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Cholangiocarcinoma Understanding the details

Cholangiocarcinoma is a molecularly
heterogeneous disease1

The heterogeneity of genetic alterations of cholangiocarcinoma provides an avenue for targeted therapeutic approaches1

of patients with cholangiocarcinoma harbour actionable genetic alterations1

Discover more about the genetic heterogenicity of CCA – download Understanding CCA’s Genetic Diversity today

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A number of actionable genetic alterations in cholangiocarcinoma have been identified1

Frequency estimates are derived from a retrospective genomic analysis of data from 6,130 patients with intrahepatic cholangiocarcinoma.1 Therapeutic classes reflect both currently approved and investigational treatment approaches.2,3

Actionable genetic alterations1,3Reported frequency (%)1Drug class1–4
IDH1/218IDH inhibitors*
FGFR212FGFR2 inhibitors*
ERBB2/HER25HER2-targeted agents*
BRAF5BRAF/MEK inhibitors†
MDM24MDM2 inhibitors‡
TMBhigh4Immune checkpoint inhibitors†
BRCA1/23PARP inhibitors‡
MET2MET inhibitors‡
MSIhigh/dMMR1Immune checkpoint inhibitors*
KRASG12C1KRAS G12C inhibitors‡
PALB2NRPARP inhibitors‡
NTRKNRNTRK inhibitors*
RETNRRET inhibitors§

*Approved by the FDA, EMA and MHRA for the treatment of cholangiocarcinoma.1,3,5–13

†FDA-approved, not EMA- or MHRA-approved for cholangiocarcinoma.1–3

‡Subject of ongoing clinical trials.1,3,4

§FDA-approved, subject to EMA conditional approval and not MHRA-approved for cholangiocarcinoma.3

Effective identification of actionable mutations in cholangiocarcinoma requires selecting the right molecular profiling approach14

  • FGFR2 fusions illustrate the structural complexity seen in fusion-driven cancers15
  • More than 150 fusion partners have been described, emphasising the importance of using NGS methods capable of detecting both known and novel rearrangements16
  • NGS-based methodologies are recommended by ESMO and considered the gold standard approach, as they enable comprehensive multiplex testing for a broad range of genomic alterations14–18

NGS testing methods are not all equivalent when it comes to molecular profiling14

Considering the diversity of alterations (mutations and fusions) in cholangiocarcinoma, NGS-testing should be performed on DNA and RNA, ideally from the same biopsy.14

Methodology Detection ability when DNA- and RNA‑based assays are conducted Example assays
Hybrid capture-based assays: detect gene fusions regardless of the fusion partnerHybrid capture assay designTwo generic adapters with target enrichment before sequencing using FGFR2 specific hybridisation probes – targeted RNA molecules are captured regardless of whether the sequence continues as wild-type FGFR2 or with an alternative sequence as a result of a fusion eventAble to detect 100% of possible rearrangements/fusions100% detection ability, no patient missedIllumina® Tissue Panels
Single-primer extension based approach: depending on panel design, detects most gene fusions regardless of the fusion partner
Single-primer extension assay design
One gene-specific primer + one generic adapter		With some panels, able to detect up to 94%–97%
of the possible rearrangements/fusions94% to 97% detection ability, 3% to 6% of patients missed		Archer Dx FusionPlex® Panels
Amplicon-based approach: detects gene fusions for which a corresponding primer pair is included in the panel design
Amplicon assay design
Two gene-specific primers		Predicted ability to detect 28.5% of the putative fusions28.5% predicted detection ability, 72% of patients missedThermoFisher Oncomine® Panels

A primer is a short, single-stranded synthetic oligonucleotide that acts as a starting point for DNA synthesis.

  • Hybrid capture-based NGS performed on DNA and RNA is the optimal test to detect most of the possible alterations (ie mutations, fusions, amplifications), in cholangiocarcinoma14
  • Use of amplicon-based NGS technologies lead to a loss of opportunity for 7 out of 10 patients14

ESMO guidelines recommend performing molecular profiling before or during first-line therapy in CCA to evaluate second-line treatment options as early as possible2,18,19

Test early
Test right
Test every
patient

Recommended biomarkers:20 IDH1, FGFR2, HER2, BRAFV600E, BRCA1/2, PALB2, KRASG12C, NTRK, RET, MSIhigh/dMMR

CCA, cholangiocarcinoma; dMMR, mismatch repair deficient; DNA, deoxyribonucleic acid; EMA, European Medicines Agency; ESMO, European Society for Medical Oncology; FDA, Food and Drug Administration; FGFR, fibroblast growth factor receptor; iCCA, intrahepatic cholangiocarcinoma; IDH, isocitrate dehydrogenase; MHRA, Medicines and Healthcare products Regulatory Agency; MSIhigh, microsatellite instability high; NGS, next-generation sequencing; NR, not reported; RNA, ribonucleic acid; TMBhigh, tumour mutational burden high.

References: 1. Kendre G, et al. J Hepatol. 2023;78(3):614–626; 2. Vogel A, et al. ESMO Open. 2025;10(1):104003; 3. Rimassa L, et al. Lancet Reg Health Eur. 2025;50:101170; 4. Banales JM, et al. Nat Rev Gastroenterol Hepatol. 2026;23(1):65–96; 5. Tibsovo Summary of Product Characteristics. Available at https://products.mhra.gov.uk/search/?search=tibsovo&page=1 [accessed June 2026]; 6. Lytgobi Summary of Product Characteristics. Available at https://products.mhra.gov.uk/search/?search=lytgobi&page=1 [accessed June 2026]; 7. Pemazyre Summary of Product Characteristics. Available at https://products.mhra.gov.uk/search/?search=pemazyre&page=1 [accessed June 2026]; 8. Keytruda Summary of Product Characteristics. Available at https://products.mhra.gov.uk/search/?search=keytruda&page=1 [accessed June 2026]; 9. Rozlytrek Summary of Product Characteristics. Available at https://products.mhra.gov.uk/search/?search=rozlytrek&page=1 [accessed June 2026]; 10. Vitrakvi Summary of Product Characteristics. Available at https://products.mhra.gov.uk/search/?search=VITRAKVI&page=1 [accessed June 2026]; 11. Ziihera US Prescribing Information. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/761416s000lbl.pdf [accessed June 2026]; 12. Ziihera Summary of Product Characteristics. Available at https://www.ema.europa.eu/en/documents/product-information/ziihera-epar-product-information_en.pdf [accessed June 2026]; 13. Ziihera Summary of Product Characteristics. Available at https://products.mhra.gov.uk/search/?search=ziihera&page=1 [accessed June 2026]; 14. Neumann O, et al. Br J Cancer. 2022;127(8):1540–1549; 15. Krook MA, et al. Br J Cancer. 2021;124(5):880–892; 16. Angerilli V, et al. Pathologica. 2023;115(2):71–82; 17. Ellinghaus P, et al. Cells. 2022;11(19):3180; 18. Mosele F, et al. Ann Oncol. 2020;31(11):1491–1505; 19. Vogel A, et al. Ann Oncol. 2023;34(2):127–140; 20. Vogel A, et al. ESMO Open. 2025;10(1):104003. Supplementary material.