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0
Mappings
0
Definitions
0
Inheritance
3
Pathophysiology
1
Histopathology
3
Phenotypes
3
Pathograph
1
Genes
3
Treatments
2
Subtypes
0
Differentials
0
Datasets
0
Trials
0
Models
13
References
1
Deep Research
🏷

Classifications

Harrison's Chapter
cancer solid tumor
ICD-O Morphology
Carcinoma

Subtypes

2
FGFR3-Mutant Urothelial Carcinoma
Most common FGFR alteration type, with activating point mutations in FGFR3 including S249C, Y373C, and R248C. These mutations cause constitutive receptor dimerization and activation.
FGFR2/3-Fusion Positive Urothelial Carcinoma
Gene fusions involving FGFR2 or FGFR3, most commonly FGFR3-TACC3, lead to constitutive kinase activation through dimerization mediated by the fusion partner.

Pathophysiology

3
FGFR3 Constitutive Activation
Activating mutations in FGFR3 cause ligand-independent receptor dimerization and autophosphorylation. The most common mutations affect cysteine residues in the extracellular domain, creating aberrant disulfide bonds that constitutively activate the receptor.
epithelial cell of urethra link
fibroblast growth factor receptor signaling pathway link ↑ INCREASED
urinary bladder link
RAS-MAPK Pathway Activation
FGFR3 activation stimulates the RAS-RAF-MEK-ERK signaling cascade through adaptor proteins FRS2 and GRB2. This drives uncontrolled urothelial cell proliferation and is a major effector of FGFR-mediated transformation.
MAPK cascade link ↑ INCREASED
PI3K-AKT Pathway Activation
FGFR3 activation recruits PI3K and activates the PI3K-AKT-mTOR signaling pathway, promoting urothelial cell survival and resistance to apoptosis.
phosphatidylinositol 3-kinase signaling link ↑ INCREASED

Histopathology

1
Urothelial Carcinoma VERY_FREQUENT
Bladder carcinomas are classified as urothelial carcinoma.
Show evidence (1 reference)
PMID:21566415 SUPPORT
"carcinomas are classified as urothelial carcinoma (UC)"
Abstract states that bladder carcinomas are classified as urothelial carcinoma.

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for FGFR-Altered Urothelial Carcinoma Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.

Phenotypes

3
Genitourinary 2
Hematuria VERY_FREQUENT Hematuria (HP:0000790)
Dysuria FREQUENT Dysuria (HP:0100518)
Constitutional 1
Fatigue FREQUENT Fatigue (HP:0012378)
🧬

Genetic Associations

1
FGFR3 (Somatic Activating Mutations and Fusions)
Show evidence (1 reference)
PMID:31264434 PARTIAL
"Specific mutations have been identified that predict response to therapy including ERCC2 mutations and cisplatin, DNA damage and repair mutations and checkpoint inhibitors, and FGFR3 mutations and FGFR tyrosine kinase inhibitors such as erdafitinib."
Supports clinically relevant FGFR3 mutations in urothelial carcinoma.
💊

Treatments

3
Erdafitinib
Action: pharmacotherapy MAXO:0000058
Agent: erdafitinib
Pan-FGFR tyrosine kinase inhibitor approved for FGFR2/3-altered locally advanced or metastatic urothelial carcinoma after platinum-containing chemotherapy. Demonstrates meaningful response rates and survival benefits in biomarker-selected patients.
Platinum-Based Chemotherapy
Action: chemotherapy MAXO:0000647
Cisplatin or carboplatin-based combination regimens remain first-line treatment for metastatic urothelial carcinoma regardless of FGFR status. Gemcitabine plus cisplatin is a standard regimen.
Immune Checkpoint Inhibitors
Action: immunotherapy Ontology label: Immunotherapy NCIT:C15262
PD-1/PD-L1 inhibitors are used in metastatic urothelial carcinoma. May be sequenced with erdafitinib in FGFR-altered tumors, though optimal sequencing strategies continue to evolve.
🔬

Biochemical Markers

1
FGFR3 Mutation Testing
{ }

Source YAML

click to show
name: FGFR-Altered Urothelial Carcinoma
creation_date: '2026-01-26T02:55:13Z'
updated_date: '2026-04-22T20:13:21Z'
description: >-
  FGFR-altered urothelial carcinoma is a molecularly-defined subset of bladder and
  upper urinary tract cancers harboring activating alterations in fibroblast growth
  factor receptors, most commonly FGFR3. FGFR3 mutations occur in approximately 15-20%
  of advanced urothelial carcinomas and are enriched in luminal-papillary subtypes.
  FGFR3 fusions, including FGFR3-TACC3, occur in a smaller subset. These alterations
  drive constitutive receptor activation and downstream RAS-MAPK and PI3K-AKT signaling.
  The identification of FGFR as an oncogenic driver led to development of erdafitinib,
  the first FDA-approved targeted therapy for metastatic urothelial carcinoma.
categories:
- Genitourinary Cancer
- Molecularly-Defined Cancer
parents:
- urothelial carcinoma
has_subtypes:
- name: FGFR3-Mutant Urothelial Carcinoma
  description: >-
    Most common FGFR alteration type, with activating point mutations in FGFR3
    including S249C, Y373C, and R248C. These mutations cause constitutive receptor
    dimerization and activation.
- name: FGFR2/3-Fusion Positive Urothelial Carcinoma
  description: >-
    Gene fusions involving FGFR2 or FGFR3, most commonly FGFR3-TACC3, lead to
    constitutive kinase activation through dimerization mediated by the fusion partner.
pathophysiology:
- name: FGFR3 Constitutive Activation
  description: >-
    Activating mutations in FGFR3 cause ligand-independent receptor dimerization
    and autophosphorylation. The most common mutations affect cysteine residues in
    the extracellular domain, creating aberrant disulfide bonds that constitutively
    activate the receptor.
  cell_types:
  - preferred_term: epithelial cell of urethra
    term:
      id: CL:1000296
      label: epithelial cell of urethra
  biological_processes:
  - preferred_term: fibroblast growth factor receptor signaling pathway
    modifier: INCREASED
    term:
      id: GO:0008543
      label: fibroblast growth factor receptor signaling pathway
  locations:
  - preferred_term: urinary bladder
    term:
      id: UBERON:0001255
      label: urinary bladder
  downstream:
  - target: RAS-MAPK Pathway Activation
    description: FGFR3 phosphorylation activates RAS-RAF-MEK-ERK signaling cascade
  - target: PI3K-AKT Pathway Activation
    description: FGFR3 phosphorylation recruits PI3K leading to AKT activation
- name: RAS-MAPK Pathway Activation
  description: >-
    FGFR3 activation stimulates the RAS-RAF-MEK-ERK signaling cascade through
    adaptor proteins FRS2 and GRB2. This drives uncontrolled urothelial cell
    proliferation and is a major effector of FGFR-mediated transformation.
  biological_processes:
  - preferred_term: MAPK cascade
    modifier: INCREASED
    term:
      id: GO:0000165
      label: MAPK cascade
- name: PI3K-AKT Pathway Activation
  description: >-
    FGFR3 activation recruits PI3K and activates the PI3K-AKT-mTOR signaling
    pathway, promoting urothelial cell survival and resistance to apoptosis.
  biological_processes:
  - preferred_term: phosphatidylinositol 3-kinase signaling
    modifier: INCREASED
    term:
      id: GO:0043491
      label: phosphatidylinositol 3-kinase/protein kinase B signal transduction
histopathology:
- name: Urothelial Carcinoma
  finding_term:
    preferred_term: Urothelial Carcinoma
    term:
      id: NCIT:C4030
      label: Urothelial Carcinoma
  frequency: VERY_FREQUENT
  description: Bladder carcinomas are classified as urothelial carcinoma.
  evidence:
  - reference: PMID:21566415
    reference_title: "Diagnosis and management of urothelial carcinoma of the bladder."
    supports: SUPPORT
    snippet: "carcinomas are classified as urothelial carcinoma (UC)"
    explanation: Abstract states that bladder carcinomas are classified as urothelial carcinoma.

