J Liver Cancer.  2025 Mar;25(1):41-51. 10.17998/jlc.2025.02.27.

Epidemiology and genomic features of biliary tract cancer and its unique features in Korea

• Woo S
• Kim Y
• Hwang S
• Chon HJ

• KMID: 2567063
• DOI: http://doi.org/10.17998/jlc.2025.02.27

Abstract

Biliary tract cancer (BTC) is a rare but highly aggressive malignancy that includes intrahepatic cholangiocarcinoma (ICC), extrahepatic cholangiocarcinoma, and gallbladder cancer (GBC). While BTC has a low global incidence, its regional variations are notable. Among nations, Korea has the second-highest incidence of BTC globally, with the highest mortality rate worldwide, underscoring the need for a deeper understanding of this cancer. Liver fluke infection and hepatitis B virus infection are key risk factors unique to Korea, contributing to regional differences in BTC incidence. Additionally, genomic alterations in Korean patients with BTC differ from those in other populations, including lower frequencies of IDH1 mutations and FGFR2 fusions in ICC and a higher prevalence of ERBB2 amplification in GBC. Recognizing the clinical significance of these alterations, ivosidenib and pemigatinib have been approved in Korea for BTC patients with IDH1 mutations and FGFR2 fusions, respectively. This review explores the epidemiology, risk factors, and molecular features of BTC, along with corresponding targeted therapies. Furthermore, we compare the unique characteristics of BTC in Korea with global data to inform future research and clinical practice.

Keyword

Biliary tract neoplasms; Epidemiology; Genomics; Molecular targeted therapy; Korea

Figure

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  Figure 1. Overall incidence of biliary tract cancer by country (2008-2012), as reported by Baria et al.5 (2022). ASR, age-standardized rate; NA, not available.

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  Figure 2. Established risk factors for BTC by nation, as reported by Choi et al.6 (2006), Lee et al.7 (2008), Parkin et al.10 (1991), Welzel et al.11 (2007), Petrick et al.12 (2017), Lee et al.13 (2015), Zhou et al.14 (2008), Donato et al.15 (2001), Barner-Rasmussen et al.16 (2021), Shin et al.17 (2010), and Wang et al.18 (2022). CI, confidence interval; HBV, hepatitis B virus; HCV, hepatitis C virus; ICC, intrahepatic cholangiocarcinoma; ECC, extrahepatic cholangiocarcinoma; BTC, biliary tract cancer.

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  Figure 3. Prevalence of molecular alterations in BTC and their distribution across anatomical locations, as reported by Hwang et al.38 (2024), Chae et al.39 (2019), Lee et al.40 (2023), Yoon et al.41 (2021), and Kim et al.42 (2020) in Korea. ICC, intrahepatic cholangiocarcinoma; ECC, extrahepatic cholangiocarcinoma; GBC, gallbladder cancer; pCCA, perihilar cholangiocarcinoma; dCCA, distal cholangiocarcinoma; BTC, biliary tract cancer.

Reference

References

1. Banales JM, Marin JJG, Lamarca A, Rodrigues PM, Khan SA, Roberts LR, et al. Cholangiocarcinoma 2020: the next horizon in mechanisms and management. Nat Rev Gastroenterol Hepatol. 2020; 17:557–588.

2. Ilyas SI, Khan SA, Hallemeier CL, Kelley RK, Gores GJ. Cholangiocarcinoma - evolving concepts and therapeutic strategies. Nat Rev Clin Oncol. 2018; 15:95–111.

3. Wang Y, Li J, Xia Y, Gong R, Wang K, Yan Z, et al. Prognostic nomogram for intrahepatic cholangiocarcinoma after partial hepatectomy. J Clin Oncol. 2013; 31:1188–1195.

4. Wang SJ, Lemieux A, Kalpathy-Cramer J, Ord CB, Walker GV, Fuller CD, et al. Nomogram for predicting the benefit of adjuvant chemoradiotherapy for resected gallbladder cancer. J Clin Oncol. 2011; 29:4627–4632.

