Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Cholangiocarcinoma — novel biological insights and therapeutic strategies

Nature Reviews Clinical Oncology (2023)Cite this article

Subjects

Abstract

In the past 5 years, important advances have been made in the scientific understanding and clinical management of cholangiocarcinoma (CCA). The cellular immune landscape of CCA has been characterized and tumour subsets with distinct immune microenvironments have been defined using molecular approaches. Among these subsets, the identification of ‘immune-desert’ tumours that are relatively devoid of immune cells emphasizes the need to consider the tumour immune microenvironment in the development of immunotherapy approaches. Progress has also made in identifying the complex heterogeneity and diverse functions of cancer-associated fibroblasts in this desmoplastic cancer. Assays measuring circulating cell-free DNA and cell-free tumour DNA are emerging as clinical tools for detection and monitoring of the disease. Molecularly targeted therapy for CCA has now become a reality, with three drugs targeting oncogenic fibroblast growth factor receptor 2 (FGFR2) fusions and one targeting neomorphic, gain-of-function variants of isocitrate dehydrogenase 1 (IDH1) obtaining regulatory approval. By contrast, immunotherapy using immune-checkpoint inhibitors has produced disappointing results in patients with CCA, underscoring the requirement for novel immune-based treatment strategies. Finally, liver transplantation for early stage intrahepatic CCA under research protocols is emerging as a viable therapeutic option in selected patients. This Review highlights and provides in-depth information on these advances.

Key points

  • Cholangiocarcinomas (CCAs) are highly desmoplastic cancers characterized by a tumour microenvironment that is poorly immunogenic, with an abundance of immunosuppressive cell types such as myeloid-derived suppressor cells and tumour-associated macrophages.

  • The desmoplasia of CCAs is associated with an abundance of heterogeneous cancer-associated fibroblasts (CAFs), with several transcriptomically diverse CAF subtypes identified.

  • Assessments of circulating tumour cells and cell-free tumour DNA are becoming important in the diagnosis and monitoring of CCA.

  • Potent oncogenic drivers of intrahepatic CCAs (iCCAs) include fibroblast growth factor receptor 2 (FGFR2) gene fusions and neomorphic, gain-of-function variants of isocitrate dehydrogenase 1 (IDH1). FGFR2 fusions and IDH1 mutations are targetable, and approved molecularly targeted therapies are now available for the treatment of CCAs harbouring these genetic aberrations.

  • The results of immune-checkpoint inhibitor monotherapy in patients with CCA have been disappointing, although the combination of gemcitabine, cisplatin and durvalumab has been approved in the first-line setting for the treatment of advanced-stage CCA.

  • Liver transplantation is an emerging option for the subset of patients with early stage iCCA occurring in the setting of cirrhosis.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Get just this article for as long as you need it

$39.95

Learn more

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Therapeutically re-engineering the TIME of CCA to reduce tumour burden.
Fig. 2: Different shades of CAF heterogeneity in CCA.

References

  1. Banales, J. M. et al. Cholangiocarcinoma: state-of-the-art knowledge and challenges. Liver Int. 39, 5–6 (2019).

    Article  PubMed  Google Scholar 

  2. Brindley, P. J. et al. Cholangiocarcinoma. Nat. Rev. Dis. Prim. 7, 65 (2021).

    Article  PubMed  Google Scholar 

  3. Banales, J. M. et al. Cholangiocarcinoma 2020: the next horizon in mechanisms and management. Nat. Rev. Gastroenterol. Hepatol. 17, 557–588 (2020).

    Article  PubMed Central  PubMed  Google Scholar 

  4. Rizvi, S., Khan, S. A., Hallemeier, C. L., Kelley, R. K. & Gores, G. J. Cholangiocarcinoma– evolving concepts and therapeutic strategies. Nat. Rev. Clin. Oncol. 15, 95–111 (2018).

    Article  CAS  PubMed  Google Scholar 

  5. Affo, S. et al. Promotion of cholangiocarcinoma growth by diverse cancer-associated fibroblast subpopulations. Cancer Cell 39, 883 (2021).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  6. Yang, J. D. et al. DNA methylation markers for detection of cholangiocarcinoma: discovery, validation, and clinical testing in biliary brushings and plasma. Hepatol. Commun. 5, 1448–1459 (2021).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  7. Zill, O. A. et al. Cell-free DNA next-generation sequencing in pancreatobiliary carcinomas. Cancer Discov. 5, 1040–1048 (2015).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  8. Wu, M. J., Shi, L., Merritt, J., Zhu, A. X. & Bardeesy, N. Biology of IDH mutant cholangiocarcinoma. Hepatology 75, 1322–1337 (2022).

    Article  CAS  PubMed  Google Scholar 

  9. Kelley, R. K., Bridgewater, J., Gores, G. J. & Zhu, A. X. Systemic therapies for intrahepatic cholangiocarcinoma. J. Hepatol. 72, 353–363 (2020).

    Article  CAS  PubMed  Google Scholar 

  10. Abou-Alfa, G. K. et al. Pemigatinib for previously treated, locally advanced or metastatic cholangiocarcinoma: a multicentre, open-label, phase 2 study. Lancet Oncol. 21, 671–684 (2020).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  11. Javle, M. et al. Infigratinib (BGJ398) in previously treated patients with advanced or metastatic cholangiocarcinoma with FGFR2 fusions or rearrangements: mature results from a multicentre, open-label, single-arm, phase 2 study. Lancet Gastroenterol. Hepatol. 6, 803–815 (2021).

    Article  PubMed  Google Scholar 

  12. Goyal, L. et al. Futibatinib for FGFR2-rearranged intrahepatic cholangiocarcinoma. N. Engl. J. Med. 388, 228–239 (2023).

    Article  CAS  PubMed  Google Scholar 

  13. US Food and Drug Administration. FDA grants accelerated approval to pemigatinib for cholangiocarcinoma with an FGFR2 rearrangement or fusion. FDA https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-pemigatinib-cholangiocarcinoma-fgfr2-rearrangement-or-fusion (2020).

