Towards a better stratification of intermediate- and high-risk non-muscle-invasive bladder cancer patients

Bladder cancer (BC) is the most common malignancy of the urinary tract and the ninth most commonly diagnosed cancer worldwide. More than 90% of BCs in Europe and in North America are transitional cell carcinomas (TCC), derived from the urothelium. Approximately 75% of patients with BC present with disease confined to the mucosa (stage Ta, carcinoma in situ [CIS]) or submucosa (stage T1). These categories are grouped as non–muscle-invasive bladder cancer (NMIBC). Up to 70% of the NMIBC cases will recur, and 15% will progress in stage and grade.

The recurrence and progression rates of NMIBC are strongly associated with several clinical and pathological factors. Based on the available prognostic factors, the European Association of Urology (EAU) Guidelines Panel on NMIBC recommended stratification of patients into three risk groups – low-, intermediate- and high-risk – that can facilitate treatment recommendations. Tumors with any of the characteristics of T1 stage, high-grade (or G3), concomitant CIS or multiple, recurrent and large (>3 cm) Ta G1G2 tumor are categorized as high-risk tumors. Management of intermediate- and high-risk NMIBC consists of transurethral resection of bladder tumor (TURBT) and bladder instillations with Bacillus Calmette-Guérin (BCG) plus intensive follow-up and maintenance BCG. Despite this intensive treatment and follow-up schedule, these patients have a high risk for disease recurrence and a moderate to high risk for progression to muscle-invasive BC (MIBC) of up to 35-55% at 5-year follow-up.

The important problem exists for the NMIBC patients within the intermediate- and high-risk group, as currently there is no accurate marker (either clinical or pathological) that can efficiently differentiate subgroups with a higher probability of progression from the ones with similar phenotypic features but with low progression risk. The current major challenge and unmet need is 1) to identify the intermediate- and high-risk NMIBC patients who are at the highest risk for disease progression, 2) to predict treatment response, and 3) to identify novel targets for treatment and to improve treatment modalities in this specific subgroup. 

We hypothesize that adding molecular markers to existing risk models may be an answer to the unmet need. This project aims to deliver a combination of discriminating –omics and immunohistopathology biomarkers integrated with systems biology tools coupled to the state-of-the-art deep learning predictive modeling in order to establish a disease mechanism-based stratification of intermediate- and high-risk NMIBC patients to predict their risk of recurrence and/or progression as well as their treatment response. This will allow a better and more reliable risk stratification of the patients when compared to the current risk calculators. The desired outcome is to facilitate the therapeutic decision-making in BC management.

Within this project, for the first time, a combinatorial approach involving epigenetics datasets as well as high-throughput proteomics, transcriptomics, lipidomics, metabolomics and immunohistopathological data from tissue sections, blood and urine is attempted, with the ultimate aim to gain higher precision in stratification and therapeutic decision-making in intermediate- and high-risk NMIBC patients. This project brings together field experts in –omics technologies, who have developed all technology platforms required for this approach, as well as clinical centers in Flanders with experience in BC treatment. Combining the expertise in –omics technologies, clinical treatment, systems biology, and bioinformatics will enable the effective development and implementation of this systems biology-based approach to directly improve patient care.