FGFR-altered cholangiocarcinoma is a molecularly defined subtype of intrahepatic cholangiocarcinoma characterized by fibroblast growth factor receptor (FGFR) alterations, primarily FGFR2 fusions or rearrangements. FGFR2 fusions occur in approximately 10-15% of intrahepatic cholangiocarcinomas and represent actionable targets. Multiple fusion partners have been identified, with BICC1, PPHLN1, and AHCYL1 being most common. FGFR inhibitors pemigatinib, futibatinib, and infigratinib have demonstrated significant activity in FGFR2 fusion-positive cholangiocarcinoma, establishing these as standard therapies for this molecularly defined subset.
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name: FGFR-Altered Cholangiocarcinoma
creation_date: '2026-01-26T02:55:13Z'
updated_date: '2026-04-22T20:13:21Z'
description: >-
FGFR-altered cholangiocarcinoma is a molecularly defined subtype of intrahepatic
cholangiocarcinoma characterized by fibroblast growth factor receptor (FGFR) alterations,
primarily FGFR2 fusions or rearrangements. FGFR2 fusions occur in approximately
10-15%
of intrahepatic cholangiocarcinomas and represent actionable targets. Multiple fusion
partners have been identified, with BICC1, PPHLN1, and AHCYL1 being most common.
FGFR
inhibitors pemigatinib, futibatinib, and infigratinib have demonstrated significant
activity in FGFR2 fusion-positive cholangiocarcinoma, establishing these as standard
therapies for this molecularly defined subset.
categories:
- Gastrointestinal Cancer
- Hepatobiliary Cancer
- Molecularly Defined Cancer
parents:
- intrahepatic cholangiocarcinoma
pathophysiology:
- name: FGFR2 Fusion and Constitutive Activation
description: >-
FGFR2 fusions join the FGFR2 kinase domain to various partner genes (BICC1, PPHLN1,
AHCYL1, and others). Partner genes typically provide oligomerization domains that
cause ligand-independent FGFR2 dimerization and constitutive kinase activation.
This drives oncogenic signaling through multiple downstream pathways.
evidence:
- reference: PMID:36535760
reference_title: "Cholangiocarcinomes avancés et gènes de fusion."
supports: PARTIAL
snippet: "Gene fusions are among the most frequent alterations, involving FGFR2 in 10-15% of iCCAs in particular, and NTRK genes at a lower frequency (<1%)."
explanation: "Supports FGFR2 fusions as frequent alterations in intrahepatic cholangiocarcinoma."
cell_types:
- preferred_term: intrahepatic cholangiocyte
term:
id: CL:0002538
label: intrahepatic cholangiocyte
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: intrahepatic bile duct
term:
id: UBERON:0003704
label: intrahepatic bile duct
downstream:
- target: MAPK Pathway Activation
description: FGFR2 activates RAS-RAF-MEK-ERK signaling cascade
- target: PI3K-AKT Pathway Activation
description: FGFR2 activates PI3K-AKT-mTOR signaling
- target: PLCgamma-PKC Pathway Activation
description: FGFR2 activates phospholipase C gamma signaling
- name: MAPK Pathway Activation
description: >-
FGFR2 activation leads to recruitment of adaptor proteins (FRS2, GRB2) that activate
RAS and the downstream MAPK cascade. This drives transcription of genes promoting
cell proliferation.
biological_processes:
- preferred_term: MAPK cascade
modifier: INCREASED
term:
id: GO:0000165
label: MAPK cascade
downstream:
- target: Enhanced Cell Proliferation
description: MAPK signaling promotes cell cycle progression
- name: PI3K-AKT Pathway Activation
description: >-
FGFR2 signaling activates PI3K through adaptor proteins, leading to AKT phosphorylation.
This promotes cell survival and resistance to apoptosis. PI3K pathway activation
may
contribute to resistance to FGFR inhibitors.
biological_processes:
- preferred_term: phosphatidylinositol 3-kinase signaling
modifier: INCREASED
term:
id: GO:0043491
label: phosphatidylinositol 3-kinase/protein kinase B signal transduction
- name: PLCgamma-PKC Pathway Activation
description: >-
FGFR2 directly phosphorylates phospholipase C gamma, leading to protein kinase
C
activation. This pathway contributes to cell migration, invasion, and other aspects
of the transformed phenotype.
- name: Enhanced Cell Proliferation
description: >-
Combined activation of MAPK, PI3K-AKT, and PLCgamma pathways drives enhanced cell
proliferation. FGFR2 fusion-positive tumors are dependent on FGFR2 signaling,
making
them vulnerable to FGFR inhibition.
biological_processes:
- preferred_term: cell population proliferation
modifier: INCREASED
term:
id: GO:0008283
label: cell population proliferation
histopathology:
- name: Well Differentiated Cholangiocarcinoma
finding_term:
preferred_term: Cholangiocarcinoma
term:
id: NCIT:C4436
label: Cholangiocarcinoma
frequency: VERY_FREQUENT
description: Most cholangiocarcinomas are well differentiated.
evidence:
- reference: PMID:12901270
reference_title: "[Cholangiocarcinoma--bile ducts cancer]."
supports: PARTIAL
snippet: "Histologically, 90-95% of CC are well differentiated"
explanation: Abstract notes that the majority of cholangiocarcinomas are well differentiated.
phenotypes:
- category: Hepatic
name: Hepatomegaly
frequency: FREQUENT
description: >-
Liver enlargement from tumor mass. Intrahepatic cholangiocarcinoma typically presents
as a hepatic mass lesion.
phenotype_term:
preferred_term: Hepatomegaly
term:
id: HP:0002240
label: Hepatomegaly
- category: Hepatic
name: Jaundice
frequency: OCCASIONAL
description: >-
Jaundice from biliary obstruction or extensive hepatic involvement. Less common
in intrahepatic than in perihilar cholangiocarcinoma.