  14. US Food and Drug Administration. FDA grants accelerated approval to infigratinib for metastatic cholangiocarcinoma. FDA https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-infigratinib-metastatic-cholangiocarcinoma (2021).

  15. US Food and Drug Administration. FDA grants accelerated approval to futibatinib for cholangiocarcinoma. FDA https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-futibatinib-cholangiocarcinoma (2022).

  16. Abou-Alfa, G. K. et al. Ivosidenib in IDH1-mutant, chemotherapy-refractory cholangiocarcinoma (ClarIDHy): a multicentre, randomised, double-blind, placebo-controlled, phase 3 study. Lancet Oncol. 21, 796–807 (2020).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  17. US Food and Drug Administration. FDA approves ivosidenib for advanced or metastatic cholangiocarcinoma. FDA https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-ivosidenib-advanced-or-metastatic-cholangiocarcinoma (2022).

  18. Gravely, A. K., Vibert, E. & Sapisochin, G. Surgical treatment of intrahepatic cholangiocarcinoma. J. Hepatol. https://doi.org/10.1016/j.jhep.2022.01.004 (2022).

    Article  PubMed  Google Scholar 

  19. Wang, J., Loeuillard, E., Gores, G. J. & Ilyas, S. I. Cholangiocarcinoma: what are the most valuable therapeutic targets – cancer-associated fibroblasts, immune cells, or beyond T cells? Expert. Opin. Ther. Targets 25, 835–845 (2021).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  20. Loeuillard, E. et al. Targeting tumor-associated macrophages and granulocytic myeloid-derived suppressor cells augments PD-1 blockade in cholangiocarcinoma. J. Clin. Invest. 130, 5380–5396 (2020).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  21. Ruffolo, L. I. et al. GM-CSF drives myelopoiesis, recruitment and polarisation of tumour-associated macrophages in cholangiocarcinoma and systemic blockade facilitates antitumour immunity. Gut 71, 1386–1398 (2022).

    Article  CAS  PubMed  Google Scholar 

  22. Zhang, Q. et al. Gut microbiome directs hepatocytes to recruit MDSCs and promote cholangiocarcinoma. Cancer Discov. 11, 1248–1267 (2021).

    Article  CAS  PubMed  Google Scholar 

  23. Gani, F. et al. Program death 1 immune checkpoint and tumor microenvironment: implications for patients with intrahepatic cholangiocarcinoma. Ann. Surg. Oncol. 23, 2610–2617 (2016).

    Article  PubMed  Google Scholar 

  24. Zhou, G. et al. Reduction of immunosuppressive tumor microenvironment in cholangiocarcinoma by ex vivo targeting immune checkpoint molecules. J. Hepatol. 71, 753–762 (2019).

    Article  PubMed  Google Scholar 

  25. Ghidini, M. et al. Characterisation of the immune-related transcriptome in resected biliary tract cancers. Eur. J. Cancer 86, 158–165 (2017).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  26. Ma, L. et al. Tumor cell biodiversity drives microenvironmental reprogramming in liver cancer. Cancer Cell 36, 418–430.e6 (2019).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  27. Fabris, L., Sato, K., Alpini, G. & Strazzabosco, M. The tumor microenvironment in cholangiocarcinoma progression. Hepatology 73, 75–85 (2021).

    Article  PubMed  Google Scholar 

  28. Piha-Paul, S. A. et al. Efficacy and safety of pembrolizumab for the treatment of advanced biliary cancer: results from the KEYNOTE-158 and KEYNOTE-028 studies. Int. J. Cancer 147, 2190–2198 (2020).

    Article  CAS  PubMed  Google Scholar 

  29. Buettner, S. et al. The impact of neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio among patients with intrahepatic cholangiocarcinoma. Surgery 164, 411–418 (2018).

    Article  PubMed  Google Scholar 

  30. Peng, D. et al. Lymphocyte to monocyte ratio predicts resectability and early recurrence of Bismuth-Corlette type IV hilar cholangiocarcinoma. J. Gastrointest. Surg. 24, 330–340 (2020).

    Article  PubMed  Google Scholar 

  31. Tsilimigras, D. I. et al. The systemic immune-inflammation index predicts prognosis in intrahepatic cholangiocarcinoma: an international multi-institutional analysis. HPB 22, 1667–1674 (2020).

    Article  PubMed  Google Scholar 

  32. Sun, D. et al. CD86+/CD206+ tumor-associated macrophages predict prognosis of patients with intrahepatic cholangiocarcinoma. PeerJ 8, e8458 (2020).

    Article  PubMed Central  PubMed  Google Scholar 

  33. Yuan, D. et al. Kupffer cell-derived TNF triggers cholangiocellular tumorigenesis through JNK due to chronic mitochondrial dysfunction and ROS. Cancer Cell 31, 771–789.e6 (2017).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  34. Boulter, L. et al. WNT signaling drives cholangiocarcinoma growth and can be pharmacologically inhibited. J. Clin. Invest. 125, 1269–1285 (2015).

    Article  PubMed Central  PubMed  Google Scholar 

  35. Dwyer, B. J. et al. TWEAK/Fn14 signalling promotes cholangiocarcinoma niche formation and progression. J. Hepatol. 74, 860–872 (2021).

    Article  CAS  PubMed  Google Scholar 

  36. Veglia, F., Perego, M. & Gabrilovich, D. Myeloid-derived suppressor cells coming of age. Nat. Immunol. 19, 108–119 (2018).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  37. Xu, X. D. et al. Circulating myeloid-derived suppressor cells in patients with pancreatic cancer. Hepatobiliary Pancreat. Dis. Int. 15, 99–105 (2016).

    Article  PubMed  Google Scholar 

  38. Meyer, C. et al. Frequencies of circulating MDSC correlate with clinical outcome of melanoma patients treated with ipilimumab. Cancer Immunol. Immunother. 63, 247–257 (2014).

