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Bladder Cancer (C67)

Bladder cancer is a malignant neoplasm arising from the tissues of the urinary bladder, most commonly from the urothelial lining that normally stores and transports urine. The vast majority of cases are classified as urothelial carcinoma (formerly called transitional cell carcinoma), although squamous cell carcinoma, adenocarcinoma, and small cell variants can also occur. Bladder cancer is among the most common urologic malignancies and occurs more frequently in older adults, particularly men. Major risk factors include cigarette smoking, occupational exposure to aromatic amines and industrial chemicals, chronic bladder irritation, pelvic radiation, certain chemotherapeutic agents such as cyclophosphamide, and chronic infections such as schistosomiasis in endemic regions. The disease ranges from non–muscle-invasive tumors confined to the mucosa or lamina propria to aggressive muscle-invasive and metastatic disease capable of widespread dissemination. Pathophysiologically, bladder cancer develops through accumulation of genetic and epigenetic alterations affecting pathways that regulate cell proliferation, DNA repair, apoptosis, and cellular differentiation. Common molecular abnormalities include FGFR3 mutations, TP53 alterations, RB pathway disruption, HER2 signaling changes, and increased PD-L1 expression in some advanced tumors. Clinically, painless gross hematuria is the most common presenting symptom, although patients may also experience urinary frequency, urgency, dysuria, pelvic pain, or obstructive symptoms. Diagnosis is established through cystoscopy with transurethral resection and histopathologic evaluation, often supplemented by urine cytology and imaging studies. Treatment depends on disease stage and may include intravesical therapy, surgical resection, chemotherapy, radiation therapy, targeted therapy, antibody-drug conjugates, immunotherapy, or combinations of these modalities.

Causes

The etiology of bladder cancer is multifactorial and involves chronic exposure of the urothelial lining to carcinogenic substances that induce cumulative genetic and epigenetic damage. Cigarette smoking is the most significant risk factor, accounting for the majority of cases, because tobacco-derived carcinogens are filtered by the kidneys and concentrated in urine, where they directly contact the bladder epithelium. Occupational exposure to aromatic amines and industrial chemicals used in dye, rubber, leather, textile, and petroleum industries also substantially increases risk. Additional contributing factors include chronic bladder irritation and inflammation, long-term indwelling catheters, recurrent urinary tract infections, pelvic radiation therapy, and exposure to cyclophosphamide metabolites such as acrolein. In regions where schistosomiasis is endemic, chronic infection with Schistosoma haematobium strongly predisposes to squamous cell carcinoma of the bladder. Over time, these environmental and inflammatory insults promote mutations in pathways regulating cell cycle control, DNA repair, apoptosis, and cellular differentiation, ultimately driving malignant transformation of the urothelium.

Pathophysiology

The pathophysiology of bladder cancer involves progressive genetic and molecular alterations within the urothelial lining that lead to uncontrolled cellular proliferation, resistance to apoptosis, and invasive tumor growth. Chronic exposure to urinary carcinogens—particularly tobacco-derived chemicals—causes repeated DNA damage within urothelial cells, promoting mutations in key regulatory pathways such as TP53, RB, FGFR3, PI3K/AKT, and cell cycle control mechanisms. Distinct molecular pathways contribute to different disease phenotypes, with low-grade non–muscle-invasive tumors often associated with FGFR3 mutations and high-grade invasive tumors more commonly linked to TP53 and RB dysfunction. As malignant transformation progresses, tumor cells acquire the ability to evade immune surveillance, stimulate angiogenesis, degrade extracellular matrix barriers, and invade the lamina propria and detrusor muscle. Muscle-invasive disease carries a substantially greater risk of lymphatic and hematogenous metastasis to lymph nodes, liver, lungs, and bone. The tumor microenvironment, inflammatory signaling, and immune checkpoint pathways such as PD-1/PD-L1 also play important roles in tumor progression and therapeutic responsiveness, particularly in advanced urothelial carcinoma.

