Genomic testing in intrahepatic cholangiocarcinoma (iCCA)

The introduction of next-generation sequencing (NGS) technologies has opened new horizons for a better understanding of the molecular basis of cholangiocarcinoma (CCA), and for the identification and evaluation of potential new treatments tailored to the molecular characteristics of patients’ tumours¹

The high frequency of potentially targetable genomic alterations in iCCA strongly supports the need for molecular profiling²

European Society for Medical Oncology (ESMO) Clinical Practice Guidelines for patients with CCA

The ESMO Clinical Practice Guidelines now recommend the use of NGS and second-line targeted therapies in patients with CCA harbouring genomic alterations³

Click below for more key recommendations:³

Treatment algorithm for biliary tract cancer

genomic-testing.esmo.treatment_algorithm.alt

Reprinted from Annals of Oncology 2023, Volume 34/Issue 2, Vogel A, et al. Biliary tract cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up, P127–40,³ with permission from the European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved.

Methodology matters

A variety of molecular profiling methods are now available, with NGS and fluorescence in situ hybridisation (FISH) among the most common assays^4,5

There are some important differences between the 2 methods:

NGS

NGS allows the opportunity, in a molecular target-rich disease like iCCA, to analyse a tissue sample for multiple alterations at the same time. Therefore, although the specimen size for NGS is initially larger and the turnaround time may be longer, it may preclude the need for further biopsies for the purposes of molecular testing^6–8

FISH

FISH was originally designed to identify 1 specific, predetermined alteration at a time. Although more recent FISH assays can detect multiple prespecified genetic alterations, NGS can provide additional information not possible through FISH^4,5

Biopsy technique

Biopsy technique should account for planned molecular profiling as well as diagnostic needs

Compared with the tissue required for a histological diagnosis, additional tissue may be required to satisfy emerging molecular profiling needs in iCCA^12,13

A molecular profiling plan should be considered early on, including tissue requirements for the specific planned biomarker test when determining biopsy technique^12,13

Although more invasive than fine-needle aspiration, core-needle biopsy provides important pathological details about the tumour and typically yields enough tissue to allow for comprehensive molecular profiling^12-14

Key differences in biopsy techniques

Core-needle biopsy^12-14	Fine-needle aspiration¹²
Advantages Acquires more tissue Allows for additional histological and immunohistochemical testing Allows for more comprehensive molecular profiling Acquires more structured tissue Provides information on cytology and tissue architecture	Advantages Less invasive Results can be obtained quickly May be associated with fewer complications
Considerations More invasive	Considerations Acquires limited amount of tissue, which does not allow for further testing or comprehensive molecular profiling

Core-needle biopsy^12-14

Fine-needle aspiration¹²

Advantages

Acquires more tissue
- Allows for additional histological and immunohistochemical testing
- Allows for more comprehensive molecular profiling
Acquires more structured tissue
- Provides information on cytology and tissue architecture

Advantages

Less invasive
Results can be obtained quickly
May be associated with fewer complications

Considerations

More invasive

Considerations

Acquires limited amount of tissue, which does not allow for further testing or comprehensive molecular profiling

Once the biopsy is performed, the tissue should be processed promptly and prepared according to the specific needs of the molecular profiling assay selected⁶

Liquid biopsy

Compared to traditional tissue sampling methods, liquid biopsy is less invasive and can be serially repeated, allowing real-time monitoring of the tumour genomic profile and/or response to therapy¹⁵

Diagnostic biomarkers and potential therapeutic targets can be detected by analysing cellular components such as cell-free DNA (cfDNA), circulating tumour DNA (ctDNA), proteins, cytokines and serum metabolites¹⁵

Analysis of cfDNA/ctDNA via NGS has identified a range of genomic alterations in patients with biliary tract tumours, including tumour protein P53 (TP53), B-Raf proto-oncogene (BRAF), FGFR2 and isocitrate dehydrogenase alpha-1 (IDHA1) mutations, erb-b2 receptor tyrosine kinase 2 (ERBB2) amplifications and FGFR2 fusions¹⁵

However, the role of liquid biopsy in clinical practice for patients with cholangiocarcinoma is still marginal and further research is necessary¹⁵

A multidisciplinary approach to unresectable or metastatic iCCA may enable a more comprehensive understanding of disease biology and treatment options¹⁶

REFERENCES: 1. Simile MM, et al. Medicina (Kaunas). 2019;55:42. 2. Lowery MA, et al. Clin Cancer Res. 2018;24:4154–61. 3. Vogel A, et al. Ann Oncol. 2023;34:127–40; 4. Dudley JC, et al. J Mol Diagn. 2016;18:124–30. 5. Hu L, et al. Biomark Res. 2014;2:3. 6. Cree IA, et al. J Clin Pathol. 2014;67:923–31. 7. Damodaran S, et al. Am Soc Clin Oncol Educ Book. 2015;e175–e182. 8. Su D, et al. J Exp Clin Cancer Res. 2017;36:121. 9. Jain A, et al. JCO Precis Oncol. 2018;2:1–12. 10. Silverman IM, et al. Cancer Discov. 2021;11:326–39. 11. Barr FG. Expert Rev Mol Diagn. 2016;16:921–3. 12. Wee A. J Gastrointest Oncol. 2013;4:5–7. 13. Stewart CJR, et al. J Clin Pathol. 2002;55:93–7. 14. International Consensus Group for Hepatocellular Neoplasia. Hepatology; 2009;49:658–64. 15. Rompianesi G, et al. World J Gastrointest Oncol. 2021;13:332–50. 16. Patel T. Nat Rev Gastroenterol Hepatol. 2011;8:189–200.

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