    Article  CAS  PubMed  Google Scholar 

  39. Song, G. et al. Single-cell transcriptomic analysis suggests two molecularly subtypes of intrahepatic cholangiocarcinoma. Nat. Commun. 13, 1642 (2022).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  40. Bao, X. et al. Molecular subgroups of intrahepatic cholangiocarcinoma discovered by single-cell RNA sequencing-assisted multiomics analysis. Cancer Immunol. Res. 10, 811–828 (2022).

    Article  CAS  PubMed  Google Scholar 

  41. Keenan, B. P. et al. Circulating monocytes associated with anti-PD-1 resistance in human biliary cancer induce T cell paralysis. Cell Rep. 40, 111384 (2022).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  42. Tavazoie, M. F. et al. LXR/ApoE activation restricts innate immune suppression in cancer. Cell 172, 825–840.e18 (2018).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  43. Vonderheide, R. H. CD40 agonist antibodies in cancer immunotherapy. Annu. Rev. Med. 71, 47–58 (2020).

    Article  CAS  PubMed  Google Scholar 

  44. Diggs, L. P. et al. CD40-mediated immune cell activation enhances response to anti-PD-1 in murine intrahepatic cholangiocarcinoma. J. Hepatol. 74, 1145–1154 (2021).

    Article  CAS  PubMed  Google Scholar 

  45. Wabitsch, S. et al. Anti-PD-1 in combination with trametinib suppresses tumor growth and improves survival of intrahepatic cholangiocarcinoma in mice. Cell Mol. Gastroenterol. Hepatol. 12, 1166–1178 (2021).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  46. Affo, S., Yu, L. X. & Schwabe, R. F. The role of cancer-associated fibroblasts and fibrosis in liver cancer. Annu. Rev. Pathol. 12, 153–186 (2017).

    Article  CAS  PubMed  Google Scholar 

  47. Brivio, S., Cadamuro, M., Strazzabosco, M. & Fabris, L. Tumor reactive stroma in cholangiocarcinoma: the fuel behind cancer aggressiveness. World J. Hepatol. 9, 455–468 (2017).

    Article  PubMed Central  PubMed  Google Scholar 

  48. Sirica, A. E., Campbell, D. J. & Dumur, C. I. Cancer-associated fibroblasts in intrahepatic cholangiocarcinoma. Curr. Opin. Gastroenterol. 27, 276–284 (2011).

    Article  CAS  PubMed  Google Scholar 

  49. Sirica, A. E. & Gores, G. J. Desmoplastic stroma and cholangiocarcinoma: clinical implications and therapeutic targeting. Hepatology 59, 2397–2402 (2014).

    Article  PubMed  Google Scholar 

  50. Fabris, L. et al. The tumour microenvironment and immune milieu of cholangiocarcinoma. Liver Int. 39, 63–78 (2019).

    Article  PubMed  Google Scholar 

  51. Mertens, J. C. et al. Therapeutic effects of deleting cancer-associated fibroblasts in cholangiocarcinoma. Cancer Res. 73, 897–907 (2013).

    Article  CAS  PubMed  Google Scholar 

  52. Chen, Y., McAndrews, K. M. & Kalluri, R. Clinical and therapeutic relevance of cancer-associated fibroblasts. Nat. Rev. Clin. Oncol. 18, 792–804 (2021).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  53. Campbell, D. J., Dumur, C. I., Lamour, N. F., Dewitt, J. L. & Sirica, A. E. Novel organotypic culture model of cholangiocarcinoma progression. Hepatol. Res. 42, 1119–1130 (2012).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  54. Biffi, G. & Tuveson, D. A. Diversity and biology of cancer-associated fibroblasts. Physiol. Rev. 101, 147–176 (2021).

    Article  CAS  PubMed  Google Scholar 

  55. Kalluri, R. The biology and function of fibroblasts in cancer. Nat. Rev. Cancer 16, 582–598 (2016).

    Article  CAS  PubMed  Google Scholar 

  56. Bhattacharjee, S. et al. Tumor restriction by type I collagen opposes tumor-promoting effects of cancer-associated fibroblasts. J. Clin. Invest. https://doi.org/10.1172/JCI146987 (2021).

    Article  PubMed Central  PubMed  Google Scholar 

  57. Martin-Serrano, M. A. et al. Novel microenvironment-based classification of intrahepatic cholangiocarcinoma with therapeutic implications. Gut https://doi.org/10.1136/gutjnl-2021-326514 (2022).

    Article  PubMed  Google Scholar 

  58. Zhang, M. et al. Single-cell transcriptomic architecture and intercellular crosstalk of human intrahepatic cholangiocarcinoma. J. Hepatol. 73, 1118–1130 (2020).

    Article  CAS  PubMed  Google Scholar 

  59. Ravichandra, A., Bhattacharjee, S. & Affo, S. Cancer-associated fibroblasts in intrahepatic cholangiocarcinoma progression and therapeutic resistance. Adv. Cancer Res. 156, 201–226 (2022).

    Article  PubMed  Google Scholar 

  60. Chen, Y. et al. Type I collagen deletion in αSMA+ myofibroblasts augments immune suppression and accelerates progression of pancreatic cancer. Cancer Cell 39, 548–565.e6 (2021).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  61. Liu, M. C. et al. Sensitive and specific multi-cancer detection and localization using methylation signatures in cell-free DNA. Ann. Oncol. 31, 745–759 (2020).

    Article  CAS  PubMed  Google Scholar 

  62. Cohen, J. D. et al. Detection and localization of surgically resectable cancers with a multi-analyte blood test. Science 359, 926–930 (2018).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  63. Wasenang, W., Chaiyarit, P., Proungvitaya, S. & Limpaiboon, T. Serum cell-free DNA methylation of OPCML and HOXD9 as a biomarker that may aid in differential diagnosis between cholangiocarcinoma and other biliary diseases. Clin. Epigenetics 11, 39 (2019).