phenotype_term:
preferred_term: Jaundice
term:
id: HP:0000952
label: Jaundice
- category: Gastrointestinal
name: Abdominal Pain
frequency: FREQUENT
description: >-
Right upper quadrant pain or discomfort from tumor mass or liver capsule involvement.
phenotype_term:
preferred_term: Abdominal pain
term:
id: HP:0002027
label: Abdominal pain
- category: Constitutional
name: Weight Loss
frequency: FREQUENT
description: >-
Unintentional weight loss from cancer cachexia and decreased oral intake.
phenotype_term:
preferred_term: Weight loss
term:
id: HP:0001824
label: Weight loss
- category: Constitutional
name: Fatigue
frequency: FREQUENT
description: >-
Fatigue from hepatic dysfunction and advanced disease burden.
phenotype_term:
preferred_term: Fatigue
term:
id: HP:0012378
label: Fatigue
- category: Gastrointestinal
name: Nausea
frequency: OCCASIONAL
description: >-
Nausea from hepatic dysfunction or as a treatment-related side effect.
phenotype_term:
preferred_term: Nausea
term:
id: HP:0002018
label: Nausea
biochemical:
- name: CA 19-9
notes: >-
Carbohydrate antigen 19-9 is frequently elevated in cholangiocarcinoma. Useful
for
monitoring treatment response when elevated at baseline.
- name: Serum Phosphate
notes: >-
Hyperphosphatemia is a class effect of FGFR inhibitors due to inhibition of FGFR-mediated
renal phosphate excretion. Requires monitoring and management during FGFR inhibitor
therapy.
- name: Liver Function Tests
notes: >-
Elevated alkaline phosphatase, GGT, and potentially bilirubin. Transaminases may
be
elevated with hepatic involvement.
genetic:
- name: FGFR2 Fusions
association: Somatic Gene Fusion
notes: >-
FGFR2 fusions occur in 10-15% of intrahepatic cholangiocarcinomas. Common partners
include BICC1, PPHLN1, AHCYL1, TACC3, MGEA5, and others. Over 100 different fusion
partners have been identified. Detected by RNA-based NGS, FISH, or break-apart
assays.
evidence:
- reference: PMID:35871236
reference_title: "Genomic architecture of FGFR2 fusions in cholangiocarcinoma and its implication for molecular testing."
supports: PARTIAL
snippet: "Recently, several actionable genetic aberrations were identified with significant enrichment in intrahepatic CCA, including FGFR2 gene fusions with a prevalence of 10-15%."
explanation: "Abstract reports FGFR2 fusion prevalence in intrahepatic cholangiocarcinoma."
- name: FGFR2 Mutations/Amplifications
association: Somatic Alterations
notes: >-
Activating FGFR2 point mutations and amplifications are less common than fusions
but may also respond to FGFR inhibitors. V564F/I gatekeeper mutations are associated
with acquired resistance.
- name: FGFR Resistance Mutations
association: Secondary Resistance
notes: >-
Acquired resistance to FGFR inhibitors often involves secondary FGFR2 kinase domain
mutations (V564F, N549H/K, E565A, L617V, K659M). Polyclonal resistance is common.
Monitoring for resistance mutations helps guide subsequent therapy.
treatments:
- name: Pemigatinib
description: >-
Selective FGFR1-3 inhibitor approved for previously treated FGFR2 fusion/rearrangement
positive cholangiocarcinoma. FIGHT-202 trial demonstrated 36% objective response
rate
with 9.1 months median duration of response. Now also approved in first-line
(FIGHT-302).
treatment_term:
preferred_term: pharmacotherapy
term:
id: MAXO:0000058
label: pharmacotherapy
therapeutic_agent:
- preferred_term: pemigatinib
term:
id: NCIT:C121553
label: Pemigatinib
- name: Futibatinib
description: >-
Irreversible pan-FGFR inhibitor approved for previously treated FGFR2 fusion/rearrangement
positive cholangiocarcinoma. FOENIX-CCA2 trial demonstrated 42% response rate.
May
retain activity against some resistance mutations due to covalent binding mechanism.
treatment_term:
preferred_term: pharmacotherapy
term:
id: MAXO:0000058
label: pharmacotherapy
therapeutic_agent:
- preferred_term: futibatinib
term:
id: NCIT:C114283
label: Futibatinib
- name: Infigratinib
description: >-
Selective FGFR1-3 inhibitor approved for previously treated FGFR2 fusion positive
cholangiocarcinoma. Demonstrated approximately 23% response rate in pivotal study.
treatment_term:
preferred_term: pharmacotherapy
term:
id: MAXO:0000058
label: pharmacotherapy
therapeutic_agent:
- preferred_term: infigratinib
term:
id: NCIT:C88302
label: Infigratinib
- name: Gemcitabine plus Cisplatin
description: >-
First-line standard chemotherapy for advanced cholangiocarcinoma. May be used
before
FGFR inhibitors or in combination approaches. FGFR inhibitors increasingly moving
to first-line setting.
treatment_term:
preferred_term: chemotherapy
term:
id: MAXO:0000647
label: chemotherapy
- name: Gemcitabine plus Cisplatin plus Durvalumab
description: >-
Addition of anti-PD-L1 durvalumab to gemcitabine/cisplatin is now standard first-line
treatment for advanced biliary tract cancers (TOPAZ-1 trial). Sequencing with
FGFR
inhibitors being defined.
treatment_term:
preferred_term: immunotherapy
term:
id: NCIT:C15262
label: Immunotherapy
therapeutic_agent:
- preferred_term: durvalumab
term:
id: NCIT:C103194
label: Durvalumab
- preferred_term: cisplatin
term:
id: CHEBI:27899
label: cisplatin
- name: Surgical Resection
description: >-
Surgery offers the only potential cure for cholangiocarcinoma. Hepatectomy with
adequate margins for intrahepatic tumors. FGFR status does not change surgical
approach for resectable disease.