Clinical features

The clinical features of bladder cancer most commonly include painless gross hematuria, which is the classic presenting symptom and may occur intermittently during early disease. Some patients present with microscopic hematuria detected incidentally on urinalysis. As the tumor enlarges or becomes more invasive, irritative lower urinary tract symptoms such as urinary frequency, urgency, dysuria, nocturia, and suprapubic discomfort may develop due to irritation of the bladder mucosa. Muscle-invasive or advanced disease can produce pelvic pain, flank pain from ureteral obstruction, urinary retention, or constitutional symptoms such as fatigue and weight loss. Metastatic spread may lead to bone pain, lower extremity edema, respiratory symptoms, or hepatic dysfunction depending on the organs involved. Because hematuria may initially be transient or mistaken for urinary tract infection or benign urologic conditions, early diagnosis is sometimes delayed despite the presence of clinically significant disease.

Diagnosis

The diagnosis of bladder cancer is established through a combination of clinical evaluation, urine testing, endoscopic assessment, and histopathologic confirmation. Patients commonly present with painless hematuria, prompting evaluation with urinalysis, urine cytology, and imaging studies such as CT urography to assess the urinary tract for masses, obstruction, or upper tract involvement. The definitive diagnostic procedure is cystoscopy, which allows direct visualization of bladder lesions and enables transurethral resection of bladder tumor (TURBT) for tissue sampling and staging. Histopathologic examination determines tumor type, grade, depth of invasion, and the presence of muscle involvement, which are critical for treatment planning and prognosis. Additional staging studies may include CT, MRI, PET/CT, or bone scanning in patients with suspected locally advanced or metastatic disease. Molecular and biomarker testing, including assessment of FGFR alterations or PD-L1 expression, may also be performed in advanced urothelial carcinoma to guide targeted therapy and immunotherapy selection.

Mechanism of action videos

Biological pathways

  • p53 signaling pathway
  • VEGF signaling pathway
  • Signaling by FGFR3 fusions in cancer
  • Cell cycle
  • Bladder cancer
  • Adherens junction
  • Signaling by FGFR in disease
  • PI3K/AKT Signaling in Cancer
  • IRS-related events triggered by IGF1R
  • IRS-mediated signalling
  • Generic Transcription Pathway
  • Diseases of signal transduction by growth factor receptors and second messengers
  • Insulin receptor signalling cascade
  • IGF1R signaling cascade
  • Signaling by Type 1 Insulin-like Growth Factor 1 Receptor (IGF1R)
  • Constitutive Signaling by Aberrant PI3K in Cancer
  • Signaling by Receptor Tyrosine Kinases
  • RNA Polymerase II Transcription
  • Gene expression (Transcription)
  • PIP3 activates AKT signaling
  • MAPK family signaling cascades
  • Signaling by Insulin receptor
  • Signaling by FGFR
  • Negative regulation of the PI3K/AKT network
  • RAF/MAP kinase cascade
  • Intracellular signaling by second messengers
  • MAPK1/MAPK3 signaling
  • Transcriptional Regulation by TP53
  • PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling
  • PI3K Cascade
  • Signal Transduction
  • Oncogene Induced Senescence
  • Downstream signaling of activated FGFR2
  • SHC-mediated cascade:FGFR2
  • FRS-mediated FGFR2 signaling
  • Signaling by ERBB2 KD Mutants
  • TP53 Regulates Transcription of DNA Repair Genes
  • Signaling by ERBB2 in Cancer
  • Signaling by ALK
  • Regulation of TP53 Expression and Degradation