    Article  PubMed Central  PubMed  Google Scholar 

  64. Ettrich, T. J. et al. Genotyping of circulating tumor DNA in cholangiocarcinoma reveals diagnostic and prognostic information. Sci. Rep. 9, 13261 (2019).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  65. Mody, K. et al. Circulating tumor DNA profiling of advanced biliary tract cancers. JCO Precis. Oncol. 3, 1–9 (2019).

    PubMed  Google Scholar 

  66. Moreno Luna, L. E. et al. Advanced cytologic techniques for the detection of malignant pancreatobiliary strictures. Gastroenterology 131, 1064–1072 (2006).

    Article  PubMed  Google Scholar 

  67. Barr Fritcher, E. G. et al. An optimized set of fluorescence in situ hybridization probes for detection of pancreatobiliary tract cancer in cytology brush samples. Gastroenterology 149, 1813–1824.e1 (2015).

    Article  CAS  PubMed  Google Scholar 

  68. Gonda, T. A. et al. Mutation profile and fluorescence in situ hybridization analyses increase detection of malignancies in biliary strictures. Clin. Gastroenterol. Hepatol. 15, 913–919.e1 (2017).

    Article  CAS  PubMed  Google Scholar 

  69. Singhi, A. D. et al. Integrating next-generation sequencing to endoscopic retrograde cholangiopancreatography (ERCP)-obtained biliary specimens improves the detection and management of patients with malignant bile duct strictures. Gut 69, 52–61 (2020).

    Article  CAS  PubMed  Google Scholar 

  70. Arechederra, M. et al. Next-generation sequencing of bile cell-free DNA for the early detection of patients with malignant biliary strictures. Gut 71, 1141–1151 (2022).

    Article  CAS  PubMed  Google Scholar 

  71. Andresen, K. et al. Four DNA methylation biomarkers in biliary brush samples accurately identify the presence of cholangiocarcinoma. Hepatology 61, 1651–1659 (2015).

    Article  CAS  PubMed  Google Scholar 

  72. Loi, E. et al. HOXD8 hypermethylation as a fully sensitive and specific biomarker for biliary tract cancer detectable in tissue and bile samples. Br. J. Cancer 126, 1783–1794 (2022).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  73. Shigehara, K. et al. Real-time PCR-based analysis of the human bile microRNAome identifies miR-9 as a potential diagnostic biomarker for biliary tract cancer. PLoS ONE 6, e23584 (2011).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  74. Han, H. S. et al. Bile-derived circulating extracellular miR-30d-5p and miR-92a-3p as potential biomarkers for cholangiocarcinoma. Hepatobiliary Pancreat. Dis. Int. 19, 41–50 (2020).

    Article  PubMed  Google Scholar 

  75. Berchuck, J. E. et al. The clinical landscape of cell-free DNA alterations in 1671 patients with advanced biliary tract cancer. Ann. Oncol. 33, 1269–1283 (2022).

    Article  CAS  PubMed  Google Scholar 

  76. Andersen, J. B. et al. Genomic and genetic characterization of cholangiocarcinoma identifies therapeutic targets for tyrosine kinase inhibitors. Gastroenterology 142, 1021–1031.e15 (2012).

    Article  CAS  PubMed  Google Scholar 

  77. Montal, R. et al. Molecular classification and therapeutic targets in extrahepatic cholangiocarcinoma. J. Hepatol. 73, 315–327 (2020).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  78. Sia, D. et al. Integrative molecular analysis of intrahepatic cholangiocarcinoma reveals 2 classes that have different outcomes. Gastroenterology 144, 829–840 (2013).

    Article  CAS  PubMed  Google Scholar 

  79. Job, S. et al. Identification of four immune subtypes characterized by distinct composition and functions of tumor microenvironment in intrahepatic cholangiocarcinoma. Hepatology 72, 965–981 (2020).

    Article  CAS  PubMed  Google Scholar 

  80. Lowery, M. A. et al. Comprehensive molecular profiling of intrahepatic and extrahepatic cholangiocarcinomas: potential targets for intervention. Clin. Cancer Res. 24, 4154–4161 (2018).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  81. Weinberg, B. A. et al. Molecular profiling of biliary cancers reveals distinct molecular alterations and potential therapeutic targets. J. Gastrointest. Oncol. 10, 652–662 (2019).

    Article  PubMed Central  PubMed  Google Scholar 

  82. Wardell, C. P. et al. Genomic characterization of biliary tract cancers identifies driver genes and predisposing mutations. J. Hepatol. 68, 959–969 (2018).

    Article  CAS  PubMed  Google Scholar 

  83. Jusakul, A. et al. Whole-genome and epigenomic landscapes of etiologically distinct subtypes of cholangiocarcinoma. Cancer Discov. 7, 1116–1135 (2017).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  84. Nakamura, H. et al. Genomic spectra of biliary tract cancer. Nat. Genet. 47, 1003–1010 (2015).

    Article  CAS  PubMed  Google Scholar 

  85. Boscoe, A. N., Rolland, C. & Kelley, R. K. Frequency and prognostic significance of isocitrate dehydrogenase 1 mutations in cholangiocarcinoma: a systematic literature review. J. Gastrointest. Oncol. 10, 751–765 (2019).

    Article  PubMed Central  PubMed  Google Scholar 

  86. Chaisaingmongkol, J. et al. Common molecular subtypes among Asian hepatocellular carcinoma and cholangiocarcinoma. Cancer Cell 32, 57–70.e3 (2017).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  87. Chan-On, W. et al. Exome sequencing identifies distinct mutational patterns in liver fluke-related and non-infection-related bile duct cancers. Nat. Genet. 45, 1474–1478 (2013).

    Article  CAS  PubMed  Google Scholar 

  88. Bekaii-Saab, T. S., Bridgewater, J. & Normanno, N. Practical considerations in screening for genetic alterations in cholangiocarcinoma. Ann. Oncol. 32, 1111–1126 (2021).