treatment_term:
preferred_term: surgical procedure
term:
id: MAXO:0000004
label: surgical procedure
disease_term:
preferred_term: FGFR-altered cholangiocarcinoma
term:
id: MONDO:0003210
label: intrahepatic cholangiocarcinoma
classifications:
icdo_morphology:
classification_value: Adenocarcinoma
harrisons_chapter:
- classification_value: cancer
- classification_value: solid tumor
references:
- reference: DOI:10.1016/j.jhep.2023.10.041
title: Convergent MAPK pathway alterations mediate acquired resistance to FGFR inhibitors in FGFR2 fusion-positive cholangiocarcinoma
found_in:
- FGFR_Altered_Cholangiocarcinoma-deep-research-falcon.md
findings:
- statement: Convergent MAPK pathway alterations mediate acquired resistance to FGFR inhibitors in FGFR2 fusion-positive cholangiocarcinoma
supporting_text: Convergent MAPK pathway alterations mediate acquired resistance to FGFR inhibitors in FGFR2 fusion-positive cholangiocarcinoma
- reference: DOI:10.1093/oncolo/oyae170
title: <i>FGFR2</i> fusion/rearrangement is associated with favorable prognosis and immunoactivation in patients with intrahepatic cholangiocarcinoma
found_in:
- FGFR_Altered_Cholangiocarcinoma-deep-research-falcon.md
findings:
- statement: Increasing evidence highlights that fibroblast growth factor receptor 2 (FGFR2) fusion/rearrangement shows important therapeutic value for patients with intrahepatic cholangiocarcinoma (ICC).
supporting_text: Increasing evidence highlights that fibroblast growth factor receptor 2 (FGFR2) fusion/rearrangement shows important therapeutic value for patients with intrahepatic cholangiocarcinoma (ICC).
evidence:
- reference: DOI:10.1093/oncolo/oyae170
reference_title: <i>FGFR2</i> fusion/rearrangement is associated with favorable prognosis and immunoactivation in patients with intrahepatic cholangiocarcinoma
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Increasing evidence highlights that fibroblast growth factor receptor 2 (FGFR2) fusion/rearrangement shows important therapeutic value for patients with intrahepatic cholangiocarcinoma (ICC).
explanation: Deep research cited this publication as relevant literature for FGFR Altered Cholangiocarcinoma.
- reference: DOI:10.1136/gutjnl-2023-330029
title: British Society of Gastroenterology guidelines for the diagnosis and management of cholangiocarcinoma
found_in:
- FGFR_Altered_Cholangiocarcinoma-deep-research-falcon.md
findings:
- statement: These guidelines for the diagnosis and management of cholangiocarcinoma (CCA) were commissioned by the British Society of Gastroenterology liver section.
supporting_text: These guidelines for the diagnosis and management of cholangiocarcinoma (CCA) were commissioned by the British Society of Gastroenterology liver section.
evidence:
- reference: DOI:10.1136/gutjnl-2023-330029
reference_title: British Society of Gastroenterology guidelines for the diagnosis and management of cholangiocarcinoma
supports: SUPPORT
evidence_source: OTHER
snippet: These guidelines for the diagnosis and management of cholangiocarcinoma (CCA) were commissioned by the British Society of Gastroenterology liver section.
explanation: Deep research cited this publication as relevant literature for FGFR Altered Cholangiocarcinoma.
- reference: DOI:10.1158/1078-0432.ccr-22-2036
title: 'FDA Approval Summary: Pemigatinib for Previously Treated, Unresectable Locally Advanced or Metastatic Cholangiocarcinoma with FGFR2 Fusion or Other Rearrangement'
found_in:
- FGFR_Altered_Cholangiocarcinoma-deep-research-falcon.md
findings:
- statement: 'FDA Approval Summary: Pemigatinib for Previously Treated, Unresectable Locally Advanced or Metastatic Cholangiocarcinoma with FGFR2 Fusion or Other Rearrangement'
supporting_text: On April 17, 2020, the FDA granted accelerated approval to pemigatinib (PEMAZYRE, Incyte Corporation) for the treatment of adults with previously treated, unresectable locally advanced or metastatic cholangiocarcinoma with an FGFR2 fusion or other rearrangement as detected by an FDA-approved test.
evidence:
- reference: DOI:10.1158/1078-0432.ccr-22-2036
reference_title: 'FDA Approval Summary: Pemigatinib for Previously Treated, Unresectable Locally Advanced or Metastatic Cholangiocarcinoma with FGFR2 Fusion or Other Rearrangement'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: On April 17, 2020, the FDA granted accelerated approval to pemigatinib (PEMAZYRE, Incyte Corporation) for the treatment of adults with previously treated, unresectable locally advanced or metastatic cholangiocarcinoma with an FGFR2 fusion or other rearrangement as detected by an FDA-approved test.
explanation: Deep research cited this publication as relevant literature for FGFR Altered Cholangiocarcinoma.
- reference: DOI:10.1158/1078-0432.ccr-23-3780
title: Clinical Value of Liquid Biopsy in Patients with <i>FGFR2</i> Fusion–Positive Cholangiocarcinoma During Targeted Therapy
found_in:
- FGFR_Altered_Cholangiocarcinoma-deep-research-falcon.md
findings:
- statement: 'FGFR2 fusions occur in 10% to 15% of patients with intrahepatic cholangiocarcinoma (iCCA), potentially benefiting from FGFR inhibitors (FGFRi).'
supporting_text: 'FGFR2 fusions occur in 10% to 15% of patients with intrahepatic cholangiocarcinoma (iCCA), potentially benefiting from FGFR inhibitors (FGFRi).'
evidence:
- reference: DOI:10.1158/1078-0432.ccr-23-3780
reference_title: Clinical Value of Liquid Biopsy in Patients with <i>FGFR2</i> Fusion–Positive Cholangiocarcinoma During Targeted Therapy
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: 'FGFR2 fusions occur in 10% to 15% of patients with intrahepatic cholangiocarcinoma (iCCA), potentially benefiting from FGFR inhibitors (FGFRi).'
explanation: Deep research cited this publication as relevant literature for FGFR Altered Cholangiocarcinoma.