phenotypes:
- category: Genitourinary
  name: Hematuria
  frequency: VERY_FREQUENT
  diagnostic: true
  description: >-
    Gross or microscopic hematuria is the most common presenting symptom of
    urothelial carcinoma. May be intermittent and painless initially.
  phenotype_term:
    preferred_term: Hematuria
    term:
      id: HP:0000790
      label: Hematuria
- category: Genitourinary
  name: Dysuria
  frequency: FREQUENT
  description: >-
    Painful urination may occur due to bladder irritation or tumor involvement.
    Often associated with urinary frequency and urgency.
  phenotype_term:
    preferred_term: Dysuria
    term:
      id: HP:0100518
      label: Dysuria
- category: Systemic
  name: Fatigue
  frequency: FREQUENT
  description: >-
    Constitutional symptoms including fatigue are common in advanced disease
    and may be related to anemia from chronic blood loss.
  phenotype_term:
    preferred_term: Fatigue
    term:
      id: HP:0012378
      label: Fatigue
biochemical:
- name: FGFR3 Mutation Testing
  notes: >-
    Molecular testing for FGFR3 mutations and fusions is required for erdafitinib
    eligibility. FDA-approved companion diagnostics include therascreen FGFR RGQ RT-PCR.
genetic:
- name: FGFR3
  association: Somatic Activating Mutations and Fusions
  notes: >-
    FGFR3 alterations occur in 15-20% of metastatic urothelial carcinomas. Common
    mutations include S249C, Y373C, R248C, and G370C. FGFR3-TACC3 fusions and other
    rearrangements also activate the pathway. FGFR2 alterations are less common.
  evidence:
  - reference: PMID:31264434
    reference_title: "Evolving Role of Genomics in Genitourinary Neoplasms."
    supports: PARTIAL
    snippet: "Specific mutations have been identified that predict response to therapy including ERCC2 mutations and cisplatin, DNA damage and repair mutations and checkpoint inhibitors, and FGFR3 mutations and FGFR tyrosine kinase inhibitors such as erdafitinib."
    explanation: "Supports clinically relevant FGFR3 mutations in urothelial carcinoma."
treatments:
- name: Erdafitinib
  description: >-
    Pan-FGFR tyrosine kinase inhibitor approved for FGFR2/3-altered locally advanced
    or metastatic urothelial carcinoma after platinum-containing chemotherapy.
    Demonstrates meaningful response rates and survival benefits in biomarker-selected
    patients.
  treatment_term:
    preferred_term: pharmacotherapy
    term:
      id: MAXO:0000058
      label: pharmacotherapy
    therapeutic_agent:
    - preferred_term: erdafitinib
      term:
        id: NCIT:C103273
        label: Erdafitinib
- name: Platinum-Based Chemotherapy
  description: >-
    Cisplatin or carboplatin-based combination regimens remain first-line treatment
    for metastatic urothelial carcinoma regardless of FGFR status. Gemcitabine plus
    cisplatin is a standard regimen.
  treatment_term:
    preferred_term: chemotherapy
    term:
      id: MAXO:0000647
      label: chemotherapy
- name: Immune Checkpoint Inhibitors
  description: >-
    PD-1/PD-L1 inhibitors are used in metastatic urothelial carcinoma. May be
    sequenced with erdafitinib in FGFR-altered tumors, though optimal sequencing
    strategies continue to evolve.
  treatment_term:
    preferred_term: immunotherapy
    term:
      id: NCIT:C15262
      label: Immunotherapy
disease_term:
  preferred_term: urothelial carcinoma
  term:
    id: MONDO:0040679
    label: urothelial carcinoma