    Article  CAS  PubMed  Google Scholar 

  89. Lamarca, A. et al. Molecular profiling in daily clinical practice: practicalities in advanced cholangiocarcinoma and other biliary tract cancers. J. Clin. Med. https://doi.org/10.3390/jcm9092854 (2020).

    Article  PubMed Central  PubMed  Google Scholar 

  90. National Comprehensive Cancer Network. NCCN guidelines: hepatobiliary cancer. NCCN https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1438 (2022).

  91. Haugsten, E. M., Wiedlocha, A., Olsnes, S. & Wesche, J. Roles of fibroblast growth factor receptors in carcinogenesis. Mol. Cancer Res. 8, 1439–1452 (2010).

    Article  CAS  PubMed  Google Scholar 

  92. Babina, I. S. & Turner, N. C. Advances and challenges in targeting FGFR signalling in cancer. Nat. Rev. Cancer 17, 318–332 (2017).

    Article  CAS  PubMed  Google Scholar 

  93. Wu, Y. M. et al. Identification of targetable FGFR gene fusions in diverse cancers. Cancer Discov. 3, 636–647 (2013).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  94. Graham, R. P. et al. Fibroblast growth factor receptor 2 translocations in intrahepatic cholangiocarcinoma. Hum. Pathol. 45, 1630–1638 (2014).

    Article  CAS  PubMed  Google Scholar 

  95. Arai, Y. et al. Fibroblast growth factor receptor 2 tyrosine kinase fusions define a unique molecular subtype of cholangiocarcinoma. Hepatology 59, 1427–1434 (2014).

    Article  CAS  PubMed  Google Scholar 

  96. Becker, Z. BridgeBio says it’s undeterred after Truseltiq partner withdraws application, discontinues drug. FIERCE Pharma https://www.fiercepharma.com/pharma/bridgebios-cancer-drug-truseltiqs-future-unclear-partner-helsinn-withdrawing-nda (2022).

  97. Droz Dit Busset, M. et al. Derazantinib for patients with intrahepatic cholangiocarcinoma harboring FGFR2 fusions/rearrangements: primary results from the phase II study FIDES-01 [abstract 47P]. Ann. Oncol. 32 (Suppl. 5), S376 (2021).

    Article  Google Scholar 

  98. Krook, M. A. et al. Efficacy of FGFR inhibitors and combination therapies for acquired resistance in FGFR2-fusion cholangiocarcinoma. Mol. Cancer Ther. 19, 847–857 (2020).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  99. Krook, M. A. et al. Tumor heterogeneity and acquired drug resistance in FGFR2-fusion-positive cholangiocarcinoma through rapid research autopsy. Cold Spring Harb. Mol. Case Stud. https://doi.org/10.1101/mcs.a004002 (2019).

    Article  PubMed Central  PubMed  Google Scholar 

  100. Goyal, L. et al. Polyclonal secondary FGFR2 mutations drive acquired resistance to FGFR inhibition in patients with FGFR2 fusion-positive cholangiocarcinoma. Cancer Discov. 7, 252–263 (2017).

    Article  CAS  PubMed  Google Scholar 

  101. Goyal, L. et al. TAS-120 overcomes resistance to ATP-competitive FGFR inhibitors in patients with FGFR2 fusion-positive intrahepatic cholangiocarcinoma. Cancer Discov. 9, 1064–1079 (2019).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  102. Sootome, H. et al. Futibatinib is a novel irreversible FGFR 1-4 inhibitor that shows selective antitumor activity against FGFR-deregulated tumors. Cancer Res. 80, 4986–4997 (2020).

    Article  CAS  PubMed  Google Scholar 

  103. Meric-Bernstam, F. et al. Futibatinib, an irreversible FGFR1-4 inhibitor, in patients with advanced solid tumors harboring FGF/FGFR aberrations: a phase I dose-expansion study. Cancer Discov. 12, 402–415 (2022).

    Article  CAS  PubMed  Google Scholar 

  104. Casaletto, J. et al. RLY-4008, a novel precision therapy for FGFR2-driven cancers designed to potently and selectively inhibit FGFR2 and FGFR2 resistance mutations [abstract]. Cancer Res. 81 (Suppl. 13), 1455 (2021).

    Article  Google Scholar 

  105. Franovic, A. et al. Activity of KIN-3248, a next-generation pan-FGFR inhibitor, against acquired FGFR-gatekeeper and molecular-brake drug resistance mutations [abstract]. J. Clin. Oncol. 40 (Suppl. 4), 461 (2022).

    Article  Google Scholar 

  106. Goyal, L. et al. First results of RLY-4008, a potent and highly selective FGFR2 inhibitor in a first-in-human study in patients with FGFR2-altered cholangiocarcinoma and multiple solid tumors [abstract]. Mol. Cancer Ther. 20 (Suppl. 12), P02-02 (2021).

    Article  Google Scholar 

  107. Lu, C. & Thompson, C. B. Metabolic regulation of epigenetics. Cell Metab. 16, 9–17 (2012).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  108. Inoue, S. et al. Mutant IDH1 downregulates ATM and alters DNA repair and sensitivity to DNA damage independent of TET2. Cancer Cell 30, 337–348 (2016).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  109. Sulkowski, P. L. et al. 2-Hydroxyglutarate produced by neomorphic IDH mutations suppresses homologous recombination and induces PARP inhibitor sensitivity. Sci. Transl. Med. https://doi.org/10.1126/scitranslmed.aal2463 (2017).

    Article  PubMed Central  PubMed  Google Scholar 

  110. Valle, J. W., Lamarca, A., Goyal, L., Barriuso, J. & Zhu, A. X. New horizons for precision medicine in biliary tract cancers. Cancer Discov. 7, 943–962 (2017).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  111. Subbiah, V. et al. Dabrafenib plus trametinib in patients with BRAFV600E-mutated biliary tract cancer (ROAR): a phase 2, open-label, single-arm, multicentre basket trial. Lancet Oncol. 21, 1234–1243 (2020).