5. Baria K, De Toni EN, Yu B, Jiang Z, Kabadi SM, Malvezzi M. Worldwide incidence and mortality of biliary tract cancer. Gastro Hep Adv. 2022; 1:618–626.

6. Choi D, Lim JH, Lee KT, Lee JK, Choi SH, Heo JS, et al. Cholangiocarcinoma and Clonorchis sinensis infection: a case-control study in Korea. J Hepatol. 2006; 44:1066–1073.

7. Lee TY, Lee SS, Jung SW, Jeon SH, Yun SC, Oh HC, et al. Hepatitis B virus infection and intrahepatic cholangiocarcinoma in Korea: a case-control study. Am J Gastroenterol. 2008; 103:1716–1720.

8. Khan SA, Tavolari S, Brandi G. Cholangiocarcinoma: epidemiology and risk factors. Liver Int. 2019; 39 Suppl 1:19–31.

9. Tyson GL, El-Serag HB. Risk factors for cholangiocarcinoma. Hepatology. 2011; 54:173–184.

10. Parkin DM, Srivatanakul P, Khlat M, Chenvidhya D, Chotiwan P, Insiripong S, et al. Liver cancer in Thailand. I. A case-control study of cholangiocarcinoma. Int J Cancer. 1991; 48:323–328.

11. Welzel TM, Graubard BI, El-Serag HB, Shaib YH, Hsing AW, Davila JA, et al. Risk factors for intrahepatic and extrahepatic cholangiocarcinoma in the United States: a population-based case-control study. Clin Gastroenterol Hepatol. 2007; 5:1221–1228.

12. Petrick JL, Yang B, Altekruse SF, Van Dyke AL, Koshiol J, Graubard BI, et al. Risk factors for intrahepatic and extrahepatic cholangiocarcinoma in the United States: a population-based study in SEER-Medicare. PLoS One. 2017; 12:e0186643.

13. Lee BS, Cha BH, Park EC, Roh J. Risk factors for perihilar cholangiocarcinoma: a hospital-based case-control study. Liver Int. 2015; 35:1048–1053.

14. Zhou YM, Yin ZF, Yang JM, Li B, Shao WY, Xu F, et al. Risk factors for intrahepatic cholangiocarcinoma: a case-control study in China. World J Gastroenterol. 2008; 14:632–635.

15. Donato F, Gelatti U, Tagger A, Favret M, Ribero ML, Callea F, et al. Intrahepatic cholangiocarcinoma and hepatitis C and B virus infection, alcohol intake, and hepatolithiasis: a case-control study in Italy. Cancer Causes Control. 2001; 12:959–964.

16. Barner-Rasmussen N, Pukkala E, Hadkhale K, Färkkilä M. Risk factors, epidemiology and prognosis of cholangiocarcinoma in Finland. United European Gastroenterol J. 2021; 9:1128–1135.

17. Shin HR, Oh JK, Masuyer E, Curado MP, Bouvard V, Fang YY, et al. Epidemiology of cholangiocarcinoma: an update focusing on risk factors. Cancer Sci. 2010; 101:579–585.

18. Wang Y, Yuan Y, Gu D. Hepatitis B and C virus infections and the risk of biliary tract cancers: a meta-analysis of observational studies. Infect Agent Cancer. 2022; 17:45.

19. Burak K, Angulo P, Pasha TM, Egan K, Petz J, Lindor KD. Incidence and risk factors for cholangiocarcinoma in primary sclerosing cholangitis. Am J Gastroenterol. 2004; 99:523–526.

20. Kim HJ, Kim JS, Joo MK, Lee BJ, Kim JH, Yeon JE, et al. Hepatolithiasis and intrahepatic cholangiocarcinoma: a review. World J Gastroenterol. 2015; 21:13418–13431.

21. Tazuma S. Gallstone disease: epidemiology, pathogenesis, and classification of biliary stones (common bile duct and intrahepatic). Best Pract Res Clin Gastroenterol. 2006; 20:1075–1083.

