Abstract
About 70% of bladder cancers (BCs) are diagnosed as non-muscle-invasive BCs (NMIBCs), while the remaining are muscle-invasive BCs (MIBCs). The European Association of Urology (EAU) guidelines stratify NMIBCs into low, intermediate, and high risk for treatment options. Low-risk NMIBCs undergo only the transurethral resection of the bladder (TURB), whereas for intermediate-risk and high-risk NMIBCs, the transurethral resection of the bladder (TURB) with or without Bacillus Calmette-Guérin (BCG) immune or chemotherapy is the standard treatment. A minority of NMIBCs show unfavorable prognosis. High-risk NMIBCs have a high rate of disease recurrence and/or progression to muscle-invasive tumor and BCG treatment failure. The heterogeneous nature of NMIBCs poses challenges for clinical decision-making. In 2020, the EAU made some changes to NMIBCs BCG failure definitions and treatment options, highlighting the need for reliable molecular markers for improving the predictive accuracy of currently available risk tables. Nowadays, next-generation sequencing (NGS) has revolutionized the study of cancer biology, providing diagnostic, prognostic, and therapy response biomarkers in support of precision medicine. Integration of NGS with other cutting-edge technologies might help to decipher also bladder tumor surrounding aspects such as immune system, stromal component, microbiome, and urobiome; altogether, this might impact the clinical outcomes of NMBICs especially in the BCG responsiveness. This review focuses on NMIBCs with unfavorable prognoses, providing molecular prognostic factors from tumor immune and stromal cells, and the perspective of urobiome and microbiome profiling on therapy response. We provide information on the cornerstone of immunotherapy and new promising bladder-preserving treatments and ongoing clinical trials for BCG–unresponsive NMIBCs.
Highlights
In the United States, urothelial carcinoma of the bladder represents the most frequent urothelial neoplasm, and the fourth most common cancer in men (McConkey and Lerner, 2019; Siegel et al, 2020)
- Intravesical chemotherapeutic drugs, alone or in combination, are used for high-risk non-muscle-invasive BCs (NMIBCs) such as pirarubicin, gemcitabine, and epirubicin (Kang et al, 2016); intravesical application of mitomycin C is a chemotherapeutic agent most used in patients who do not respond to Bacillus Calmette-Guérin (BCG) (Fankhauser et al, 2020)
Most bladder cancer (BC) are non-muscleinvasive and can be curable according to risk stratification into low, intermediate, and high risk; the minority of patients who do not respond to BCG immunotherapy poses a great challenge for the clinical decision-making
Summary
In the United States, urothelial carcinoma of the bladder represents the most frequent urothelial neoplasm, and the fourth most common cancer in men (McConkey and Lerner, 2019; Siegel et al, 2020). In 2020, the EAU made changes for NMIBC BCG failure definitions and treatment options (Table 1), since novel promising bladderpreserving treatments are currently under evaluation It has highlighted the need for reliable molecular markers for improving the predictive accuracy of currently available risk tables (Babjuk et al, 2019; Soukup et al, 2020). In BC research, the integration of NGS technologies with cutting-edge approaches might help to decipher other tumor-relevant aspects such as immune and stromal component, microbiome, and urobiome modifications. This might impact the clinical outcomes of NMIBCs, especially for the BCG responsiveness. The ongoing Food and Drug Administration (FDA)-approved clinical trials
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