This trial aims at investigating the diagnostic ability of a combined diagnostic panel including systematic endoscopic evaluation (SEE), blood-based ctDNA assay, and urine-based cfDNA assay to predict the presence of residual tumor remaining in the bladder at cystectomy.

Patients who are planned for cystectomy due to bladder cancer will be considered for enrollment based on inclusion and exclusion criteria.

The principle outcome of this study is to determine the negative predictive value (NPV) of finding no muscle invasive (pT2) tumor in seeT0 patients with a negative result on the ctDNA assay prior to radical cystectomy.

Eligible candidates for radical cystectomy and INSITE trial:

• Patients with high grade T1 urothelial carcinoma who elect for "early" /upfront cystectomy
• Patients with non-muscle invasive high grade Ta urothelial carcinoma or carcinoma in situ who have relapsed or are refractory / unresponsive to intravesical therapy and have elected to undergo cystectomy
• cT2-T3 muscle invasive urothelial carcinoma (irrespective of receipt of neo-adjuvant chemotherapy) Prior to cystectomy, tissue (transurethral resection of bladder tumor), urine and blood samples will be obtained at baseline for urine biopsy, ctDNA testing and future correlative studies.

After anesthetic induction for radical cystectomy, the patient will undergo rigid cystoscopy with targeted transurethral resection (TUR) of visible tumor or tumor bed, and two additional random bladder biopsies of normal-appearing bladder mucosa. Urine and blood samples will be obtained day of procedure for utilization for urine biopsy, ctDNA, and future correlative studies.

Following cystectomy, a diagnostic testing panel of pre-cystectomy cystoscopic and biopsy findings, ctDNA, and urine biopsy will be compared to final pathologic specimen.

Blood samples will be obtained 4-6 weeks (±2 weeks) post-procedure and 6 months (±1 month) post-procedure for analysis and ctDNA for post-procedure surveillance and other additional correlative studies. Additional blood sample collections at 12 months and 24 months post-procedure are optional.

Inclusion Criteria:

1. Properly counselled patients with high grade T1 disease who elect for cystectomy
2. Properly counselled patients with non-muscle invasive high grade Ta urothelial carcinoma or carcinoma in situ who are unresponsive to intravesical therapy and have elected cystectomy
3. cT2-T3 muscle invasive urothelial carcinoma for planned cystectomy
4. Patient who have received prior intravesical therapy or multiple TURBTs can be enrolled (data regarding number of previous TURBTs and type of intravesical therapy will be collected).
5. Male or female patients age >=18 years at the time of consent.
6. Able and willing to comply with study requirements.
7. Patients must have a non-contrast phase component for CT scans of chest/abdomen/pelvis either pre-existing (prior to accrual) or obtained during the screening process.
8. Patients who undergo neoadjuvant systemic therapy for muscle invasive disease must be enrolled before starting systemic therapy.
9. Ability to understand and willingness to sign a written informed consent and HIPAA authorization document.

Exclusion Criteria:

1. Patients who undergo cystectomy with non-curative intent will be excluded.
2. Patients who have undergone previous definitive pelvic radiation for the purpose of treating bladder malignancy.
3. Patients who are pregnant or nursing.

Patients who are planned for cystectomy due to bladder cancer will be considered for enrollment based on inclusion and exclusion criteria. Eligible patients will have bio specimen collected in accordance with the trial protocol.