22. Xiao HY, Chai JY, Fang YY, Lai YS. The spatial-temporal risk profiling of Clonorchis sinensis infection over 50 years implies the effectiveness of control programs in South Korea: a geostatistical modeling study. Lancet Reg Health West Pac. 2023; 33:100697.

23. Jeong YI, Shin HE, Lee SE, Cheun HI, Ju JW, Kim JY, et al. Prevalence of Clonorchis sinensis infection among residents along 5 major rivers in the Republic of Korea. Korean J Parasitol. 2016; 54:215–219.

24. Lee MR, Ju JW, Baek SO, Lee YJ, Lee ES, Lee HI. Infection status of intestinal helminths in 2023. Public Health Wkly Rep. 2024; 17:1227–1239.

25. World Health Organization (WHO). Global hepatitis report 2024: action for access in low- and middle-income countries [Internet]. Geneva (CH): WHO; [cited YYYY MMM DD]. Available from: https://www.who.int/publications/i/item/9789240091672.

26. Korea Disease Control and Prevention Agency. Trend in hepatitis B surface antigen positivity rate [Internet]. Daejeon (KR): Korean Statistical Information Service; [cited YYYY MMM DD]. Available from: https://kosis.kr/statHtml/statHtml.do?orgId=177&tblId=DT_11702_N109&conn_path=I2.

27. Kim LY, Yoo JJ, Chang Y, Jo H, Cho YY, Lee S, et al. The epidemiology of hepatitis B virus infection in Korea: 15-year analysis. J Korean Med Sci. 2024; 39:e22.

28. Jiao Y, Pawlik TM, Anders RA, Selaru FM, Streppel MM, Lucas DJ, et al. Exome sequencing identifies frequent inactivating mutations in BAP1, ARID1A and PBRM1 in intrahepatic cholangiocarcinomas. Nat Genet. 2013; 45:1470–1473.

29. Borad MJ, Champion MD, Egan JB, Liang WS, Fonseca R, Bryce AH, et al. Integrated genomic characterization reveals novel, therapeutically relevant drug targets in FGFR and EGFR pathways in sporadic intrahepatic cholangiocarcinoma. PLoS Genet. 2014; 10:e1004135.

30. Farshidfar F, Zheng S, Gingras MC, Newton Y, Shih J, Robertson AG, et al. Integrative genomic analysis of cholangiocarcinoma identifies distinct IDH-mutant molecular profiles. Cell Rep. 2017; 18:2780–2794.

31. Zhang Y, Ma Z, Li C, Wang C, Jiang W, Chang J, et al. The genomic landscape of cholangiocarcinoma reveals the disruption of post-transcriptional modifiers. Nat Commun. 2022; 13:3061.

32. Nakamura H, Arai Y, Totoki Y, Shirota T, Elzawahry A, Kato M, et al. Genomic spectra of biliary tract cancer. Nat Genet. 2015; 47:1003–1010.

33. Bridgewater JA, Goodman KA, Kalyan A, Mulcahy MF. Biliary tract cancer: epidemiology, radiotherapy, and molecular profiling. Am Soc Clin Oncol Educ Book. 2016; 35:e194. –e203.

34. Mody K, Jain P, El-Refai SM, Azad NS, Zabransky DJ, Baretti M, et al. Clinical, genomic, and transcriptomic data profiling of biliary tract cancer reveals subtype-specific immune signatures. JCO Precis Oncol. 2022; 6:e2100510.

35. Simbolo M, Fassan M, Ruzzenente A, Mafficini A, Wood LD, Corbo V, et al. Multigene mutational profiling of cholangiocarcinomas identifies actionable molecular subgroups. Oncotarget. 2014; 5:2839–2852.

36. Kumar-Sinha C, Vats P, Tran N, Robinson DR, Gunchick V, Wu YM, et al. Genomics driven precision oncology in advanced biliary tract cancer improves survival. Neoplasia. 2023; 42:100910.