classifications:
  icdo_morphology:
    classification_value: Carcinoma
  harrisons_chapter:
  - classification_value: cancer
  - classification_value: solid tumor
references:
- reference: DOI:10.1002/cac2.12602
  title: '<i>FGFR3</i> alterations in bladder cancer: Sensitivity and resistance to targeted therapies'
  found_in:
  - FGFR_Altered_Urothelial_Carcinoma-deep-research-falcon.md
  findings:
  - statement: In this review, we revisit the pivotal role of fibroblast growth factor receptor 3 (FGFR3) in bladder cancer (BLCA), underscoring its prevalence in both non‐muscle‐invasive and muscle‐invasive forms of the disease.
    supporting_text: In this review, we revisit the pivotal role of fibroblast growth factor receptor 3 (FGFR3) in bladder cancer (BLCA), underscoring its prevalence in both non‐muscle‐invasive and muscle‐invasive forms of the disease.
    evidence:
    - reference: DOI:10.1002/cac2.12602
      reference_title: '<i>FGFR3</i> alterations in bladder cancer: Sensitivity and resistance to targeted therapies'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: In this review, we revisit the pivotal role of fibroblast growth factor receptor 3 (FGFR3) in bladder cancer (BLCA), underscoring its prevalence in both non‐muscle‐invasive and muscle‐invasive forms of the disease.
      explanation: Deep research cited this publication as relevant literature for FGFR Altered Urothelial Carcinoma.
- reference: DOI:10.1007/s10147-024-02583-3
  title: 'Phase 3 THOR Japanese subgroup analysis: erdafitinib in advanced or metastatic urothelial cancer and fibroblast growth factor receptor alterations'
  found_in:
  - FGFR_Altered_Urothelial_Carcinoma-deep-research-falcon.md
  findings:
  - statement: 'Phase 3 THOR Japanese subgroup analysis: erdafitinib in advanced or metastatic urothelial cancer and fibroblast growth factor receptor alterations'
    supporting_text: In the THOR trial (NCT03390504) Cohort 1, erdafitinib demonstrated significantly prolonged overall survival (OS) (median 12.1 versus 7.8 months) and reduced risk of death by 36% (hazard ratio 0.64, P = 0.005) compared with chemotherapy in metastatic urothelial carcinoma (mUC) patients with FGFR alterations who progressed after ≥ 1 prior treatments, including anti-PD-(L)1.
    evidence:
    - reference: DOI:10.1007/s10147-024-02583-3
      reference_title: 'Phase 3 THOR Japanese subgroup analysis: erdafitinib in advanced or metastatic urothelial cancer and fibroblast growth factor receptor alterations'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: In the THOR trial (NCT03390504) Cohort 1, erdafitinib demonstrated significantly prolonged overall survival (OS) (median 12.1 versus 7.8 months) and reduced risk of death by 36% (hazard ratio 0.64, P = 0.005) compared with chemotherapy in metastatic urothelial carcinoma (mUC) patients with FGFR alterations who progressed after ≥ 1 prior treatments, including anti-PD-(L)1.
      explanation: Deep research cited this publication as relevant literature for FGFR Altered Urothelial Carcinoma.
- reference: DOI:10.1038/s41467-024-55331-6
  title: AI allows pre-screening of FGFR3 mutational status using routine histology slides of muscle-invasive bladder cancer
  found_in:
  - FGFR_Altered_Urothelial_Carcinoma-deep-research-falcon.md
  findings:
  - statement: AI allows pre-screening of FGFR3 mutational status using routine histology slides of muscle-invasive bladder cancer
    supporting_text: AI allows pre-screening of FGFR3 mutational status using routine histology slides of muscle-invasive bladder cancer
- reference: DOI:10.1158/1078-0432.ccr-23-1283
  title: 'Clinical and Genomic Landscape of FGFR3-Altered Urothelial Carcinoma and Treatment Outcomes with Erdafitinib: A Real-World Experience'
  found_in:
  - FGFR_Altered_Urothelial_Carcinoma-deep-research-falcon.md
  findings:
  - statement: 'Erdafitinib is the only FDA-approved targeted therapy for FGFR2/3-altered metastatic urothelial cancer.'
    supporting_text: 'Erdafitinib is the only FDA-approved targeted therapy for FGFR2/3-altered metastatic urothelial cancer.'
    evidence:
    - reference: DOI:10.1158/1078-0432.ccr-23-1283
      reference_title: 'Clinical and Genomic Landscape of FGFR3-Altered Urothelial Carcinoma and Treatment Outcomes with Erdafitinib: A Real-World Experience'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: 'Erdafitinib is the only FDA-approved targeted therapy for FGFR2/3-altered metastatic urothelial cancer.'
      explanation: Deep research cited this publication as relevant literature for FGFR Altered Urothelial Carcinoma.
- reference: DOI:10.1172/jci169241
  title: FGFR inhibition augments anti–PD-1 efficacy in murine FGFR3-mutant bladder cancer by abrogating immunosuppression
  found_in:
  - FGFR_Altered_Urothelial_Carcinoma-deep-research-falcon.md
  findings:
  - statement: FGFR inhibition augments anti–PD-1 efficacy in murine FGFR3-mutant bladder cancer by abrogating immunosuppression
    supporting_text: FGFR inhibition augments anti–PD-1 efficacy in murine FGFR3-mutant bladder cancer by abrogating immunosuppression
- reference: DOI:10.1186/s12943-023-01897-6
  title: The Impact of FGFR3 Alterations on the Tumor Microenvironment and the Efficacy of Immune Checkpoint Inhibitors in Bladder Cancer
  found_in:
  - FGFR_Altered_Urothelial_Carcinoma-deep-research-falcon.md
  findings:
  - statement: Currently, only limited knowledge is available regarding the phenotypic association between fibroblast growth factor receptor 3 (FGFR3) alterations and the tumor microenvironment (TME) in bladder cancer (BLCA).
    supporting_text: Currently, only limited knowledge is available regarding the phenotypic association between fibroblast growth factor receptor 3 (FGFR3) alterations and the tumor microenvironment (TME) in bladder cancer (BLCA).
    evidence:
    - reference: DOI:10.1186/s12943-023-01897-6
      reference_title: The Impact of FGFR3 Alterations on the Tumor Microenvironment and the Efficacy of Immune Checkpoint Inhibitors in Bladder Cancer
      supports: SUPPORT
      evidence_source: OTHER
      snippet: Currently, only limited knowledge is available regarding the phenotypic association between fibroblast growth factor receptor 3 (FGFR3) alterations and the tumor microenvironment (TME) in bladder cancer (BLCA).
      explanation: Deep research cited this publication as relevant literature for FGFR Altered Urothelial Carcinoma.
- reference: DOI:10.2478/acph-2024-0005
  title: A comprehensive overview of selective and novel fibroblast growth factor receptor inhibitors as a potential anticancer modality
  found_in:
  - FGFR_Altered_Urothelial_Carcinoma-deep-research-falcon.md
  findings:
  - statement: The arrival of comprehensive genome sequencing has accelerated the understanding of genetically aberrant advanced cancers and target identification for possible cancer treatment.
    supporting_text: The arrival of comprehensive genome sequencing has accelerated the understanding of genetically aberrant advanced cancers and target identification for possible cancer treatment.
    evidence:
    - reference: DOI:10.2478/acph-2024-0005
      reference_title: A comprehensive overview of selective and novel fibroblast growth factor receptor inhibitors as a potential anticancer modality
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: The arrival of comprehensive genome sequencing has accelerated the understanding of genetically aberrant advanced cancers and target identification for possible cancer treatment.
      explanation: Deep research cited this publication as relevant literature for FGFR Altered Urothelial Carcinoma.
- reference: DOI:10.3389/fimmu.2023.1258388
  title: 'Treatment approaches for FGFR-altered urothelial carcinoma: targeted therapies and immunotherapy'
  found_in:
  - FGFR_Altered_Urothelial_Carcinoma-deep-research-falcon.md
  findings:
  - statement: 'Treatment approaches for FGFR-altered urothelial carcinoma: targeted therapies and immunotherapy'
    supporting_text: The treatment of metastatic urothelial carcinoma has dramatically changed over the past decade with the approval of several therapies from multiple drug classes including immune checkpoint inhibitors, targeted therapies, and antibody drug conjugates.
    evidence:
    - reference: DOI:10.3389/fimmu.2023.1258388
      reference_title: 'Treatment approaches for FGFR-altered urothelial carcinoma: targeted therapies and immunotherapy'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: The treatment of metastatic urothelial carcinoma has dramatically changed over the past decade with the approval of several therapies from multiple drug classes including immune checkpoint inhibitors, targeted therapies, and antibody drug conjugates.
      explanation: Deep research cited this publication as relevant literature for FGFR Altered Urothelial Carcinoma.
- reference: DOI:10.3390/curroncol31110511
  title: The Evolving Molecular Landscape and Actionable Alterations in Urologic Cancers
  found_in:
  - FGFR_Altered_Urothelial_Carcinoma-deep-research-falcon.md
  findings:
  - statement: The genetic landscape of urologic cancers has evolved with the identification of actionable mutations that impact diagnosis, prognosis, and therapeutic strategies.
    supporting_text: The genetic landscape of urologic cancers has evolved with the identification of actionable mutations that impact diagnosis, prognosis, and therapeutic strategies.
    evidence:
    - reference: DOI:10.3390/curroncol31110511
      reference_title: The Evolving Molecular Landscape and Actionable Alterations in Urologic Cancers
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: The genetic landscape of urologic cancers has evolved with the identification of actionable mutations that impact diagnosis, prognosis, and therapeutic strategies.
      explanation: Deep research cited this publication as relevant literature for FGFR Altered Urothelial Carcinoma.
- reference: DOI:10.3390/ijms25020849
  title: Molecular Targeting of the Fibroblast Growth Factor Receptor Pathway across Various Cancers
  found_in:
  - FGFR_Altered_Urothelial_Carcinoma-deep-research-falcon.md
  findings:
  - statement: Fibroblast growth factor receptors (FGFRs) are a family of receptor tyrosine kinases that are involved in the regulation of cell proliferation, survival, and development.
    supporting_text: Fibroblast growth factor receptors (FGFRs) are a family of receptor tyrosine kinases that are involved in the regulation of cell proliferation, survival, and development.
    evidence:
    - reference: DOI:10.3390/ijms25020849
      reference_title: Molecular Targeting of the Fibroblast Growth Factor Receptor Pathway across Various Cancers
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: Fibroblast growth factor receptors (FGFRs) are a family of receptor tyrosine kinases that are involved in the regulation of cell proliferation, survival, and development.
      explanation: Deep research cited this publication as relevant literature for FGFR Altered Urothelial Carcinoma.
- reference: DOI:10.3390/ijms252212126
  title: Use of 3′ Rapid Amplification of cDNA Ends (3′ RACE)-Based Targeted RNA Sequencing for Profiling of Druggable Genetic Alterations in Urothelial Carcinomas
  found_in:
  - FGFR_Altered_Urothelial_Carcinoma-deep-research-falcon.md
  findings:
  - statement: Targeted treatment of advanced or metastatic urothelial carcinomas (UCs) requires the identification of druggable mutations.
    supporting_text: Targeted treatment of advanced or metastatic urothelial carcinomas (UCs) requires the identification of druggable mutations.
    evidence:
    - reference: DOI:10.3390/ijms252212126
      reference_title: Use of 3′ Rapid Amplification of cDNA Ends (3′ RACE)-Based Targeted RNA Sequencing for Profiling of Druggable Genetic Alterations in Urothelial Carcinomas
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Targeted treatment of advanced or metastatic urothelial carcinomas (UCs) requires the identification of druggable mutations.
      explanation: Deep research cited this publication as relevant literature for FGFR Altered Urothelial Carcinoma.
- reference: DOI:10.37349/etat.2024.00240
  title: Landscape of targeted therapies for advanced urothelial carcinoma
  found_in:
  - FGFR_Altered_Urothelial_Carcinoma-deep-research-falcon.md
  findings:
  - statement: Bladder cancer (BC) is the tenth most common malignancy globally.
    supporting_text: Bladder cancer (BC) is the tenth most common malignancy globally.
    evidence:
    - reference: DOI:10.37349/etat.2024.00240
      reference_title: Landscape of targeted therapies for advanced urothelial carcinoma
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Bladder cancer (BC) is the tenth most common malignancy globally.
      explanation: Deep research cited this publication as relevant literature for FGFR Altered Urothelial Carcinoma.
- reference: DOI:10.37349/etat.2024.00279
  title: 'Targeted therapies and molecular targets in the therapeutic landscape of advanced urothelial carcinoma: state of the art and future perspectives'
  found_in:
  - FGFR_Altered_Urothelial_Carcinoma-deep-research-falcon.md
  findings:
  - statement: Advanced urothelial carcinoma (aUC) has a dismal prognosis, with a 5-year survival rate of approximately 10%.
    supporting_text: Advanced urothelial carcinoma (aUC) has a dismal prognosis, with a 5-year survival rate of approximately 10%.
    evidence:
    - reference: DOI:10.37349/etat.2024.00279
      reference_title: 'Targeted therapies and molecular targets in the therapeutic landscape of advanced urothelial carcinoma: state of the art and future perspectives'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Advanced urothelial carcinoma (aUC) has a dismal prognosis, with a 5-year survival rate of approximately 10%.
      explanation: Deep research cited this publication as relevant literature for FGFR Altered Urothelial Carcinoma.
📚