Clinical trials

  • Consolidative Radiation Therapy or Cystectomy After Initial Favorable Response Succeeding Enfortumab Vedotin Plus Pembrolizumab (REINFORCE)--- A Phase I/II Pilot Feasibility Trial
  • A Phase 2 Multicenter, Open-Label Study Evaluating the Efficacy and Safety of TYRA-300 in Participants With FGFR3 Altered Low Grade, Intermediate Risk Non-Muscle Invasive Bladder Cancer (SURF302)
  • FORAGER-2: A Phase 3, Randomized, Double-blind, Placebo-controlled Study Evaluating the Efficacy and Safety of Vepugratinib Combined With Enfortumab Vedotin and Pembrolizumab in Adults With Untreated Locally Advanced or Metastatic Urothelial Carcinoma With an FGFR3 Genetic Alteration
  • A Randomized, Open-Label, Phase 2/3 Study of Datopotamab Deruxtecan (Dato-DXd) Plus Carboplatin or Cisplatin Versus Gemcitabine Plus Carboplatin or Cisplatin in Participants With Locally Advanced or Metastatic Urothelial Carcinoma (la/mUC) Who Progressed During or After Enfortumab Vedotin (EV) Plus Pembrolizumab Combination Treatment TROPION-Urothelial03 (TU03)
  • Single Arm Phase II Study of Bladder Preservation With Immunoradiotherapy After a Clinically Meaningful Response to Neoadjuvant Therapy in Patients With Muscle Invasive Bladder Cancer (BRIGHT)
  • An Open Label, Multicenter, Single Arm Phase II Study to Evaluate the Activity and Tolerability of the Novel mTOR Inhibitor, MLN0128 (TAK-228), in Patients With Locally Advanced or Metastatic Transitional Cell Carcinoma of the Urothelial Tract Whose Tumors Harbor a TSC1 and/or a TSC2 Mutation
  • DART: Dual Anti-CTLA-4 and Anti-PD-1 Blockade in Rare Tumors
  • Phase II Study of Bladder-SparIng ChemoradiatioN With Durvalumab in Clinical Stage III, Node PosItive BladdeR CancEr (INSPIRE)
  • Randomized Phase II Trial of Pembrolizumab and Radiation vs. Radiation and Concurrent Chemotherapy for High-Grade T1 Bladder Cancer (PARRC Trial)
  • Enfortumab Vedotin in Combination With Pembrolizumab for Locally Advanced and/or Node Positive Urothelial Carcinoma Prior to Surgery (EV-ECLIPSE)
  • First-in-human, Open-label, Multi-site, Phase I/IIa, Dose Escalation Trial With Expansion Cohorts to Evaluate Safety and Preliminary Efficacy of BNT329 in Participants With Advanced Solid Tumors Known to Express CA19-9
  • A Pilot Study of Tazemetostat and Pembrolizumab (MK-3475) in Advanced Urothelial Carcinoma
  • Phase III Randomized Adjuvant Study of Pembrolizumab in muScle invaSive and locAlly aDvanced urOthelial caRcinoma (AMBASSADOR) Versus Observation
  • A Randomized, Phase 2 Trial to Evaluate the Safety and Efficacy of Eribulin Mesylate in Combination With Atezolizumab Compared to Atezolizumab Alone in Subjects With Locally Advanced or Metastatic Transitional Cell Urothelial Cancer Where Cisplatin-Based Treatment is Not an Option
  • A Phase 1 Study of Cabozantinib Plus Nivolumab (CaboNivo) Alone or in Combination With Ipilimumab (CaboNivoIpi) in Patients With Advanced/Metastatic Urothelial Carcinoma and Other Genitourinary Tumors
  • MAIN-CAV: Phase III Randomized Trial of Maintenance Cabozantinib and Avelumab vs Maintenance Avelumab After First-Line Platinum-Based Chemotherapy in Patients With Metastatic Urothelial Cancer
  • Phase Ib Trial of Erdafitinib Combined With Enfortumab Vedotin Following Prior Therapies for Metastatic Urothelial Carcinoma With FGFR2/3 Genetic Alterations
  • MODERN: An Integrated Phase 2/3 and Phase 3 Trial of MRD-Based Optimization of ADjuvant ThErapy in URothelial CaNcer
  • A Phase III Randomized Trial of Eribulin (NSC #707389) With Gemcitabine Versus Standard of Care (Physician's Choice) for Treatment of Metastatic Urothelial Carcinoma Refractory to, or Ineligible for, Anti PD1/PDL1 Therapy