37. Mondaca S, Razavi P, Xu C, Offin M, Myers M, Scaltriti M, et al. Genomic characterization of ERBB2-driven biliary cancer and a case of response to ado-trastuzumab emtansine. JCO Precis Oncol. 2019; 3:1–9.

38. Hwang S, Woo S, Kang B, Kang H, Kim JS, Lee SH, et al. Concordance of ctDNA and tissue genomic profiling in advanced biliary tract cancer. J Hepatol. 2024; S0168-8278(24)02641-2.

39. Chae H, Kim D, Yoo C, Kim KP, Jeong JH, Chang HM, et al. Therapeutic relevance of targeted sequencing in management of patients with advanced biliary tract cancer: DNA damage repair gene mutations as a predictive biomarker. Eur J Cancer. 2019; 120:31–39.

40. Lee SH, Cheon J, Lee S, Kang B, Kim C, Shim HS, et al. ARID1A mutation from targeted next-generation sequencing predicts primary resistance to gemcitabine and cisplatin chemotherapy in advanced biliary tract cancer. Cancer Res Treat. 2023; 55:1291–1302.

41. Yoon JG, Kim MH, Jang M, Kim H, Hwang HK, Kang CM, et al. Molecular characterization of biliary tract cancer predicts chemotherapy and programmed death 1/programmed death-ligand 1 blockade responses. Hepatology. 2021; 74:1914–1931.

42. Kim NI, Noh MG, Kim JH, Won EJ, Lee YJ, Hur Y, et al. Frequency and prognostic value of IDH mutations in korean patients with cholangiocarcinoma. Front Oncol. 2020; 10:1514.

43. Abou-Alfa GK, Macarulla T, Javle MM, Kelley RK, Lubner SJ, Adeva J, et al. Ivosidenib in IDH1-mutant, chemotherapy-refractory cholangiocarcinoma (ClarIDHy): a multicentre, randomised, double-blind, placebo-controlled, phase 3 study. Lancet Oncol. 2020; 21:796–807.

44. Boscoe AN, Rolland C, Kelley RK. Frequency and prognostic significance of isocitrate dehydrogenase 1 mutations in cholangiocarcinoma: a systematic literature review. J Gastrointest Oncol. 2019; 10:751–765.

45. Scott AJ, Sharman R, Shroff RT. Precision medicine in biliary tract cancer. J Clin Oncol. 2022; 40:2716–2734.

46. Goyal L, Shi L, Liu LY, de la Cruz FF, Lennerz JK, Raghavan S, et al. TAS-120 overcomes resistance to ATP-competitive FGFR inhibitors in patients with FGFR2 fusion-positive intrahepatic cholangiocarcinoma. Cancer Discov. 2019; 9:1064–1079.

47. Okamura R, Kurzrock R, Mallory RJ, Fanta PT, Burgoyne AM, Clary BM, et al. Comprehensive genomic landscape and precision therapeutic approach in biliary tract cancers. Int J Cancer. 2021; 148:702–712.

48. Cao J, Hu J, Liu S, Meric-Bernstam F, Abdel-Wahab R, Xu J, et al. Intrahepatic cholangiocarcinoma: genomic heterogeneity between Eastern and Western Patients. JCO Precis Oncol. 2020; 4:557–569.

49. Boerner T, Drill E, Pak LM, Nguyen B, Sigel CS, Doussot A, et al. Genetic determinants of outcome in intrahepatic cholangiocarcinoma. Hepatology. 2021; 74:1429–1444.

50. Lamarca A, Kapacee Z, Breeze M, Bell C, Belcher D, Staiger H, et al. Molecular profiling in daily clinical practice: practicalities in advanced cholangiocarcinoma and other biliary tract cancers. J Clin Med. 2020; 9:2854.