    Article  CAS  PubMed  Google Scholar 

  112. US Food and Drug Administration. FDA grants accelerated approval of dabrafenib in combination with trametinib for unresectable or metastatic solid tumors with BRAF V600E mutation. FDA https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-dabrafenib-combination-trametinib-unresectable-or-metastatic-solid (2022).

  113. Subbiah, V. et al. Pan-cancer efficacy of vemurafenib in BRAFV600-mutant non-melanoma cancers. Cancer Discov. 10, 657–663 (2020).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  114. Galdy, S. et al. HER2/HER3 pathway in biliary tract malignancies; systematic review and meta-analysis: a potential therapeutic target? Cancer Metastasis Rev. 36, 141–157 (2017).

    Article  CAS  PubMed  Google Scholar 

  115. Javle, M. et al. Pertuzumab and trastuzumab for HER2-positive, metastatic biliary tract cancer (MyPathway): a multicentre, open-label, phase 2a, multiple basket study. Lancet Oncol. 22, 1290–1300 (2021).

    Article  CAS  PubMed  Google Scholar 

  116. Ohba, A. et al. Trastuzumab deruxtecan (T-DXd; DS-8201) in patients (pts) with HER2-expressing unresectable or recurrent biliary tract cancer (BTC): an investigator-initiated multicenter phase 2 study (HERB trial) [abstract]. J. Clin. Oncol. 40 (Suppl. 16), 4006 (2022).

    Article  Google Scholar 

  117. Lee, C. K. et al. Trastuzumab plus FOLFOX for HER2-positive biliary tract cancer refractory to gemcitabine and cisplatin: a multi-institutional phase 2 trial of the Korean Cancer Study Group (KCSG-HB19-14). Lancet Gastroenterol. Hepatol. https://doi.org/10.1016/S2468-1253(22)00335-1 (2022).

    Article  PubMed Central  PubMed  Google Scholar 

  118. Harding, J. J. et al. Targeting HER2 mutation-positive advanced biliary tract cancers with neratinib: final results from the phase 2 SUMMIT basket trial. J. Clin. Oncol. 40, 4079–4079 (2022).

    Article  Google Scholar 

  119. Meric-Bernstam, F. et al. Zanidatamab (ZW25) in HER2-positive biliary tract cancers (BTCs): results from a phase I study [abstract]. J. Clin. Oncol. 39 (Suppl. 3), 299 (2021).

    Article  Google Scholar 

  120. Westphalen, C. B. et al. Genomic context of NTRK1/2/3 fusion-positive tumours from a large real-world population. NPJ Precis. Oncol. 5, 69 (2021).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  121. Drilon, A. et al. Efficacy of larotrectinib in TRK fusion-positive cancers in adults and children. N. Engl. J. Med. 378, 731–739 (2018).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  122. US Food and Drug Administration. FDA approves larotrectinib for solid tumors with NTRK gene fusions. FDA https://www.fda.gov/drugs/fda-approves-larotrectinib-solid-tumors-ntrk-gene-fusions-0 (2018).

  123. Doebele, R. C. et al. Entrectinib in patients with advanced or metastatic NTRK fusion-positive solid tumours: integrated analysis of three phase 1-2 trials. Lancet Oncol. 21, 271–282 (2020).

    Article  CAS  PubMed  Google Scholar 

  124. US Food and Drug Administration. FDA approves entrectinib for NTRK solid tumors and ROS-1 NSCLC. FDA https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-entrectinib-ntrk-solid-tumors-and-ros-1-nsclc (2019).

  125. Parimi, V. et al. Genomic landscape of 891 RET fusions detected across diverse solid tumor types. NPJ Precis. Oncol. 7, 10 (2023).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  126. Subbiah, V. et al. Pan-cancer efficacy of pralsetinib in patients with RET fusion-positive solid tumors from the phase 1/2 ARROW trial. Nat. Med. 28, 1640–1645 (2022).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  127. Subbiah, V. et al. Tumour-agnostic efficacy and safety of selpercatinib in patients with RET fusion-positive solid tumours other than lung or thyroid tumours (LIBRETTO-001): a phase 1/2, open-label, basket trial. Lancet Oncol. 23, 1261–1273 (2022).

    Article  CAS  PubMed  Google Scholar 

  128. Valle, J. W., Kelley, R. K., Nervi, B., Oh, D. Y. & Zhu, A. X. Biliary tract cancer. Lancet 397, 428–444 (2021).

    Article  CAS  PubMed  Google Scholar 

  129. Lamarca, A., Edeline, J. & Goyal, L. How I treat biliary tract cancer. ESMO Open 7, 100378 (2022).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  130. Le, D. T. et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science 357, 409–413 (2017).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  131. Maio, M. et al. Pembrolizumab in microsatellite instability high or mismatch repair deficient cancers: updated analysis from the phase 2 KEYNOTE-158 study. Ann. Oncol. https://doi.org/10.1016/j.annonc.2022.05.519 (2022).

    Article  PubMed  Google Scholar 

  132. US Food and Drug Administration. FDA grants accelerated approval to pembrolizumab for first tissue/site agnostic indication. FDA https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-pembrolizumab-first-tissuesite-agnostic-indication (2017).

  133. US Food and Drug Administration. FDA approves pembrolizumab for adults and children with TMB-H solid tumors. FDA https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-pembrolizumab-adults-and-children-tmb-h-solid-tumors (2020).

  134. Marabelle, A. et al. Association of tumour mutational burden with outcomes in patients with advanced solid tumours treated with pembrolizumab: prospective biomarker analysis of the multicohort, open-label, phase 2 KEYNOTE-158 study. Lancet Oncol. 21, 1353–1365 (2020).