References & Deep Research

References

13
<i>FGFR3</i> alterations in bladder cancer: Sensitivity and resistance to targeted therapies
1 finding
In this review, we revisit the pivotal role of fibroblast growth factor receptor 3 (FGFR3) in bladder cancer (BLCA), underscoring its prevalence in both non‐muscle‐invasive and muscle‐invasive forms of the disease.
"In this review, we revisit the pivotal role of fibroblast growth factor receptor 3 (FGFR3) in bladder cancer (BLCA), underscoring its prevalence in both non‐muscle‐invasive and muscle‐invasive forms of the disease."
Show evidence (1 reference)
DOI:10.1002/cac2.12602 SUPPORT Human Clinical
"In this review, we revisit the pivotal role of fibroblast growth factor receptor 3 (FGFR3) in bladder cancer (BLCA), underscoring its prevalence in both non‐muscle‐invasive and muscle‐invasive forms of the disease."
Deep research cited this publication as relevant literature for FGFR Altered Urothelial Carcinoma.
Phase 3 THOR Japanese subgroup analysis: erdafitinib in advanced or metastatic urothelial cancer and fibroblast growth factor receptor alterations
1 finding
Phase 3 THOR Japanese subgroup analysis: erdafitinib in advanced or metastatic urothelial cancer and fibroblast growth factor receptor alterations
"In the THOR trial (NCT03390504) Cohort 1, erdafitinib demonstrated significantly prolonged overall survival (OS) (median 12.1 versus 7.8 months) and reduced risk of death by 36% (hazard ratio 0.64, P = 0.005) compared with chemotherapy in metastatic urothelial carcinoma (mUC) patients with FGFR..."
Show evidence (1 reference)
DOI:10.1007/s10147-024-02583-3 SUPPORT Human Clinical
"In the THOR trial (NCT03390504) Cohort 1, erdafitinib demonstrated significantly prolonged overall survival (OS) (median 12.1 versus 7.8 months) and reduced risk of death by 36% (hazard ratio 0.64, P = 0.005) compared with chemotherapy in metastatic urothelial carcinoma (mUC) patients with FGFR..."
Deep research cited this publication as relevant literature for FGFR Altered Urothelial Carcinoma.
AI allows pre-screening of FGFR3 mutational status using routine histology slides of muscle-invasive bladder cancer
1 finding
AI allows pre-screening of FGFR3 mutational status using routine histology slides of muscle-invasive bladder cancer
"AI allows pre-screening of FGFR3 mutational status using routine histology slides of muscle-invasive bladder cancer"
Clinical and Genomic Landscape of FGFR3-Altered Urothelial Carcinoma and Treatment Outcomes with Erdafitinib: A Real-World Experience
1 finding
Erdafitinib is the only FDA-approved targeted therapy for FGFR2/3-altered metastatic urothelial cancer.
"Erdafitinib is the only FDA-approved targeted therapy for FGFR2/3-altered metastatic urothelial cancer."
Show evidence (1 reference)
DOI:10.1158/1078-0432.ccr-23-1283 SUPPORT Human Clinical
"Erdafitinib is the only FDA-approved targeted therapy for FGFR2/3-altered metastatic urothelial cancer."
Deep research cited this publication as relevant literature for FGFR Altered Urothelial Carcinoma.
FGFR inhibition augments anti–PD-1 efficacy in murine FGFR3-mutant bladder cancer by abrogating immunosuppression
1 finding
FGFR inhibition augments anti–PD-1 efficacy in murine FGFR3-mutant bladder cancer by abrogating immunosuppression
"FGFR inhibition augments anti–PD-1 efficacy in murine FGFR3-mutant bladder cancer by abrogating immunosuppression"
The Impact of FGFR3 Alterations on the Tumor Microenvironment and the Efficacy of Immune Checkpoint Inhibitors in Bladder Cancer
1 finding
Currently, only limited knowledge is available regarding the phenotypic association between fibroblast growth factor receptor 3 (FGFR3) alterations and the tumor microenvironment (TME) in bladder cancer (BLCA).
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Deep Research

1
Falcon
1. Disease Information
Edison Scientific Literature 34 citations 2026-04-05T15:10:29.547464

1. Disease Information

1.1 Definition and overview

FGFR‑altered urothelial carcinoma is not a separate histopathologic diagnosis, but a molecularly defined subset of urothelial carcinoma characterized by oncogenic alterations in FGFR2 and/or FGFR3 that can predict sensitivity to FGFR‑targeted therapy (notably erdafitinib). In a real‑world genomic/clinical cohort, Guercio et al. describe FGFR‑altered UC as tumors harboring oncogenic FGFR3 mutations or FGFR2/3 fusions, which are “established predictive biomarkers for erdafitinib.” (guercio2023clinicalandgenomic pages 2-4)

1.2 Key identifiers (availability in retrieved evidence)

  • ICD codes / MeSH / OMIM / Orphanet / MONDO: A distinct “FGFR‑altered UC” code was not identified in the retrieved evidence. In practice, coding is typically done at the disease-site level (e.g., bladder cancer / urothelial carcinoma) with FGFR status stored as a biomarker attribute.