- reference: DOI:10.1158/1078-0432.ccr-24-1834
title: Understanding and Overcoming Resistance to Selective FGFR Inhibitors across <i>FGFR2</i> -Driven Malignancies
found_in:
- FGFR_Altered_Cholangiocarcinoma-deep-research-falcon.md
findings:
- statement: 'Understanding resistance to selective FGFR inhibitors is crucial to improve the clinical outcomes of patients with FGFR2-driven malignancies.'
supporting_text: 'Understanding resistance to selective FGFR inhibitors is crucial to improve the clinical outcomes of patients with FGFR2-driven malignancies.'
evidence:
- reference: DOI:10.1158/1078-0432.ccr-24-1834
reference_title: Understanding and Overcoming Resistance to Selective FGFR Inhibitors across <i>FGFR2</i> -Driven Malignancies
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: 'Understanding resistance to selective FGFR inhibitors is crucial to improve the clinical outcomes of patients with FGFR2-driven malignancies.'
explanation: Deep research cited this publication as relevant literature for FGFR Altered Cholangiocarcinoma.
- reference: DOI:10.2147/dddt.s559328
title: 'Fibroblast Growth Factor Receptor (FGFR) Inhibitors for the Treatment of Cholangiocarcinoma: Key Therapeutic Developments and Knowledge Gaps'
found_in:
- FGFR_Altered_Cholangiocarcinoma-deep-research-falcon.md
findings:
- statement: 'Fibroblast Growth Factor Receptor (FGFR) Inhibitors for the Treatment of Cholangiocarcinoma: Key Therapeutic Developments and Knowledge Gaps'
supporting_text: 'Fibroblast Growth Factor Receptor (FGFR) Inhibitors for the Treatment of Cholangiocarcinoma: Key Therapeutic Developments and Knowledge Gaps'
- reference: DOI:10.21873/anticanres.17046
title: Antitumor Activity of Tasurgratinib as an Orally Available FGFR1-3 Inhibitor in Cholangiocarcinoma Models With FGFR2-fusion
found_in:
- FGFR_Altered_Cholangiocarcinoma-deep-research-falcon.md
findings:
- statement: Antitumor Activity of Tasurgratinib as an Orally Available FGFR1-3 Inhibitor in Cholangiocarcinoma Models With FGFR2-fusion
supporting_text: Antitumor Activity of Tasurgratinib as an Orally Available FGFR1-3 Inhibitor in Cholangiocarcinoma Models With FGFR2-fusion
- reference: DOI:10.3350/cmh.2024.0318
title: Burden of mortality from hepatocellular carcinoma and biliary tract cancers by race and ethnicity and sex in US, 2018–2023
found_in:
- FGFR_Altered_Cholangiocarcinoma-deep-research-falcon.md
findings:
- statement: s/The trends in mortality of hepatocellular carcinoma (HCC) and biliary tract cancers stratified by sex and race/ethnicity in the US continue to evolve.
supporting_text: s/The trends in mortality of hepatocellular carcinoma (HCC) and biliary tract cancers stratified by sex and race/ethnicity in the US continue to evolve.
evidence:
- reference: DOI:10.3350/cmh.2024.0318
reference_title: Burden of mortality from hepatocellular carcinoma and biliary tract cancers by race and ethnicity and sex in US, 2018–2023
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: s/The trends in mortality of hepatocellular carcinoma (HCC) and biliary tract cancers stratified by sex and race/ethnicity in the US continue to evolve.
explanation: Deep research cited this publication as relevant literature for FGFR Altered Cholangiocarcinoma.
- reference: DOI:10.3389/fmed.2024.1384314
title: 'Global, regional, and national burden and trends analysis of gallbladder and biliary tract cancer from 1990 to 2019 and predictions to 2030: a systematic analysis for the Global Burden of Disease Study 2019'
found_in:
- FGFR_Altered_Cholangiocarcinoma-deep-research-falcon.md
findings:
- statement: Our aim was to explore the disease burden caused by gallbladder and biliary tract cancer globally, regionally, and nationally, by age and sex.
supporting_text: Our aim was to explore the disease burden caused by gallbladder and biliary tract cancer globally, regionally, and nationally, by age and sex.
evidence:
- reference: DOI:10.3389/fmed.2024.1384314
reference_title: 'Global, regional, and national burden and trends analysis of gallbladder and biliary tract cancer from 1990 to 2019 and predictions to 2030: a systematic analysis for the Global Burden of Disease Study 2019'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Our aim was to explore the disease burden caused by gallbladder and biliary tract cancer globally, regionally, and nationally, by age and sex.
explanation: Deep research cited this publication as relevant literature for FGFR Altered Cholangiocarcinoma.
- reference: DOI:10.3390/cancers17183052
title: 'Chronic Liver Disease Associated Cholangiocarcinoma: Genomic Insights and Precision Therapeutic Strategies'
found_in:
- FGFR_Altered_Cholangiocarcinoma-deep-research-falcon.md
findings:
- statement: Cholangiocarcinoma (CCA) is a highly heterogeneous malignancy arising from the biliary epithelium, with an increasing incidence and poor prognosis worldwide.
supporting_text: Cholangiocarcinoma (CCA) is a highly heterogeneous malignancy arising from the biliary epithelium, with an increasing incidence and poor prognosis worldwide.
evidence:
- reference: DOI:10.3390/cancers17183052
reference_title: 'Chronic Liver Disease Associated Cholangiocarcinoma: Genomic Insights and Precision Therapeutic Strategies'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Cholangiocarcinoma (CCA) is a highly heterogeneous malignancy arising from the biliary epithelium, with an increasing incidence and poor prognosis worldwide.
explanation: Deep research cited this publication as relevant literature for FGFR Altered Cholangiocarcinoma.
