, clinical data are collected for one additional year to reveal potential recurrences after the final urine sampling. Urine sampling has been completed for >200 patients, and ~6000 urine samples have been biobanked. In 2022, we performed an interim analysis focusing on evaluation of quality. The main goal was to identify potential improvement points. Specific goals were as follows: 1) Evaluate whether there are unexpected differences in DNA concentration or methylation levels in urine samples from different hospitals 2) Evaluate the value of collecting 2 parallel urine samples per clinical control 3) Validate the thresholds used to score a biomarker as positive or negative, and - based on these thresholds - validate the sensitivity of the test at inclusion point The results were satisfactory. The interim analysis confirmed that the study protocol works well, and that the data are of good and comparable quality across hospitals. The scoring threshold was validated We have annual joint meetings for all project participants, the most recent Jan 2023. In the meeting, the study progression and relevant clinical aspects were discussed. The meeting was also an arena for exchanging experiences, and for ensuring standardization and consistency regarding patient inclusion, follow-up, and reporting of clinical data. In addition, smaller meetings are arranged by the project coordinators (H Pharo and HM Vedeld). Autumn 2023, meetings were organized both for the study nurses and for the user panel. The topics of the meeting with the study nurses were patient inclusion status and experiences with the urine filtration device, follow-up of patients and reporting of clinical data. In the user panel meeting, patient perspectives related to a future clinical implementation of the urine test was discussed and resulted in relevant and useful feedback. The multi-centre study was presented by project coordinator Heidi Pharo at 2 scientific conferences/seminars autumn 2023; an oral presentation at a Nordic one-day seminar in Copenhagen (Bio-Rad), and with a poster at the international conference NextGen Omics 2023 (London). For the latter, Pharo received the "young scientist award" for the best poster presentation. The multi-center trial has previously been presented at "Kirurgisk høstmøte" in Oslo by Rolf Wahlqvist (clinical responsible; 2022) and by Guro Lind (project PI; 2020), as well as at the international conference Biomarker Week Online (arranged by Oxford Global; Lind May 2021). In 2023, we have continued to optimize and standardize sample collection and analyses. An improved version of the urine filtration device used for sample processing is under development by collaborator Per Guldberg (Danish cancer society; Copenhagen).We have contributed withimprovement points. The aim is to develop a smaller, cheaper, more environmentally-friendly and more user-friendly version. We have also invested in a new instrument for test analysis, the QX600, which allows multiplexing. This will increase efficiency, both in terms of reduced sample material and costs. We are currently optimizing and validating these analyzes.

In Norway, bladder cancer is the 5th most common cancer and contributes significantly to morbidity and mortality. Despite being such a common disease, bladder cancer is under-prioritized and understudied. The vast majority of bladder cancers are non-muscle invasive and generally have a good prognosis, but as many as 50 to 70% of the patients experience recurrence and 10-20% progress to more aggressive muscle invasive bladder cancer. Due to the high recurrence rate, bladder cancer patients are frequently surveilled by cystoscopy after curative treatment. Cystoscopy is the gold standard for both diagnosis and surveillance of bladder cancer, but is invasive with suboptimal accuracy, and the frequent use makes bladder cancer one of the most expensive cancer types to manage for society. A non-invasive urinary test based on suitable biomarkers have the potential to replace parts of the cystoscopies and contribute to improved clinical management of bladder cancer. Indeed, such a non-invasive test has been requested for a long time, from both patients and urologists, and represents the clinical practice of tomorrow with clear benefits for the patients and the society. We have recently developed a biomarker-based urine test for detection of bladder cancer, with promising initial results. A national multi-center clinical study aiming at demonstrating the clinical utility of this test was partly granted last year from the health regions. Here we apply for coverage of the remaining costs to fully fund the study.