1.3 Synonyms and alternative names

Common usage in the literature includes: * FGFR2/3‑altered urothelial carcinoma (testi2024targetedtherapiesand pages 11-13, benjamin2023treatmentapproachesfor pages 3-4) * FGFR3‑altered bladder cancer (guercio2023clinicalandgenomic pages 6-7) * FGFR3‑mutant urothelial carcinoma (bannier2024aiallowsprescreening pages 1-2)

1.4 Data provenance (patient-level vs aggregated)

Evidence includes: * Aggregated disease-level and biomarker-level resources (e.g., cohort multi‑omics in metastatic UC; reviews) (antar2024theevolvingmolecular pages 3-5, shang2024landscapeoftargeted pages 3-5) * Patient-level institutional clinical genomics + outcomes (real‑world erdafitinib outcomes, paired primary/metastasis discordance, cfDNA evolution) (guercio2023clinicalandgenomic pages 1-2, guercio2023clinicalandgenomic pages 6-7)


2. Etiology

2.1 Disease causal factors (mechanistic)

FGFR‑altered UC is driven by somatic activating alterations in FGFR signaling (primarily FGFR3), promoting urothelial tumor initiation/maintenance via pro‑proliferative and pro‑survival signaling (MAPK/PI3K/STAT) (shang2024landscapeoftargeted pages 3-5, shan2024moleculartargetingof pages 4-5).

2.2 Risk factors for urothelial carcinoma (UC)

Major risk factors for UC in general (not specific to FGFR subtype) include: * Tobacco smoking (listed as a major UC risk factor) (mitiushkina2024useof3′ pages 1-2, ferreira2023epimarkersforbladder pages 19-26) * Occupational exposure to aromatic amines (mitiushkina2024useof3′ pages 1-2) * Contaminated drinking water (mitiushkina2024useof3′ pages 1-2) * Family history + lifestyle interactions: in a population cohort, individuals with an affected first‑degree relative had elevated risk, and smokers with positive family history showed a strong interaction (HR 3.60; RERI 0.72), indicating gene–environment interplay at the level of familial susceptibility and smoking exposure (guercio2023clinicalandgenomic pages 1-2).

2.3 Protective factors

High-quality protective-factor evidence specific to FGFR‑altered UC was not identified in the retrieved evidence. For UC overall, prevention strategies generally focus on risk-factor avoidance (e.g., smoking cessation, reducing occupational carcinogen exposure), but quantitative protective estimates were not captured in the extracted evidence.

2.4 Gene–environment interactions

Direct GxE interactions tied specifically to FGFR alterations were not captured in the extracted 2023–2024 evidence. However, familial predisposition interacting with smoking for bladder cancer risk has been quantified (guercio2023clinicalandgenomic pages 1-2).


3. Phenotypes (clinical presentation)

3.1 Core clinical phenotypes of UC

Key presenting features of urothelial bladder cancer include: * Hematuria (gross or microscopic) as the most common presenting sign; one source notes “the most common presenting sign is hematuria (gross or microscopic)” (ferreira2023epimarkersforbladder pages 26-29). * Dysuria and polyuria also occur (ferreira2023epimarkersforbladder pages 26-29). * Stage association: visible hematuria is described as being “usually associated with more advanced stage/grade.” (ferreira2023epimarkersforbladder pages 26-29)

Upper tract UC (UTUC) is not extensively phenotyped in the extracted symptom-focused evidence, but UTUC is described as more aggressive with high invasiveness at diagnosis (60% invasive at diagnosis) (mitiushkina2024useof3′ pages 1-2).

3.2 Age of onset and distribution

  • Bladder cancer is predominantly a disease of older adults; one summary reports ~80% of patients are older than 65 years (ferreira2023epimarkersforbladder pages 19-26).

3.3 Stage distribution at diagnosis (UC overall)

  • NMIBC predominates: majority are NMIBC (70–80%), while MIBC accounts for ~20–30% at diagnosis (ferreira2023epimarkersforbladder pages 26-29).
  • Metastatic at diagnosis: about 5% of bladder cancers are metastatic at diagnosis (mitiushkina2024useof3′ pages 1-2).

3.4 Suggested HPO terms (examples)

  • Hematuria — HP:0000790
  • Dysuria — HP:0100518
  • Polyuria — HP:0000103
  • Urinary urgency — HP:0000012 (common in bladder cancer symptom clusters; not directly quantified in extracted evidence)

3.5 Quality-of-life impact

Direct validated QoL instrument data (e.g., EQ‑5D/SF‑36) specific to FGFR‑altered UC were not identified in extracted evidence; however, urinary symptoms (hematuria, dysuria, polyuria) are clinically burdensome (ferreira2023epimarkersforbladder pages 26-29).


4. Genetic / Molecular Information (FGFR alterations)

4.1 Causal/driver genes

  • FGFR3 is the dominant driver in this subtype; FGFR2 alterations occur but are comparatively rare in UC (guercio2023clinicalandgenomic pages 1-2, guercio2023clinicalandgenomic pages 2-4).

4.2 Alteration types and prevalence (key statistics)

Guercio et al. reported stage-stratified frequencies of FGFR3 alterations predictive of erdafitinib sensitivity: * NMIBC: 39% (199/504) * MIBC: 14% (75/526) * Localized UTUC: 43% (81/187) * Metastatic specimens: 26% (59/228) (guercio2023clinicalandgenomic pages 1-2)

A complementary Japanese multi‑omics cohort similarly reported FGFR3 alterations (mutations + fusions) of 44% in NMIBC and 15% in MIBC (komura2023theimpactof pages 1-2).

Metastatic biopsy profiling showed FGFR3 actionable targets in 26% of metastatic biopsies and noted that “potential therapeutic targets” were found in 73% overall (antar2024theevolvingmolecular pages 3-5).

A targeted RNA‑sequencing study found FGFR2/3 activating point mutations or fusions in 23.2% (54/233) of urothelial carcinomas, with enrichment in upper tract vs bladder (48% vs 20%) (mitiushkina2024useof3′ pages 2-3).

4.3 Pathogenic variants (examples; primarily somatic)

In a real-world metastatic erdafitinib-treated cohort, common FGFR3 alterations included: * S249C (59%), Y373C (9%), R248C (9%) * FGFR3–TACC3 fusions (13%) (guercio2023clinicalandgenomic pages 6-7)

4.4 Somatic vs germline

The evidence base here pertains to tumor somatic alterations and tumor-derived cfDNA evolution under therapy (guercio2023clinicalandgenomic pages 2-4). Germline FGFR2/3 causes of UC were not supported by extracted evidence.

4.5 Tumor heterogeneity and discordance

Clinically important sampling issue: among paired primary tumors and metachronous metastases, 26% showed discordant FGFR3 status, raising concern about using archival primary tissue alone for selection (guercio2023clinicalandgenomic pages 1-2, guercio2023clinicalandgenomic pages 2-4).