    Article  CAS  PubMed  Google Scholar 

  135. Ma, K. et al. PD-L1 and PD-1 expression correlate with prognosis in extrahepatic cholangiocarcinoma. Oncol. Lett. 14, 250–256 (2017).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  136. Zhu, Y. et al. Programmed death ligand 1 expression in human intrahepatic cholangiocarcinoma and its association with prognosis and CD8+ T-cell immune responses. Cancer Manag. Res. 10, 4113–4123 (2018).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  137. Fluxa, P. et al. High CD8+ and absence of Foxp3+ T lymphocytes infiltration in gallbladder tumors correlate with prolonged patients survival. BMC Cancer 18, 243 (2018).

    Article  PubMed Central  PubMed  Google Scholar 

  138. Goeppert, B. et al. Major histocompatibility complex class I expression impacts on patient survival and type and density of immune cells in biliary tract cancer. Br. J. Cancer 113, 1343–1349 (2015).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  139. Sun, D. et al. Anti-PD-1 therapy combined with chemotherapy in patients with advanced biliary tract cancer. Cancer Immunol. Immunother. 68, 1527–1535 (2019).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  140. Sahai, V. et al. A multicenter randomized phase II study of nivolumab in combination with gemcitabine/cisplatin or ipilimumab as first-line therapy for patients with advanced unresectable biliary tract cancer (BilT-01) [abstract]. J. Clin. Oncol. 38 (Suppl. 15), 4582 (2020).

    Article  Google Scholar 

  141. Liu, T. et al. Toripalimab with chemotherapy as first-line treatment for advanced biliary tract tumors: a preliminary analysis of safety and efficacy of an open-label phase II clinical study [abstract 53P]. Ann. Oncol. 31 (Suppl. 4), S261 (2020).

    Article  Google Scholar 

  142. Oh, D. Y. et al. Gemcitabine and cisplatin plus durvalumab with or without tremelimumab in chemotherapy-naive patients with advanced biliary tract cancer: an open-label, single-centre, phase 2 study. Lancet Gastroenterol. Hepatol. 7, 522–532 (2022).

    Article  PubMed  Google Scholar 

  143. Oh, D.-Y. et al. Durvalumab plus gemcitabine and cisplatin in advanced biliary tract cancer. NEJM Evid. https://doi.org/10.1056/EVIDoa2200015 (2022).

    Article  Google Scholar 

  144. Burris, H. A. et al. Patient-reported outcomes for the phase 3 TOPAZ-1 study of durvalumab plus gemcitabine and cisplatin in advanced biliary tract cancer [abstract]. J. Clin. Oncol. 40 (Suppl. 16), 4070 (2022).

    Article  Google Scholar 

  145. He, A. et al. Outcomes by primary tumour location in patients with advanced biliary tract cancer treated with durvalumab or placebo plus gemcitabine and cisplatin in the phase 3 TOPAZ-1 study [abstract O-1]. Ann. Oncol. 33 (Suppl. 4), S378 (2022).

    Article  Google Scholar 

  146. Okusaka, T. et al. Outcomes by disease status in patients with advanced biliary tract cancer treated wtih durvalumab or placebo plus gemcitabine and cisplatin in the phase 3 TOPAZ-1 study [abstract 93P]. Ann. Oncol. 33 (Suppl. 9), S1471 (2022).

    Article  Google Scholar 

  147. Vogel, A. et al. Regional subgroup analysis of the phase 3 TOPAZ-1 study of durvalumab (D) plus gemcitabine and cisplatin (GC) in advanced biliary tract cancer (BTC) [abstract]. J. Clin. Oncol. 40 (Suppl. 16), 4075 (2022).

    Article  Google Scholar 

  148. US Food and Drug Administration. FDA D.I.S.C.O. burst edition: FDA approval of Imfinzi (durvalumab) for adult patients with locally advanced or metastatic biliary tract cancer. FDA https://www.fda.gov/drugs/resources-information-approved-drugs/fda-disco-burst-edition-fda-approval-imfinzi-durvalumab-adult-patients-locally-advanced-or (2022).

  149. Kelley, R. K. et al. Pembrolizumab in combination with gemcitabine and cisplatin compared with gemcitabine and cisplatin alone for patients with advanced biliary tract cancer (KEYNOTE-966): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet https://doi.org/10.1016/S0140-6736(23)00727-4 (2023).

    Article  PubMed  Google Scholar 

  150. Villaneuva, L. et al. Lenvatinib plus pembrolizumab for patients with previously treated biliary tract cancers in the multicohort phase II LEAP-005 study [abstract]. J. Clin. Oncol. 39 (Suppl. 3), 321 (2021).

    Article  Google Scholar 

  151. Sapisochin, G. et al. Transplant oncology in primary and metastatic liver tumors: principles, evidence, and opportunities. Ann. Surg. 273, 483–493 (2021).

    Article  PubMed  Google Scholar 

  152. McMillan, R. R. et al. Survival following liver transplantation for locally advanced, unresectable intrahepatic cholangiocarcinoma. Am. J. Transpl. 22, 823–832 (2022).

    Article  CAS  Google Scholar 

  153. Ivanics, T., Toso, C., Ilyas, S. I. & Sapisochin, G. Transplant oncology in locally advanced intrahepatic cholangiocarcinoma: one more step on a long road. Am. J. Transpl. 22, 685–686 (2022).

    Article  Google Scholar 

  154. Jain, A. et al. Cholangiocarcinoma with FGFR genetic aberrations: a unique clinical phenotype. JCO Precis. Oncol. 2, 1–12 (2018).

    PubMed  Google Scholar 

  155. Franssen, S. et al. Comparison of hepatic arterial infusion pump chemotherapy vs resection for patients with multifocal intrahepatic cholangiocarcinoma. JAMA Surg. https://doi.org/10.1001/jamasurg.2022.1298 (2022).

    Article  PubMed Central  PubMed  Google Scholar 

  156. Sapisochin, G. et al. “Very early” intrahepatic cholangiocarcinoma in cirrhotic patients: should liver transplantation be reconsidered in these patients? Am. J. Transpl. 14, 660–667 (2014).