- reference: DOI:10.3390/cancers18030531
title: 'FGFR2-Rearranged Biliary Tract Cancer: Biology, Resistance Mechanisms, and Emerging Therapeutic Strategies'
found_in:
- FGFR_Altered_Cholangiocarcinoma-deep-research-falcon.md
findings:
- statement: Fibroblast growth factor receptor 2 (FGFR2) rearrangements represent one of the most actionable molecular alterations in biliary tract cancer, particularly in intrahepatic cholangiocarcinoma (iCCA).
supporting_text: Fibroblast growth factor receptor 2 (FGFR2) rearrangements represent one of the most actionable molecular alterations in biliary tract cancer, particularly in intrahepatic cholangiocarcinoma (iCCA).
evidence:
- reference: DOI:10.3390/cancers18030531
reference_title: 'FGFR2-Rearranged Biliary Tract Cancer: Biology, Resistance Mechanisms, and Emerging Therapeutic Strategies'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Fibroblast growth factor receptor 2 (FGFR2) rearrangements represent one of the most actionable molecular alterations in biliary tract cancer, particularly in intrahepatic cholangiocarcinoma (iCCA).
explanation: Deep research cited this publication as relevant literature for FGFR Altered Cholangiocarcinoma.
- reference: DOI:10.3390/curroncol31070266
title: 'Integrating Molecular Insights into Biliary Tract Cancer Management: A Review of Personalized Therapeutic Strategies'
found_in:
- FGFR_Altered_Cholangiocarcinoma-deep-research-falcon.md
findings:
- statement: Biliary tract cancers (BTCs) are rare and aggressive malignancies with an increasing incidence and poor prognosis.
supporting_text: Biliary tract cancers (BTCs) are rare and aggressive malignancies with an increasing incidence and poor prognosis.
evidence:
- reference: DOI:10.3390/curroncol31070266
reference_title: 'Integrating Molecular Insights into Biliary Tract Cancer Management: A Review of Personalized Therapeutic Strategies'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Biliary tract cancers (BTCs) are rare and aggressive malignancies with an increasing incidence and poor prognosis.
explanation: Deep research cited this publication as relevant literature for FGFR Altered Cholangiocarcinoma.
Cholangiocarcinoma (CCA) is a malignant tumor of the biliary epithelium and is commonly classified anatomically into intrahepatic (iCCA), perihilar, and extrahepatic forms (patel2023fdaapprovalsummary pages 1-3). The most clinically actionable FGFR‑altered form is FGFR2 fusion/rearrangement–positive iCCA, in which oncogenic FGFR2 gene fusions/rearrangements (structural variants) define a molecular subtype that can be treated with FGFR tyrosine kinase inhibitors (TKIs) (patel2023fdaapprovalsummary pages 1-3, gonzalezmedina2024clinicalvalueof pages 1-2).
Most knowledge for “FGFR‑altered CCA” is derived from aggregated disease‑level resources (clinical trials, cohort studies, guidelines, and translational studies), not single‑patient EHRs; exceptions include case reports (not emphasized here) and small observational cohorts (gonzalezmedina2024clinicalvalueof pages 1-2, kim2024burdenofmortality pages 1-3).
FGFR2 fusion/rearrangement in iCCA is best conceptualized as an oncogenic driver alteration that results in ligand‑independent FGFR signaling and downstream proliferative/survival pathway activation (MAPK and PI3K axis), creating a therapeutically targetable dependency (xin2026fgfr2rearrangedbiliarytract pages 8-10, diperi2024convergentmapkpathway pages 1-3).
Many established CCA risk factors reflect chronic biliary inflammation, biliary obstruction, chronic liver disease, infections, and carcinogenic exposures.
Authoritative guideline summary (BSG Gut 2024; published Sep 2024): - The guideline provides effect estimates for multiple exposures, including very high relative risks for choledochal cysts and choledocholithiasis, elevated risks for cirrhosis, and increased odds for liver fluke infection (Opisthorchis viverrini/Clonorchis spp.) (rushbrook2024britishsocietyof pages 5-5). - Example values explicitly stated in the guideline excerpt include: - Choledochal cyst: meta‑analysis RR 26.7 (and another estimate 34.9 in the same table) (rushbrook2024britishsocietyof pages 5-5). - Choledocholithiasis: meta‑analysis RR 10.1 (and another estimate 18.6) (rushbrook2024britishsocietyof pages 5-5). - Cirrhosis: meta‑analysis RR 15.3 (additional estimate 3.8) (rushbrook2024britishsocietyof pages 5-5). - Thorotrast exposure: retrospective study RR >300 (rushbrook2024britishsocietyof pages 5-5).
Review summary (Current Oncology 2024; published Jun 2024): A BTC review lists major risk factors as “cholelithiasis, biliary flukes in Asia, chronic inflammatory diseases of the bile ducts, metabolic syndrome-associated liver diseases… tobacco use, chronic hepatitis B and C infections, and cirrhosis” (rosbuxo2024integratingmolecularinsights pages 1-2).
No validated protective genetic variants or definitive environmental protective factors specific to FGFR‑altered iCCA were identified in the retrieved sources. Prevention is therefore largely addressed as risk‑factor reduction for biliary tract cancers broadly (e.g., metabolic risk) (su2024globalregionaland pages 1-2).
Direct gene–environment interaction evidence specific to FGFR2 fusion iCCA was not identified in the retrieved 2023–2024 sources. Etiology‑stratified genomic reviews suggest that molecular landscapes vary by etiologic background (e.g., fluke‑associated vs non‑fluke CCA) (oura2025chronicliverdisease pages 13-14).