5. Mechanism / Pathophysiology

5.1 Molecular pathways downstream of FGFR3 alterations

FGFR3 activation can occur via missense mutations or FGFR3–TACC3 fusions: * Fusions: FGFR3–TACC3 fusions drive constitutive activation of MAPK, PI3K/AKT, and STAT3 signaling; altered TACC3 function may contribute to mitotic defects/aneuploidy (shang2024landscapeoftargeted pages 3-5). * Missense mutations: gain‑of‑function missense mutations can drive ligand-independent dimerization and increased kinase activity (shan2024moleculartargetingof pages 4-5).

5.2 Molecular subtype context and tumor microenvironment (TME)

FGFR3 alterations are strongly associated with luminal biology: * In a large Japanese cohort, FGFR3 alterations were linked to luminal papillary enrichment: “LumP was significantly more prevalent in aFGFR3” (komura2023theimpactof pages 1-2). * FGFR3-altered tumors are often characterized as having reduced T‑cell infiltration and a “non–T cell–inflamed” microenvironment in multiple mechanistic discussions (okato2024fgfrinhibitionaugments pages 1-2, komura2023theimpactof pages 1-2).

5.3 Immune checkpoint inhibitor (ICI) response heterogeneity and proposed immune targets

Komura et al. reported clinically relevant response heterogeneity: * In CPI-treated patients, overall ORR was similar between intact vs altered FGFR3: 20% vs 31% (p=0.467) (komura2023theimpactof pages 1-2). * In the LumP subtype, ORR differed markedly: LumP/aFGFR3 50% vs LumP/iFGFR3 5% (p=0.022) (komura2023theimpactof pages 1-2). * Transcriptome analysis highlighted TIM3 as the most upregulated immune-related gene in iFGFR3, and authors propose TIM3 as a target for iFGFR3 and IDO1/CCL24 for LumP/iFGFR3 (komura2023theimpactof pages 1-2).

5.4 Resistance mechanisms to FGFR inhibition

Evidence-supported resistance mechanisms include: * On-target second-site FGFR3 mutations (e.g., kinase-domain mutations, including gatekeeper-like changes) emerging in cfDNA during erdafitinib therapy (guercio2023clinicalandgenomic pages 6-7). * Bypass/parallel pathway alterations: emergent cfDNA alterations included TP53, AKT1, and second-site FGFR3 mutations (guercio2023clinicalandgenomic pages 6-7, guercio2023clinicalandgenomic pages 2-4). * A proposed metabolic/hypoxia-linked resistance program: upregulation of P4HA2 via a HIF1α feedback loop reducing ROS and mediating acquired resistance to erdafitinib (shang2024landscapeoftargeted pages 3-5).

5.5 Suggested GO terms (examples)

  • FGFR signaling pathway (e.g., GO:0008543 fibroblast growth factor receptor signaling pathway)
  • MAPK cascade (GO:0000165)
  • PI3K/AKT signaling (e.g., GO:0014065 phosphatidylinositol 3-kinase signaling)
  • STAT3 signaling (e.g., GO:0046427 positive regulation of JAK-STAT cascade)
  • Regulation of T cell proliferation (GO:0042129) (relevant to Treg expansion effects described) (okato2024fgfrinhibitionaugments pages 1-2)

5.6 Suggested Cell Ontology (CL) terms (examples)

  • Urothelial cell (CL class; urothelium-derived carcinoma)
  • Regulatory T cell (CL:0000815) (Treg expansion/abrogation under combined therapy in murine model) (okato2024fgfrinhibitionaugments pages 1-2)

6. Diagnostics

6.1 Standard UC diagnostics (brief)

Standard clinical diagnosis relies on cystoscopy, pathology, and staging. Molecular FGFR testing is added to identify candidates for FGFR-targeted therapy.

6.2 FGFR alteration testing approaches

Tissue-based NGS and cfDNA * In real‑world practice, tumor sequencing (e.g., targeted panel NGS) was used to identify oncogenic FGFR alterations, and cfDNA was used for longitudinal monitoring under erdafitinib (guercio2023clinicalandgenomic pages 2-4).

RNA-based approaches (fusion detection and breadth) * A targeted RNA-seq (3′ RACE) approach detected FGFR2/3 alterations in 23.2% overall and found that 8/11 FGFR3 rearrangements were undetectable by commonly used PCR kits, highlighting fusion-detection limitations of some PCR strategies (mitiushkina2024useof3′ pages 1-2, mitiushkina2024useof3′ pages 2-3).

Companion diagnostic / RT‑PCR * The QIAGEN therascreen FGFR RGQ RT‑PCR assay is referenced as the companion diagnostic used to select patients eligible for erdafitinib (bannier2024aiallowsprescreening pages 2-3, jain2024acomprehensiveoverview pages 8-10).

AI-based prescreening on H&E slides (2024 development) A Nature Communications study developed a deep-learning H&E prescreening tool to triage FGFR3 mutation testing: * Reported that the model achieved sensitivity >93% on advanced/metastatic cases while reducing molecular testing by ~40% on average (bannier2024aiallowsprescreening pages 1-2). * External performance included AUC values around 0.82–0.89 in independent cohorts (bannier2024aiallowsprescreening pages 1-2).

6.3 Practical implementation note

Because FGFR3 status can be discordant between primary and metastasis (26% discordance), testing the most recent/metastatic specimen when feasible is supported by real‑world evidence (guercio2023clinicalandgenomic pages 1-2, guercio2023clinicalandgenomic pages 2-4).


7. Outcome / Prognosis

7.1 General UC outcomes by stage

A bladder-cancer biomarker resource summarized SEER-like stage survival gradients: ~96% 5‑year survival for mucosa‑confined disease and ~7% for distant metastasis (ferreira2023epimarkersforbladder pages 26-29). These are not FGFR‑specific.

7.2 FGFR-altered vs unselected prognosis

The extracted evidence is mixed and context-dependent: * FGFR3 alterations are enriched in earlier-stage disease (NMIBC, papillary phenotypes), which often carries better prognosis, but metastatic FGFR‑altered UC remains lethal. * In metastatic biopsies, FGFR3 is one of the most common actionable targets (26%), emphasizing clinical relevance in advanced disease (antar2024theevolvingmolecular pages 3-5).

7.3 Prognostic factors during FGFR inhibitor therapy

Real‑world erdafitinib outcomes were relatively short in a heavily pretreated cohort (median PFS 2.8 months; OS 6.6 months) and TP53 co-alterations were implicated as unfavorable in response analyses (guercio2023clinicalandgenomic pages 6-7).


8. Treatment (current applications and real‑world implementation)

8.1 Approved targeted therapy: erdafitinib

Erdafitinib is the only widely cited FDA-approved targeted therapy for metastatic UC with select FGFR2/3 alterations in the evidence base (guercio2023clinicalandgenomic pages 2-4, benjamin2023treatmentapproachesfor pages 3-4).

Key pivotal and real‑world outcomes are summarized in the table below.