    Article  CAS  Google Scholar 

  157. Sapisochin, G. et al. Liver transplantation for “very early” intrahepatic cholangiocarcinoma: international retrospective study supporting a prospective assessment. Hepatology 64, 1178–1188 (2016).

    Article  CAS  PubMed  Google Scholar 

  158. Jung, D. H. et al. Clinicopathological features and prognosis of intrahepatic cholangiocarcinoma after liver transplantation and resection. Ann. Transpl. 22, 42–52 (2017).

    Article  Google Scholar 

  159. De Martin, E. et al. Analysis of liver resection versus liver transplantation on outcome of small intrahepatic cholangiocarcinoma and combined hepatocellular-cholangiocarcinoma in the setting of cirrhosis. Liver Transpl. 26, 785–798 (2020).

    Article  PubMed  Google Scholar 

  160. Lunsford, K. E. et al. Liver transplantation for locally advanced intrahepatic cholangiocarcinoma treated with neoadjuvant therapy: a prospective case-series. Lancet Gastroenterol. Hepatol. 3, 337–348 (2018).

    Article  PubMed  Google Scholar 

  161. Ito, T. et al. A 3-decade, single-center experience of liver transplantation for cholangiocarcinoma: impact of era, tumor size, location, and neoadjuvant therapy. Liver Transpl. 28, 386–396 (2022).

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

The work of the authors is supported by the US National Institutes of Health (NIH)/National Cancer Institute (NCI) grants SPORE P50 CA210964 (to S.I.I. and G.J.G.) and 1K08CA236874 (to S.I.I.). The work of S.A. is supported by a fellowship from “la Caixa” Foundation (ID 100010434) and by the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement no. 847648. The work of L.G. is supported by American Cancer Society Clinical Scientist Development Grant 134013‐CSDG‐19‐163‐01‐TBG and NIH/NCI Gastrointestinal Cancer SPORE P50 CA127003. A.L. has received funding from The Christie Charity and the European Union’s Horizon 2020 research and innovation programme (grant no. 82551, ESCALON). J.D.Y. has received an American College of Gastroenterology Junior Faculty Development Award and a U.S. Department of Defense Peer Reviewed Cancer Research Program Career Development Award (CA 191051).

Author information

Authors and Affiliations

  1. Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA

    Sumera I. Ilyas & Gregory J. Gores

  2. Department of Immunology, Mayo Clinic, Rochester, MN, USA

    Sumera I. Ilyas

  3. Liver, Digestive System and Metabolism Research, Institut d’Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain

    Silvia Affo

  4. Department of Medicine, Mass General Cancer Center, Harvard Medical School, Boston, MA, USA

    Lipika Goyal

  5. Department of Oncology, OncoHealth Institute, Fundación Jiménez Díaz University Hospital, Madrid, Spain

    Angela Lamarca

  6. Department of Medical Oncology, The Christie NHS Foundation, Manchester, UK

    Angela Lamarca

  7. Division of Cancer Sciences, University of Manchester, Manchester, UK

    Angela Lamarca

  8. Ajmera Transplant Program and HPB Surgical Oncology, Toronto General Hospital, University of Toronto, Toronto, Canada

    Gonzalo Sapisochin

  9. Karsh Division of Gastroenterology and Hepatology, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA

    Ju Dong Yang

Authors
  1. Sumera I. Ilyas
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Silvia Affo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Lipika Goyal
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Angela Lamarca
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Gonzalo Sapisochin
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ju Dong Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Gregory J. Gores
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

S.I.I., J.D.Y. and G.J.G. contributed substantially to discussion of the content and reviewed and/or edited the manuscript before submission. All authors contributed to researching data for the article and writing the manuscript.

Corresponding author

Correspondence to Gregory J. Gores.

Ethics declarations

Competing interests

S.I.I. serves as an adviser and consultant to AstraZeneca. L.G. has received research funding (via her institution) from Adaptimmune, Bayer, Bristol Myers Squibb, Eisai, Eli Lilly, Genentech, Incyte, Leap Therapeutics, Loxo Oncology, Macrogenics, Merck, Novartis, Nucana, QED Therapeutics, Relay Therapeutics, Servier and Taiho Oncology, and serves as an adviser or consultant to Alentis Therapeutics, AstraZeneca, Black Diamond, Exelixis, Genentech, H3Biomedicine, Incyte, QED Therapeutics, Servier, Sirtex Medical, Taiho Oncology and Transthera Bio. A.L. declares travel and educational support from Advanced Accelerator Applications, Bayer, Delcath, Ipsen, Mylan, Novartis, Pfizer and SirtEx; speaker’s honoraria from Advanced Accelerator Applications, AstraZeneca, Eisai, Incyte, Ipsen, Merck, Pfizer, QED Therapeutics and Servier; and advisory or consultancy roles with Albireo Pharma, AstraZeneca, Boehringer Ingelheim, Boston Scientific, Eisai, GENFIT, Ipsen, Nutricia, QED Therapeutics, Roche, Servier and TransThera Biosciences; and is a member of the Knowledge Network and NETConnect Initiatives funded by Ipsen. G.S. has received grant support from Roche, and declares consultancy roles with AstraZeneca, Chiesi, Evidera, Integra, Novartis and Roche. S.A., J.D.Y. and G.J.G. declare no competing interests.

Peer review

Peer review information

Nature Reviews Clinical Oncology thanks C. Berasain, H. Francis, T. Greten, and J. Harding for their contribution to the peer review of this work.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Related links

ClinicalTrials.gov: https://clinicaltrials.gov/

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and Permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ilyas, S.I., Affo, S., Goyal, L. et al. Cholangiocarcinoma — novel biological insights and therapeutic strategies. Nat Rev Clin Oncol (2023). https://doi.org/10.1038/s41571-023-00770-1

Download citation

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1038/s41571-023-00770-1

Search

Advanced search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer