Assessement of the Concordance of Genomic Alterations Between Urine and Tissue in High-Risk NMIBC Patients

The study population concerns :

• Group 1 : patients with high-risk NMIBC treated by BCG therapy
• Group 2 : patients with MIBC treated by radical cystectomy. This group will be considered as a positive control.

During their conventional follow-up, a urine collection will be performed to each patient for testing of cell-free DNA. Genomic analysis of the primary tumor will be carried out on the tumor samples resetced during the initial diagnosis.

Inclusion Criteria:

Common Inclusion Criteria

• Age ≥18 years at the time of screening.
• Capable of giving signed informed consent
• BCG-naïve (patients who have not received prior intravesical BCG or who previously received but stopped BCG more than 3 years before study entry are eligible).
• No prior radiotherapy to the bladder.
• ECOG (Eastern Cooperative Oncology Group) performance status of 0 or 1.
• At screening, tumor tissue provision from the initial surgery, formalin-fixed and paraffin-embedded (FFPE) is mandatory for DNA extraction and next-generation sequencing.
• Absence of metastasis, as confirmed by a negative CT or MRI scan of the pelvis, abdomen and chest, no more than 4 weeks prior to the enrolment.
• Life expectancy of at least 12 weeks.
• Must be a candidate for BCG treatment.
• Adequate organ and marrow function as defined below:

Hemoglobin ≥9.0 g/dL Absolute neutrophil count ≥1.0 × 109/L Platelet count ≥75 × 109/L Serum bilirubin ≤1.5 × the upper limit of normal (ULN). This will not apply to patients with confirmed Gilbert's syndrome, who will be allowed in consultation with their physician.

Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 × ULN Measured creatinine clearance (CL) >40 mL/min or calculated creatinine CL >40 mL/min as determined by Cockcroft-Gault (using actual body weight) Males Creatinine CL = (Weight (kg) × (140 - Age))/(72 × serum creatinine (mg/dL)) (mL/min)

Females Creatinine CL = (Weight (kg) × (140 - Age) )/(72 × serum creatinine (mg/dL)) × 0.85 (mL/min) - Being covered by a national health insurance

Specific Inclusion Criteria for Non-Muscle Invasive Bladder Cancer (NMIBC) group

• Local histological confirmation (based on pathology report) of high-risk transitional cell carcinoma of the urothelium of the urinary bladder confined to the mucosa or submucosa (predominantly urothelial even though mixed histology are allowed). A high-risk tumor is defined as one of the following:
• T1 tumor
• High grade/G3 tumor
• CIS
• Multiple and recurrent and large (with diameter of largest evaluable node ≥3 cm) tumors (all conditions must be met in this point)
• Complete resection of all Ta/T1 papillary disease prior to enrolment, with the most recent TURBT (Trans Urethral Resection of Bladder Tumor) occurring 2 months or less prior to signing informed consent for this study. Patients with residual CIS after TURBT are eligible.
• At least one additional resection of the primary tumor has been performed in case of T1 tumors, or incomplete initial TURB, or in case of doubt about the completeness of a TURB, or if there is no muscle in the specimen (can be omitted if primary CIS (In situ cancer) only was found.)

Specific Inclusion Criteria for Muscle Invasive Bladder Cancer (MIBC) group Patients with histologically proven muscle-invasive bladder cancer (MIBC) scheduled before radical cystectomy.

Non-Inclusion Criteria:

Common Non-inclusion Criteria

• Evidence of lymphovascular invasion of bladder tumor, except if treatment with BCG is deemed to be the only clinically viable treatment (ie, clinical candidates of cystectomy and/or chemotherapy, etc are excluded).
• Known or documented absolute and/or relative contraindication of adjuvant intravesical BCG treatment.
• Concurrent extravesical (ie, urethra, ureter, or renal pelvis), non-muscle-invasive transitional cell carcinoma of the urothelium.
• Any concurrent chemotherapy, Intra Peritoneal, biologic, or hormonal therapy for cancer treatment. Concurrent use of hormonal therapy for non-cancer-related conditions (eg, hormone replacement therapy) is acceptable.
• Concurrent treatment with systemic immunostimulatory agents prior to the first dose of study treatment.
• History of allogenic organ transplantation. Patients with any history of allogenic stem cell transplantation are also excluded
• History of active primary immunodeficiency
• Pregnant or breastfeeding women
• Being deprived of liberty or under guardianship

Specific Non-inclusion Criteria for NMIBC group

- Evidence of muscle-invasive, locally advanced, metastatic, and/or extra-vesical bladder cancer (ie, T2, T3, T4, and / or stage IV)