Therapy/setting Eligibility biomarker Key outcomes (ORR, median PFS, median OS) Key safety notes Publication (journal, year) and URL
BLC2001: erdafitinib, phase 2, previously treated metastatic/advanced UC Prespecified FGFR2/3 alterations; responses higher in FGFR3 mutations than FGFR2/3 fusions ORR 40% (CR 3%, PR 37%); median PFS 5.5 months; median OS 13.8 months. In one summary, ORR was 49% for FGFR3 mutations vs 16% for FGFR2/3 fusions (testi2024targetedtherapiesand pages 11-13, benjamin2023treatmentapproachesfor pages 3-4, shang2024landscapeoftargeted pages 3-5) Common AEs: hyperphosphatemia, stomatitis, diarrhea; ocular toxicity/central serous retinopathy ~21–23%; grade ≥3 AEs 46%; 13% discontinued due to AEs (testi2024targetedtherapiesand pages 11-13, benjamin2023treatmentapproachesfor pages 3-4) Frontiers in Immunology (2023), Benjamin & Hsu. https://doi.org/10.3389/fimmu.2023.1258388 ; Exploration of Targeted Anti-tumor Therapy (2024), Testi et al. https://doi.org/10.37349/etat.2024.00279
THOR cohort 1: erdafitinib vs chemotherapy after prior therapy, NCT03390504 Metastatic/advanced UC with select FGFR alterations Median OS 12.1 vs 7.8 months; median PFS 5.6 vs 2.7 months; ORR 46% vs 12% for erdafitinib vs chemotherapy (benjamin2023treatmentapproachesfor pages 3-4, shang2024landscapeoftargeted pages 3-5) Toxicities common; one summary states treatment-related AEs in all patients and 67% grade 3–4 with hyperphosphatemia frequent (shang2024landscapeoftargeted pages 3-5) Frontiers in Immunology (2023), Benjamin & Hsu. https://doi.org/10.3389/fimmu.2023.1258388 ; Exploration of Targeted Anti-tumor Therapy (2024), Shang et al. https://doi.org/10.37349/etat.2024.00240
THOR Japanese subgroup: erdafitinib vs chemotherapy Metastatic UC with FGFR alterations in Japanese subgroup of THOR Median OS 25.4 vs 12.4 months; median PFS 8.4 vs 2.9 months; ORR 57.1% vs 15.4% for erdafitinib vs chemotherapy (guercio2023clinicalandgenomic pages 1-2) Any-grade treatment-related AEs occurred in all patients in both arms, but grade 3/4 AEs and discontinuations were lower with erdafitinib; no new safety signals (guercio2023clinicalandgenomic pages 1-2) International Journal of Clinical Oncology (2024), Matsubara et al. https://doi.org/10.1007/s10147-024-02583-3
NORSE: erdafitinib monotherapy vs erdafitinib + cetrelimab FGFR2/3-altered UC Monotherapy: ORR 44.2% (1 CR), median PFS 5.62 months. Combination: ORR 54.5% (13.6% CR), median PFS 10.97 months. Median OS not reported in current snippets (benjamin2023treatmentapproachesfor pages 3-4) Safety details not quantified in current evidence snippets (benjamin2023treatmentapproachesfor pages 3-4) Frontiers in Immunology (2023), Benjamin & Hsu. https://doi.org/10.3389/fimmu.2023.1258388
Real-world erdafitinib cohort (Guercio 2023) Metastatic FGFR2/3-altered UC; institutional tumor sequencing and cfDNA monitoring ORR 40% (12/30); median PFS 2.8 months; median OS 6.6 months. In patients previously treated with immune checkpoint blockade, ORR 35% (6/17) (guercio2023clinicalandgenomic pages 1-2, guercio2023clinicalandgenomic pages 6-7, guercio2023clinicalandgenomic pages 2-4, guercio2023clinicalandgenomic media 250123eb) Frequent AEs: hyperphosphatemia 84%, fatigue 59%, mucositis 47%; grade ≥3 mucositis 16%, palmar-plantar erythrodysesthesia 9%; dose reductions 38%, interruptions 50%, up-titration 16% (guercio2023clinicalandgenomic pages 6-7) Clinical Cancer Research (2023), Guercio et al. https://doi.org/10.1158/1078-0432.CCR-23-1283

Table: This table summarizes the main FGFR-targeted therapy datasets currently available in the evidence snippets for FGFR-altered urothelial carcinoma. It highlights efficacy, biomarker-defined eligibility, and tolerability across pivotal trials and real-world use.

Real‑world implementation challenges * Dose reductions and interruptions were common in real-world practice (38% reductions; 50% interruptions) (guercio2023clinicalandgenomic pages 6-7).

8.2 Combination approaches (2023–2024 emphasis)

  • Erdafitinib + anti–PD-1/PD-L1 approaches are under active study; the NORSE dataset suggests improved ORR and PFS with erdafitinib + cetrelimab compared with monotherapy (ORR 54.5% vs 44.2%; median PFS 10.97 vs 5.62 months) (benjamin2023treatmentapproachesfor pages 3-4).

8.3 Experimental FGFR inhibitors and trials (selected; with NCT IDs)

  • TYRA‑300 (FGFR3‑selective)
  • NCT06995677: Phase 2; FGFR3 mutation/fusion; low‑grade intermediate‑risk NMIBC; primary endpoint complete response at 3 months (NCT06995677 chunk 1).
  • NCT05544552 is described in a 2024 review as Phase I–II TYRA‑300 in advanced UC with activating FGFR3 alterations (~310 patients; endpoints include MTD/RP2D/ORR) (testi2024targetedtherapiesand pages 4-6).
  • Erdafitinib in recurrent non-invasive bladder cancer
  • NCT04917809: oral erdafitinib in recurrent non‑invasive bladder cancer; exclusion criteria include prior FGFR inhibitors and ocular disorders; additional phase/endpoints were not present in the extracted trial text chunk (NCT04917809 chunk 2).
  • Erdafitinib pivotal THOR program
  • NCT03390504 is referenced as the THOR program comparing erdafitinib vs chemotherapy and/or pembrolizumab in advanced UC with FGFR alterations (guercio2023clinicalandgenomic pages 1-2, jain2024acomprehensiveoverview pages 8-10).

8.4 MAXO (treatment action) term suggestions

  • FGFR inhibitor therapy (e.g., “treatment with fibroblast growth factor receptor inhibitor”)
  • Immune checkpoint inhibitor therapy (for combination strategies)
  • Circulating tumor DNA monitoring (during therapy) (guercio2023clinicalandgenomic pages 2-4)

9. Prevention / Epidemiology

9.1 Epidemiology and demographics

  • Bladder cancer is common worldwide; one resource reports in 2020: 573,278 new cases and 212,536 deaths, and that bladder cancer is about three times more frequent in men and ~80% of patients are older than 65 years (ferreira2023epimarkersforbladder pages 19-26).
  • Urothelial carcinoma accounts for ~90% of bladder tumors (ferreira2023epimarkersforbladder pages 26-29, ferreira2023epimarkersforbladder pages 19-26).
  • UTUC represents ~5–10% of UCs and is more aggressive, with ~60% invasive at diagnosis (mitiushkina2024useof3′ pages 1-2).

9.2 Prevention relevance to FGFR-altered disease

Primary prevention is similar to UC overall because FGFR alterations are somatic tumor events arising in the context of UC carcinogenesis.

Primary prevention targets: * Smoking cessation (major risk factor) (mitiushkina2024useof3′ pages 1-2, ferreira2023epimarkersforbladder pages 19-26) * Minimizing occupational carcinogen exposure and contaminated water exposure (mitiushkina2024useof3′ pages 1-2)


10. Other Species / Natural Disease

No cross-species naturally occurring FGFR‑altered UC epidemiology was identified in the extracted evidence.