51. Berchuck JE, Facchinetti F, DiToro DF, Baiev I, Majeed U, Reyes S, et al. The clinical landscape of cell-free DNA alterations in 1671 patients with advanced biliary tract cancer. Ann Oncol. 2022; 33:1269–1283.

52. Ettrich TJ, Schwerdel D, Dolnik A, Beuter F, Blätte TJ, Schmidt SA, et al. Genotyping of circulating tumor DNA in cholangiocarcinoma reveals diagnostic and prognostic information. Sci Rep. 2019; 9:13261.

53. Lendvai G, Szekerczés T, Illyés I, Dóra R, Kontsek E, Gógl A, et al. Cholangiocarcinoma: classification, histopathology and molecular carcinogenesis. Pathol Oncol Res. 2020; 26:3–15.

54. Neuzillet C, Artru P, Assenat E, Edeline J, Adhoute X, Sabourin JC, et al. Optimizing patient pathways in advanced biliary tract cancers: recent advances and a French perspective. Target Oncol. 2023; 18:51–76.

55. Farha N, Dima D, Ullah F, Kamath S. Precision oncology targets in biliary tract cancer. Cancers (Basel). 2023; 15:2105.

56. Fontugne J, Augustin J, Pujals A, Compagnon P, Rousseau B, Luciani A, et al. PD-L1 expression in perihilar and intrahepatic cholangiocarcinoma. Oncotarget. 2017; 8:24644–24651.

57. Javle M, Bekaii-Saab T, Jain A, Wang Y, Kelley RK, Wang K, et al. Biliary cancer: utility of next-generation sequencing for clinical management. Cancer. 2016; 122:3838–3847.

58. Valle JW, Lamarca A, Goyal L, Barriuso J, Zhu AX. New horizons for precision medicine in biliary tract cancers. Cancer Discov. 2017; 7:943–962.

59. Yang P, Javle M, Pang F, Zhao W, Abdel-Wahab R, Chen X, et al. Somatic genetic aberrations in gallbladder cancer: comparison between Chinese and US patients. Hepatobiliary Surg Nutr. 2019; 8:604–614.

60. Giraldo NA, Drill E, Satravada BA, Dika IE, Brannon AR, Dermawan J, et al. Comprehensive molecular characterization of gallbladder carcinoma and potential targets for intervention. Clin Cancer Res. 2022; 28:5359–5367.

61. Abou-Alfa GK, Sahai V, Hollebecque A, Vaccaro G, Melisi D, Al-Rajabi R, et al. Pemigatinib for previously treated, locally advanced or metastatic cholangiocarcinoma: a multicentre, open-label, phase 2 study. Lancet Oncol. 2020; 21:671–684.

62. Goyal L, Meric-Bernstam F, Hollebecque A, Valle JW, Morizane C, Karasic TB, et al. Futibatinib for FGFR2-rearranged intrahepatic cholangiocarcinoma. N Engl J Med. 2023; 388:228–239.

63. Zhu AX, Macarulla T, Javle MM, Kelley RK, Lubner SJ, Adeva J, et al. Final overall survival efficacy results of ivosidenib for patients with advanced cholangiocarcinoma with IDH1 mutation: the phase 3 randomized clinical ClarIDHy trial. JAMA Oncol. 2021; 7:1669–1677.

64. Drilon A, Laetsch TW, Kummar S, DuBois SG, Lassen UN, Demetri GD, et al. Efficacy of larotrectinib in TRK fusion-positive cancers in adults and children. N Engl J Med. 2018; 378:731–739.

65. Doebele RC, Drilon A, Paz-Ares L, Siena S, Shaw AT, Farago AF, et al. Entrectinib in patients with advanced or metastatic NTRK fusion-positive solid tumours: integrated analysis of three phase 1-2 trials. Lancet Oncol. 2020; 21:271–282.

66. Salama AKS, Li S, Macrae ER, Park JI, Mitchell EP, Zwiebel JA, et al. Dabrafenib and trametinib in patients with tumors with BRAFV600E mutations: results of the NCI-MATCH trial subprotocol H. J Clin Oncol. 2020; 38:3895–3904.