  • Molecular Analysis for Therapy Choice (MATCH)
  • A Phase II Study of Ipilimumab, Cabozantinib, and Nivolumab in Rare Genitourinary Cancers (ICONIC)
  • Phase II Trial of Intravesical Gemcitabine and MK-3475 (Pembrolizumab) in the Treatment of Patients With BCG-Unresponsive Non-Muscle Invasive Bladder Cancer
  • A Phase II Multicenter Study of Enfortumab Vedotin With or Without Pembrolizumab in Rare Genitourinary Tumors (E-VIRTUE)
  • FORAGER-1: A Phase 1, Open-Label, Multicenter Study of LOXO-435 (LY3866288) in Locally Advanced or Metastatic Solid Tumors Including Urothelial Cancer With FGFR3 Alterations
  • A Phase 1a/1b Study of LY4052031, an Antibody-Drug Conjugate Targeting Nectin-4, in Participants With Advanced or Metastatic Urothelial Carcinoma or Other Solid Tumors
  • IZABRIGHT-Bladder01: A Randomized, Open-label, Phase 2/3 Trial of Izalontamab Brengitecan Versus Platinum-based Chemotherapy for Metastatic Urothelial Cancer in Participants With Disease Progression on or After an Immunotherapy-based Treatment
  • A Phase 3b, Randomized, Controlled Trial of Nadofaragene Firadenovec vs. Observation in Participants With Intermediate Risk Non-Muscle Invasive Bladder Cancer
  • A Phase 1 Study of Sigvotatug Vedotin in Advanced Solid Tumors
  • A Phase 1a/1b Study of BG-68501, a Selective CDK2 Inhibitor, in Participants With Advanced Solid Tumors
  • COMparative Prospective Assessment Through Clinically Integrated Randomized Trials Evaluating Intravesical Treatments: The COMPARE IT Trial
  • The Effects of Cannabis on Post Operative Recovery After Radical Cystectomy
  • A Phase II, Randomized, Multi-Center, Double-Blind, Comparative Global Study to Determine the Efficacy and Safety of Durvalumab in Combination With Olaparib for First-Line Treatment in Platinum-Ineligible Patients With Unresectable Stage IV Urothelial Cancer
  • A PHASE 3, OPEN-LABEL, RANDOMIZED STUDY TO EVALUATE ENFORTUMAB VEDOTIN IN COMBINATION WITH PEMBROLIZUMAB IN ADULT PARTICIPANTS WITH MUSCLE-INVASIVE BLADDER CANCER WHO ARE INELIGIBLE FOR OR HAVE ELECTED NOT TO UNDERGO CYSTECTOMY
  • A Phase 3, Single-Arm, Multicenter Study to Evaluate the Efficacy and Safety of UGN-102 as Primary Chemoablative Therapy in Patients With Low-Grade (LG) Non-Muscle Invasive Bladder Cancer (NMIBC) at Intermediate Risk (IR) of Recurrence
  • Phase II Study of Radiation Therapy and Anti-PD-L1 Checkpoint Inhibitor (Durvalumab) With or Without Anti-CTLA-4 Inhibition (Tremelimumab) in Patients With Unresectable, Locally Advanced, or Metastatic Urothelial Bladder Cancer That Are Ineligible or Refusing Chemotherapy
  • A Phase 1 Study to Evaluate the Tolerability, Safety, and Pharmacokinetics of TAR-210 in Japanese Participants With Bladder Cancer and Selected FGFR Mutations or Fusions
  • MC220503 Randomized Phase II Rescuing Cancer Immunotherapy With Plasma Exchange in Bladder Cancer 1 (ReCIPE-B1)
  • Phase I Study Evaluating the Safety and Tolerability of Locally Administered Anti-CD40 Agonist Antibody (2141-V11) in Subjects With Bladder Cancer
  • A Phase 3, Randomized, Open-label, Multicenter Study Evaluating the Efficacy and Safety of TAR-210 Erdafitinib Intravesical Delivery System Versus Investigator's Choice of Intravesical Chemotherapy in Participants With High-risk Non-muscle-invasive Bladder Cancer With Susceptible FGFR Alterations Who Had Received Intravesical Bacillus Calmette-Guérin (BCG)
  • A Scalable Cruciferous Vegetable Intervention to Reduce Bladder Cancer Recurrence and Progression

Therapeutic area: Oncology