Clinical presentation is often nonspecific and many patients present with advanced disease (rosbuxo2024integratingmolecularinsights pages 1-2, patel2023fdaapprovalsummary pages 1-3). The FGFR2‑fusion iCCA subgroup is clinically important primarily because it predicts benefit from FGFR inhibition rather than because it has unique pathognomonic symptoms.
(Phenotypes below reflect common CCA clinical manifestations and treatment‑related effects; frequencies were not consistently provided in retrieved sources.)
Tumor/location related - Abdominal pain — HP:0002027 - Jaundice — HP:0000952 (more typical for extrahepatic obstruction; may occur in iCCA with biliary obstruction) - Weight loss — HP:0001824 - Fatigue — HP:0012378
Laboratory abnormalities (often used clinically) - Elevated alkaline phosphatase — HP:0003155 - Elevated gamma‑glutamyltransferase — HP:0003285 (and was lower in FGFR2‑fusion cases in one surgical cohort) (liu2024fgfr2fusionrearrangementis pages 1-2) - CA19‑9 elevation — HP:0040217 (common in BTC care pathways; not quantified in retrieved evidence)
Targeted therapy adverse events (FGFR inhibitors) - Hyperphosphatemia — HP:0002905 (explicitly a common AE and key risk for pemigatinib) (patel2023fdaapprovalsummary pages 1-3, patel2023fdaapprovalsummary pages 3-5) - Dry eye / ocular toxicity — HP:0001097 / (ocular AE category) (patel2023fdaapprovalsummary pages 1-3, patel2023fdaapprovalsummary pages 3-5) - Alopecia — HP:0001596 (listed among common pemigatinib adverse reactions) (patel2023fdaapprovalsummary pages 1-3)
The retrieved 2023–2024 sources did not provide standardized QoL instrument outcomes (EQ‑5D, SF‑36, PROMIS) specific to FGFR‑altered iCCA.
In FIGHT‑202 Cohort A, FGFR2‑BICC1 was the most common in‑frame fusion (34% of in‑frame fusions) (patel2023fdaapprovalsummary pages 3-5). A broader basket‑trial synthesis similarly highlights BICC1 among common partners (erul2026fibroblastgrowthfactor pages 4-6).
FGFR2 fusions/rearrangements described here are somatic tumor alterations detected by tumor testing (tissue and/or plasma) (gonzalezmedina2024clinicalvalueof pages 1-2, patel2023fdaapprovalsummary pages 3-5).
Evidence indicates resistance can involve both on‑target FGFR2 kinase‑domain mutations and off‑target bypass alterations (MAPK; PI3K/mTOR) detected by serial tissue/ctDNA sequencing (facchinetti2024understandingandovercoming pages 1-2, diperi2024convergentmapkpathway pages 1-3).
No environmental causes are known to specifically predispose to acquisition of FGFR2 fusions, but environmental and infectious exposures contribute to cholangiocarcinoma risk overall (e.g., liver flukes, carcinogenic exposures, metabolic risk), as summarized in guidelines and global burden analyses (rushbrook2024britishsocietyof pages 5-5, su2024globalregionaland pages 1-2).
FGFR2 fusions function as actionable oncogenic drivers, and FGFR signaling interfaces strongly with canonical proliferative and survival pathways. - Translational resistance studies and reviews explicitly implicate MAPK signaling and PI3K/AKT/mTOR as key downstream pathways relevant to resistance and bypass signaling (diperi2024convergentmapkpathway pages 1-3, diperi2024convergentmapkpathway pages 3-5).
Suggested GO Biological Process terms (for annotation): - MAPK cascade — GO:0000165 - PI3K/AKT signaling — GO:0014065 (phosphatidylinositol 3‑kinase signaling) - Positive regulation of cell proliferation — GO:0008284 - Receptor tyrosine kinase signaling — GO:0007169
A key 2024 mechanistic paper concludes that acquired resistance commonly converges on MAPK re‑activation and/or new FGFR2 mutations. - In a cohort with repeat sequencing (n=17), 11/17 (64.7%) developed new FGFR2 mutations and 9/17 (52.9%) developed new MAPK pathway alterations, with 7 acquiring both (diperi2024convergentmapkpathway pages 1-3). - Longitudinal ctDNA detected emergent MAPK alterations including BRAF V600E and multiple RAS variants in an example patient (diperi2024convergentmapkpathway pages 1-3).
A prospective resistance program across FGFR2‑driven tumors found polyclonal FGFR2 kinase‑domain mutations are particularly frequent in cholangiocarcinoma. - “Polyclonal FGFR2 kinase domain mutations were frequent” in cholangiocarcinoma (14/27 patients) (facchinetti2024understandingandovercoming pages 1-2). - The study reports distinct patterns by inhibitor class: at resistance to reversible inhibitors many residues can be mutated; after futibatinib resistance was restricted to fewer hotspots including the molecular brake N550 and gatekeeper V565 (facchinetti2024understandingandovercoming pages 1-2).
A surgical cohort study suggests FGFR2 fusion/rearrangement can associate with an “immune‑activated” state (lower Tregs and N2 neutrophils, higher N1 neutrophils), supporting prognostic stratification and potential immunotherapy targeting hypotheses (liu2024fgfr2fusionrearrangementis pages 1-2).
Suggested Cell Ontology (CL) terms (for annotation): - Cholangiocyte — CL:1000427 (primary malignant lineage) - Regulatory T cell — CL:0000815 (Treg) - Neutrophil — CL:0000775
Suggested UBERON terms (for annotation): - Liver — UBERON:0002107 - Intrahepatic bile duct — UBERON:0003706 - Biliary tract — UBERON:0000059
Typically adult/older adult onset for cholangiocarcinoma overall; guideline excerpt reports median age at diagnosis 75 (population‑level CCA context) (rushbrook2024britishsocietyof pages 5-5).
