Inclusion Criteria:
* Ability to understand and willingness to provide written informed consent
* Age ≥ 18 yr at the time of consent. Eligibility is limited to adults since MIBC is not prevalent in persons under the age of 18 yr. Persons of all genders, gender identities, races, and ethnicity will be included
* New diagnosis of histologically confirmed muscle-invasive UC (TNM classification (UICC/AJCC 8th edition) of cT2-4aN0-2M0 at pathological examination and approved for either (1) systemic NAT followed by RC or (2) CRT
* Plan for treatment of MIBC with curative intent with one of the three SOC treatments as listed above
* Surgical resection, if planned, must include removal of the bladder and bilateral pelvic lymph node dissection if not already included
* Radiation therapy, if planned, must include transurethral resection of bladder tumor, followed by image guided radiotherapy plus sensitizing chemotherapy
* Representative FFPE tumor specimens from biopsy at diagnosis (including TURBT) in paraffin blocks (blocks preferred) or at least 10 unstained and 1 H\&E slides. Biopsied tumor specimen quality must have been verified by local pathology review. Fine-needle aspiration, brushing, cell pellet from pleural effusion, and lavage samples are not acceptable. For core-needle biopsy specimens, at least three cores should be submitted for evaluation
* For participants who have partners of childbearing potential: Partner and/or participant must not be planning to conceive and must follow guidelines and recommendations per the SOC for their various therapeutic interventions
Exclusion Criteria:
* Ongoing treatment with an approved or investigational anti-cancer therapy for a cancer that is distinct from UC. Hormone-replacement therapy or oral contraceptives are allowed. Ongoing systemic therapy for bladder cancer will not be exclusionary, but enrollment of this population will be limited
* Previous or concurrent cancer that is distinct from the cancer under investigation in primary site or histology, except treated cutaneous basal cell carcinoma or squamous cell carcinoma, low or intermediate risk prostate cancer under active surveillance, myeloproliferative disorders or indolent hematologic malignancies that do not require active systemic therapy, and small renal masses under active surveillance. Any cancer curatively treated \>two years prior to the first treatment for bladder cancer is permitted
