Mechanisms and Biomarkers of Response to BCG and Chemotherapy in Bladder Cancer

Almost 50 years after first use, instillation therapy with attenuated strains of Mycobacterium bovis (Bacillus Calmette-Guérin, BCG) is still the gold standard in the treatment of high-risk non-muscle invasive bladder cancer (NMIBC). However, up to 26% of patients recur within the first year and 41% within 5 years. Furthermore, progression to muscle-invasive bladder cancer (MIBC) after BCG therapy is observed in about 14% of patients, often resulting in delayed definitive therapy (e.g., radical cystectomy) with worse outcomes. Neoadjuvant platinum-based chemotherapy (NAC) has been shown to improve overall survival for patients with MIBC. However, only 40–50% of patients experience a tumor downstaging and the remaining patients are exposed to potential treatment toxicity and delay in definitive local therapy without apparent benefit. Several molecular characteristics associated with treatment response have been discovered in both bladder cancer disease states. However, no biomarkers (e.g., extracted from tissue, blood, or urine) have been validated for clinical use that reliably predict response in either NMIBC treated with BCG or MIBC treated with NAC. Therefore, this chapter aims to provide an overview of different known mechanisms of resistance to BCG in high-risk NMIBC and chemotherapy in MIBC, and how this knowledge is informing the development of predictive biomarkers.