FOLLOW-U; study protocol evaluating oncological systemic treatment response of advanced bladder cancer patients using urinoids

Abstract Background Muscle-invasive bladder cancer is an aggressive disease characterized by poor prognosis and high risk for metastases. Neo-adjuvant or induction (in case of node-positive disease) cisplatin-based combination chemotherapy followed by radical cystectomy is recommended for patients with muscle-invasive bladder cancer. However, response rates are highly variable, survival benefit is modest and generally limited to patients without residual (muscle-invasive) disease. Additionally, up to 50% of patients is cisplatin-ineligible due to comorbidities. Furthermore, (long-term) toxicity due to platinum-based chemotherapy treatment of bladder cancer can result in grade 3/4 adverse events in up to 82% of cases. Given the high rate of distant recurrences after neo-adjuvant/induction cisplatin-based chemotherapy and surgical resection, there is an urgent need for more effective treatment approaches, including strategies to evaluate and predict therapy responses. Methods The aim of this FOLLOW-U project is to enable precision medicine in muscle-invasive bladder cancer (MIBC). In this study we will use non-invasive urine-derived tumor organoid (urinoid) technology to follow tumor responses in MIBC patients undergoing systemic neo-adjuvant or induction treatment. The aim of the study is to include 60 patients receiving cisplatin-based chemotherapy and to establish 10 complete patient sets of sequential urinoid cultures before, during, and at the end of their treatment. Tumor drug sensitivity, resistance-development, and disease progression will be characterized using whole genome-, RNA-, single cell karyotype sequencing, immunohistochemistry and drug screening in a patient-specific manner. Discussion Overall, we aim to provide novel non-invasive urine-based organoid (urinoid) model-systems to study treatment resistance in muscle-invasive bladder cancer. These model-systems are patient specific and reflect the heterogeneous nature of bladder cancer at several time points over a patient’s treatment. Taken together, these urinoids model systems will provide the possibility to comprehensively study specific bladder cancer treatment and resistance over time. Ultimately, these non-invasive patient specific models can provide a follow-up tool of patients, allowing tailoring treatment efficacy to therapy sensitivity changes as they emerge.