Advanced/metastatic disease at presentation is common and drives reliance on systemic therapy (rosbuxo2024integratingmolecularinsights pages 1-2). FGFR inhibitor benefit is meaningful but limited by acquired resistance, often within months (e.g., resistance observed as progression under therapy with emergent mutations detectable in ctDNA) (gonzalezmedina2024clinicalvalueof pages 1-2, diperi2024convergentmapkpathway pages 1-3).
FGFR2 fusions/rearrangements in iCCA are somatic cancer alterations, not inherited Mendelian disorders (patel2023fdaapprovalsummary pages 3-5).
Because “FGFR‑altered cholangiocarcinoma” is molecularly defined, population incidence is usually inferred as iCCA incidence × FGFR2 fusion prevalence. Recent epidemiology sources are mostly for BTC/CCA overall.
US mortality trends (2018–2023; Clinical and Molecular Hepatology 2024, published Oct 2024): - Intrahepatic cholangiocarcinoma mortality increased with APC 3.1% (95% CI 1.2–4.9%) (kim2024burdenofmortality pages 1-3).
Global burden patterns (GBD 2019 analysis; Frontiers in Medicine 2024, published Apr 2024): - From 1990 to 2019, incident cases increased 1.85‑fold and deaths 1.82‑fold, while age‑standardized rates generally decreased (su2024globalregionaland pages 1-2). - High BMI was identified as a leading attributable risk factor, accounting for 15.2% of deaths and 15.7% of DALYs globally in 2019 (su2024globalregionaland pages 1-2).
A key operational requirement in FGFR‑altered iCCA is robust molecular testing to identify FGFR2 fusions.
Regulatory companion diagnostic: The FDA approval summary for pemigatinib states FDA “also approved the FoundationOne CDX… as a companion diagnostic for patient selection” (patel2023fdaapprovalsummary pages 1-3).
FIGHT‑202 defined eligibility by presence of “FGFR2 fusion or other rearrangement… as detected by an FDA‑approved test” (patel2023fdaapprovalsummary pages 1-3). Practical implication: tissue NGS (DNA and/or RNA fusion detection) is commonly used, with attention to tissue stewardship.
A major 2024 study in Clinical Cancer Research evaluated plasma detection and longitudinal monitoring: - Quote (Purpose): “FGFR2 fusions occur in 10% to 15% of patients with intrahepatic cholangiocarcinoma (iCCA)…” (gonzalezmedina2024clinicalvalueof pages 1-2). - Detection performance: 16/18 patients (88.9%) had FGFR2 fusion events detectable in plasma (gonzalezmedina2024clinicalvalueof pages 1-2). - Clinical management utility: increased ctDNA or emerging resistance mutations enabled “earlier detection of disease progression compared with standard radiologic imaging methods” (gonzalezmedina2024clinicalvalueof pages 1-2).
Implementation interpretation: Plasma ctDNA can complement tissue testing, especially for monitoring resistance evolution and anticipating progression, but tissue remains important for initial diagnosis and comprehensive profiling (gonzalezmedina2024clinicalvalueof pages 1-2, diperi2024convergentmapkpathway pages 1-3).
Detailed imaging algorithms were not extracted in the evidence snippets used here; however, CCA diagnosis generally requires radiologic and histopathologic confirmation, and is addressed in major guidelines (rushbrook2024britishsocietyof pages 5-5).
A 2024 precision management review reports poor relative survival in BTC: “1, 3, and 5 years post‑diagnosis estimated at 25%, 10%, and 7%, respectively” (rosbuxo2024integratingmolecularinsights pages 1-2). The same review states: “Approximately 65% of patients receive only the best supportive care at the time of diagnosis” (rosbuxo2024integratingmolecularinsights pages 1-2).
A 2024 surgical cohort study reports FGFR2 fusion/rearrangement as an “independent protective factor” for overall and relapse‑free survival and associates it with an immune‑activated microenvironment (liu2024fgfr2fusionrearrangementis pages 1-2).
Two FDA‑approved FGFR inhibitors—pemigatinib and futibatinib—are central real‑world implementations for previously treated advanced FGFR2 fusion/rearranged cholangiocarcinoma (patel2023fdaapprovalsummary pages 1-3, gonzalezmedina2024clinicalvalueof pages 1-2).