11. Model Organisms / Experimental Models

11.1 Genetically engineered mouse models (mechanistic and translational)

A 2024 JCI study used a genetically engineered murine model combining FGFR3S249C activation with Trp53R270H (UPFL) and reported that: * Tumors “recapitulate papillary histology and LumP/UROMOL class 1 transcriptional states” and that co-alteration yields high-grade NMIBC (okato2024fgfrinhibitionaugments pages 1-2). * The model showed ICI hyperprogression via Treg expansion, which was abrogated by FGFR inhibition; combined erdafitinib + ICI yielded strong efficacy in mice (okato2024fgfrinhibitionaugments pages 1-2).

11.2 Model limitations

Animal models may not capture the full molecular heterogeneity, prior treatment exposures, and sampling discordance seen in human metastatic disease (highlighted in real-world primary vs metastasis discordance) (guercio2023clinicalandgenomic pages 1-2).


12. Recent developments and expert analysis (2023–2024 emphasis)

12.1 Key 2023–2024 advances

  1. Randomized phase III evidence for erdafitinib vs chemotherapy in FGFR‑altered metastatic UC (THOR) with improved OS, PFS, and ORR (benjamin2023treatmentapproachesfor pages 3-4).
  2. Real‑world genomic/clinical datasets highlighting short durability, toxicity-driven dose modification, and frequent primary/metastasis discordance (guercio2023clinicalandgenomic pages 1-2, guercio2023clinicalandgenomic pages 6-7).
  3. TME heterogeneity and subtype-specific immunotherapy responses (e.g., LumP/aFGFR3 showing ORR 50% vs LumP/iFGFR3 5%) and new proposed immune targets (TIM3, IDO1, CCL24) (komura2023theimpactof pages 1-2).
  4. Deployment of AI prescreening on routine histology to reduce molecular testing burden while maintaining high sensitivity for FGFR3 mutation detection (bannier2024aiallowsprescreening pages 1-2).
  5. RNA-based panels expanding detection of FGFR3 rearrangements missed by common PCR kits, supporting broader adoption of RNA sequencing for fusion detection (mitiushkina2024useof3′ pages 2-3).

12.2 Expert opinions and analysis (authoritative sources)

  • Reviews stress that erdafitinib benefit can be transient, and overcoming acquired resistance is a major research priority (noeraparast2024fgfr3alterationsin pages 1-2).
  • Mechanistic work supports a rationale for combining FGFR inhibition with immunotherapy by modulating immunosuppression (Treg expansion) in FGFR3-mutant contexts (okato2024fgfrinhibitionaugments pages 1-2).

Visual summary: FGFR alteration frequencies across disease settings

The following table consolidates key stage-specific FGFR alteration frequencies from multiple cohorts.

Setting/stage Reported FGFR alteration frequency Alteration types mentioned Data source (author, journal, year) Notes
NMIBC 39% FGFR3-altered; 44% aFGFR3 in Japanese cohort Recurrent FGFR3 mutations and fusions; FGFR3-mutant disease common in non-invasive/early-stage tumors Guercio et al., Clinical Cancer Research, 2023 (guercio2023clinicalandgenomic pages 1-2, guercio2023clinicalandgenomic media 250123eb); Komura et al., Molecular Cancer, 2023 (guercio2023clinicalandgenomic pages 13-14); Bannier et al., Nature Communications, 2024 (bannier2024aiallowsprescreening pages 1-2) Bannier notes FGFR3 mutations can reach up to 80% in non-invasive papillary low-grade tumors, emphasizing strong enrichment in early-stage disease (bannier2024aiallowsprescreening pages 1-2).
MIBC 14% FGFR3-altered; 15% aFGFR3 in Japanese cohort; broadly 10–15% FGFR3-mutant in MIBC/mUC FGFR3 mutations and fusions Guercio et al., Clinical Cancer Research, 2023 (guercio2023clinicalandgenomic pages 1-2, guercio2023clinicalandgenomic media 250123eb); Komura et al., Molecular Cancer, 2023 (guercio2023clinicalandgenomic pages 13-14); Bannier et al., Nature Communications, 2024 (bannier2024aiallowsprescreening pages 1-2) Frequency drops substantially versus NMIBC; Bannier highlights 10–15% average distribution in muscle-invasive and metastatic disease (bannier2024aiallowsprescreening pages 1-2).
Localized UTUC 43% FGFR3-altered in localized upper tract specimens; FGFR2/3 alterations enriched in upper tract vs bladder (48% vs 20% in one RNA-panel cohort) Predominantly FGFR3 alterations; FGFR2/3 activating point mutations or fusions; FGFR3 rearrangements/fusions detectable by RNA methods Guercio et al., Clinical Cancer Research, 2023 (guercio2023clinicalandgenomic pages 1-2, guercio2023clinicalandgenomic media 250123eb); Mitiushkina et al., International Journal of Molecular Sciences, 2024 (mitiushkina2024useof3′ pages 2-3, mitiushkina2024useof3′ pages 1-2) Upper tract disease appears particularly enriched for FGFR pathway alterations compared with bladder UC in some cohorts (mitiushkina2024useof3′ pages 2-3, mitiushkina2024useof3′ pages 1-2).
Metastatic UC 26% FGFR3-altered metastatic specimens; 10–15% FGFR3-mutant in MIBC/mUC by pathology/AI study Oncogenic FGFR3 mutations and occasional FGFR2/3 fusions Guercio et al., Clinical Cancer Research, 2023 (guercio2023clinicalandgenomic pages 1-2, guercio2023clinicalandgenomic media 250123eb); Bannier et al., Nature Communications, 2024 (bannier2024aiallowsprescreening pages 1-2) Guercio found 26% positivity in metastatic specimens overall, but paired-sample analysis showed 26% discordance between primary and metachronous metastasis, cautioning against reliance on archival primary tissue alone (guercio2023clinicalandgenomic pages 1-2, guercio2023clinicalandgenomic pages 2-4).
mUC metastatic biopsy cohort FGFR3 actionable target in 26% of metastatic biopsies FGFR3 most common actionable target; includes mutations and at least some fusions in metastatic profiling studies Loriot et al., Nature Communications, 2024 (antar2024theevolvingmolecular pages 3-5) In a metastatic biopsy multi-omics cohort, potential therapeutic targets were found in 73% overall, with FGFR3 the most common at 26%, supporting routine metastatic-site profiling when feasible (antar2024theevolvingmolecular pages 3-5).

Table: This table summarizes reported FGFR alteration frequencies across urothelial carcinoma disease settings using only the cited evidence. It highlights stage dependence, upper-tract enrichment, and the clinically important discordance between primary and metastatic tumors.


Key limitations of this evidence package (important for KB curation)

  • A dedicated MONDO/MeSH/ICD identifier for “FGFR‑altered UC” was not established in the retrieved evidence; the subtype is best represented as urothelial carcinoma with a biomarker attribute.
  • Several guideline-level resources (e.g., NCCN/EAU) and FDA label documents were not directly retrieved here; companion diagnostic claims are therefore cited from peer‑reviewed sources that mention therascreen as the companion diagnostic (bannier2024aiallowsprescreening pages 2-3, jain2024acomprehensiveoverview pages 8-10).
  • Symptom frequencies specifically in FGFR‑altered vs FGFR‑wildtype UC were not available in extracted evidence; phenotypes are described at the UC level.

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