67. Subbiah V, Lassen U, Élez E, Italiano A, Curigliano G, Javle M, 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. 2020; 21:1234–1243.

68. Meric-Bernstam F, Makker V, Oaknin A, Oh DY, Banerjee S, GonzálezMartín A, et al. Efficacy and safety of trastuzumab deruxtecan in patients with HER2-expressing solid tumors: primary results from the DESTINYPanTumor02 phase II trial. J Clin Oncol. 2024; 42:47–58.

69. Duke ES, Bradford D, Marcovitz M, Amatya AK, Mishra-Kalyani PS, Nguyen E, et al. FDA approval summary: selpercatinib for the treatment of advanced RET fusion-positive solid tumors. Clin Cancer Res. 2023; 29:3573–3578.

70. Lee CK, Chon HJ, Cheon J, Lee MA, Im HS, Jang JS, 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. 2023; 8:56–65.

71. Javle M, Borad MJ, Azad NS, Kurzrock R, Abou-Alfa GK, George B, et al. Pertuzumab and trastuzumab for HER2-positive, metastatic biliary tract cancer (MyPathway): a multicentre, open-label, phase 2a, multiple basket study. Lancet Oncol. 2021; 22:1290–1300.

72. Cao Z, Yang Y, Liu S, Sun L, Liu Y, Luo Y, et al. FGFR2 fusions assessed by NGS, FISH, and immunohistochemistry in intrahepatic cholangiocarcinoma. J Gastroenterol. 2025; 60:235–246.

73. Ross DS, Zehir A, Cheng DT, Benayed R, Nafa K, Hechtman JF, et al. Next-generation assessment of human epidermal growth factor receptor 2 (ERBB2) amplification status: clinical validation in the context of a hybrid capture-based, comprehensive solid tumor genomic profiling assay. J Mol Diagn. 2017; 19:244–254.

74. Couturier J, Vincent-Salomon A, Nicolas A, Beuzeboc P, Mouret E, Zafrani B, et al. Strong correlation between results of fluorescent in situ hybridization and immunohistochemistry for the assessment of the ERBB2 (HER-2/ neu) gene status in breast carcinoma. Mod Pathol. 2000; 13:1238–1243.

75. Dong L, Lu D, Chen R, Lin Y, Zhu H, Zhang Z, et al. Proteogenomic characterization identifies clinically relevant subgroups of intrahepatic cholangiocarcinoma. Cancer Cell. 2022; 40:70–87.e15.

76. Wang L, Zhu H, Zhao Y, Pan Q, Mao A, Zhu W, et al. Comprehensive molecular profiling of intrahepatic cholangiocarcinoma in the Chinese population and therapeutic experience. J Transl Med. 2020; 18:273.

77. Spencer K, Pappas L, Baiev I, Maurer J, Bocobo AG, Zhang K, et al. Molecular profiling and treatment pattern differences between intrahepatic and extrahepatic cholangiocarcinoma. J Natl Cancer Inst. 2023; 115:870–880.

78. Goyal L, Meric-Bernstam F, Hollebecque A, Morizane C, Valle JW, Karasic TB, et al. Updated results of the FOENIX-CCA2 trial: efficacy and safety of futibatinib in intrahepatic cholangiocarcinoma (iCCA) harboring FGFR2 fusions/rearrangements. J Clin Oncol. 2022; 40 Suppl 16:4009.

79. Marabelle A, Le DT, Ascierto PA, Di Giacomo AM, De Jesus-Acosta A, Delord JP, et al. Efficacy of pembrolizumab in patients with noncolorectal high microsatellite instability/mismatch repair-deficient cancer: results from the phase II KEYNOTE-158 study. J Clin Oncol. 2020; 38:1–10.

80. Marabelle A, Fakih M, Lopez J, Shah M, Shapira-Frommer R, Nakagawa K, 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. 2020; 21:1353–1365.