| Therapy (drug; reversible vs irreversible) | Target/eligible alteration | Trial (name; NCT) | Setting/line | Key efficacy | Key safety signals | Regulatory/implementation note |
|---|---|---|---|---|---|---|
| Pemigatinib; selective FGFR1–3, reversible/ATP-competitive | Unresectable locally advanced or metastatic cholangiocarcinoma with FGFR2 fusion or other rearrangement; Cohort A included 107 patients, 98% with iCCA; FGFR2-BICC1 was the most common in-frame fusion partner (34%) | FIGHT-202; NCT02924376 | Previously treated; disease progressed on or after ≥1 prior therapy | ORR 35.5% (95% CI 26.5–45.3%); 3 CRs (2.8%) and 35 PRs (32.7%); median DOR 9.1 months (95% CI 6.0–13.5); 63% of responders had DOR ≥6 months and 18% ≥12 months. FDA summary also reports ORR 36% (95% CI 27–45) and median DOR 9.1 months; later update reported median PFS 7.0 months and OS 17.5 months (patel2023fdaapprovalsummary pages 3-5, patel2023fdaapprovalsummary pages 1-3, erul2026fibroblastgrowthfactor pages 4-6) | Hyperphosphatemia was a key/common AE; ocular toxicity was an important risk; common ocular events included dry eye. In 146 treated CCA patients, 99% had ≥1 AE, grade 3–4 ADRs occurred in 64%, fatal adverse reactions in 4.1% (patel2023fdaapprovalsummary pages 1-3, patel2023fdaapprovalsummary pages 3-5, erul2026fibroblastgrowthfactor pages 4-6) | FDA accelerated approval: 2020-04-17 for adults with previously treated unresectable locally advanced or metastatic CCA with FGFR2 fusion/rearrangement. FoundationOne CDX approved as companion diagnostic (patel2023fdaapprovalsummary pages 1-3) |
| Futibatinib; pan-FGFR1–4, irreversible/covalent | Previously treated unresectable, locally advanced or metastatic intrahepatic cholangiocarcinoma with FGFR2 gene fusions or other rearrangements | FOENIX-CCA2; NCT not provided in available context | Previously treated; unresectable locally advanced or metastatic iCCA | ORR 42% (95% CI 32–52%); reported median PFS ~9.0 months and median OS 21.7 months in review synthesis of phase II data (crolley2024…locally pages 2-3, xin2026fgfr2rearrangedbiliarytract pages 5-6) | Hyperphosphatemia reported among the most common treatment-emergent adverse events; ocular toxicity not explicitly quantified in available context (xin2026fgfr2rearrangedbiliarytract pages 5-6) | Received regulatory approval based on FOENIX-CCA2 phase II data; implementation note in available context emphasizes use in previously treated FGFR2-rearranged iCCA and potential activity after resistance to reversible FGFR inhibitors, but no companion diagnostic was specified in the available context (crolley2024…locally pages 2-3, gonzalezmedina2024clinicalvalueof pages 1-2) |
Table: This table summarizes the core clinical evidence for the two leading FGFR-targeted therapies used in FGFR-altered cholangiocarcinoma, focusing on pivotal trial outcomes, safety, and implementation details. It is useful for quickly comparing pemigatinib and futibatinib in the molecularly defined FGFR2-rearranged setting.
FDA accelerated approval language (Clinical Cancer Research 2023; published Oct 2023): - Quote: “On April 17, 2020, the FDA granted accelerated approval to pemigatinib… for… cholangiocarcinoma with an FGFR2 fusion or other rearrangement…” (patel2023fdaapprovalsummary pages 1-3). - Efficacy basis: ORR 36% (95% CI 27–45); median DOR 9.1 months (patel2023fdaapprovalsummary pages 1-3). A detailed breakdown reports ORR 35.5% with 2.8% CR and median DOR 9.1 months (patel2023fdaapprovalsummary pages 3-5). - Key toxicities: hyperphosphatemia and ocular toxicity highlighted as important risks (patel2023fdaapprovalsummary pages 1-3, patel2023fdaapprovalsummary pages 3-5).
Suggested MAXO terms: - FGFR inhibitor therapy — MAXO:0000758 (term name may vary by implementation; use as a targeted small‑molecule therapy action) - Molecular targeted therapy — MAXO:0000010
A 2026 synthesis reports FOENIX‑CCA2 outcomes (used here only for quantitative endpoints): ORR 42%, median PFS 9.0 months, median OS 21.7 months (xin2026fgfr2rearrangedbiliarytract pages 5-6). A 2024 review excerpt also reports FOENIX‑CCA2 ORR 42% (95% CI 32–52%) (crolley2024…locally pages 2-3).
Clinical positioning and sequencing: A 2024 liquid biopsy study notes futibatinib “has shown to be effective in some patients with acquired resistance to other FGFRi” (gonzalezmedina2024clinicalvalueof pages 1-2), consistent with the mechanistic rationale that irreversible inhibitors may retain activity against subsets of resistance mutations (facchinetti2024understandingandovercoming pages 1-2).
A 2024 resistance program supports a sequential, molecularly guided strategy: - Polyclonal FGFR2 kinase‑domain mutations are common in cholangiocarcinoma (14/27), and off‑target MAPK/PI3K alterations can co‑occur (facchinetti2024understandingandovercoming pages 1-2). - Longitudinal ctDNA and/or re‑biopsy can inform whether switching to an irreversible inhibitor is plausible, or whether bypass pathway inhibition (e.g., PI3K/mTOR) is rational in a subset (e.g., everolimus benefit in selected cases) (facchinetti2024understandingandovercoming pages 1-2).
Preclinical and translational evidence indicates MAPK pathway co‑activation can drive resistance and that MEK inhibition can be synergistic with FGFR inhibition in vitro, though not universally effective (diperi2024convergentmapkpathway pages 1-3).
(Representative examples from retrieved trials list) - FIGHT‑202 (pemigatinib): NCT02924376 — completed (patel2023fdaapprovalsummary pages 1-3). - Infigratinib phase 3 first‑line iCCA with FGFR2 fusions: NCT03773302 — terminated (trial registry evidence retrieved). - Futibatinib advanced CCA with FGFR2 fusion/rearrangement: NCT05727176 — recruiting phase 2 (trial registry evidence retrieved).
Global burden analysis identifies high BMI as a major attributable risk factor for gallbladder and biliary tract cancers (15.2% of deaths; 15.7% DALYs in 2019), supporting metabolic risk reduction as a plausible population‑level prevention strategy (su2024globalregionaland pages 1-2).
Specific screening recommendations for FGFR‑altered iCCA were not identified in the retrieved evidence excerpts. For CCA broadly, guideline efforts focus on risk factor identification and diagnostic pathways (rushbrook2024britishsocietyof pages 5-5).
No naturally occurring non‑human species entity specifically corresponding to “FGFR2 fusion iCCA” was identified from the retrieved sources. This section remains not well characterized in the current evidence set.
Multiple model classes are actively used to study FGFR2 fusion iCCA biology and resistance.
Suggested model‑related ontology hooks: - Patient‑derived xenograft model (PDX) — model type annotation - Organoid model — not directly evidenced in the extracted snippets for FGFR2 fusion iCCA here; however, organoids are broadly discussed as relevant CCA preclinical systems in recent methodological reviews (not used as primary evidence in this report).
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