Exploration of Targeted Anti-tumor Therapy

Table 1. Actionable genomic alterations in iCCA and associations with anatomic sub-type

CCA sub-type	Targeted gene	Frequency	References
iCCA	IDH1/2	10–20%	[26–28]
	FGFR	7–16%	[26, 27, 47, 50]
	BRAF V600E	5%	[26, 27, 71–75, 79]
	KRAS	8–54%	[75]
	ERBB2	8%	[26, 27]
	PI3K	7%	[26, 27]
	NTRK	≤ 1%	[84]
	BRCA1	0.4%	[92]
	BRCA2	2.7%
eCCA	KRAS	43%	[92]
	ERBB2	5–9%	[90, 94]
	PI3K	5%	[94]
	IDH1/2	2–3%	[94]
	EGFR	1%	[94]
	BRCA1	0.4%	[94]
	BRCA2	2.7%

Return to article view

IDH1/2: isocitrate dehydrogenase (NADP⁺) 1/2; FGFR: fibroblast growth factor receptor; BRAF: B-Raf proto-oncogene; KRAS: KRAS proto-oncogene; ERBB2: erb-b2 receptor tyrosine kinase 2; NTRK: neurotrophic receptor tyrosine kinase

Declarations

Author contributions

MC: conceptualization and writing original draft; MC, AS, and LF: wrote sections of the manuscript. NN: conceptualization, visualization, supervision and writing-review and editing. All authors contributed to manuscript revision, read and approved the submitted version.

Conflicts of interest

NN: personal financial interests (speaker’s fees and/or advisory boards): MSD, QIAGEN, Bayer, Biocartis, Incyte, Roche, BMS, MERCK, Thermo Fisher, Boehringer Ingelheim, AstraZeneca, Sanofi, Eli Lilly, Illumina, and Amgen Institutional; financial interests (financial support to research projects): MERCK, Sysmex, Thermo Fisher, QIAGEN, Roche, AstraZeneca, Biocartis, and Illumina. NN: non-financial interests: President, International Quality Network for Pathology (IQN Path); President-Elect, Italian Cancer Society (SIC).

Ethical approval

Not applicable.

Consent to participate

Not applicable.

Consent to publication

Not applicable.

Availability of data and materials

Not applicable.

Funding

Not applicable.

Copyright

References

Tyson GL, Duan Z, Kramer JR, Davila JA, Richardson PA, El-Serag HB. Level of alpha-fetoprotein predicts mortality among patients with hepatitis C-related hepatocellular carcinoma. Clin Gastroenterol Hepatol. 2011;9:989–94. [DOI] [PubMed] [PMC]

Khan SA, Thomas HC, Davidson BR, Taylor-Robinson SD. Cholangiocarcinoma. Lancet. 2005;366:1303–14. Erratum in: Lancet. 2006;367:1656. [DOI]

Khan SA, Toledano MB, Taylor-Robinson SD. Epidemiology, risk factors, and pathogenesis of cholangiocarcinoma. HPB (Oxford). 2008;10:77–82. [DOI] [PubMed] [PMC]

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

Zhou H, Wang H, Zhou D, Wang H, Wang Q, Zou S, et al. Hepatitis B virus-associated intrahepatic cholangiocarcinoma and hepatocellular carcinoma may hold common disease process for carcinogenesis. Eur J Cancer. 2010;46:1056–61. [DOI] [PubMed]

Blechacz BR, Gores GJ. Cholangiocarcinoma. Clin Liver Dis. 2008;12:131–50, ix. [DOI] [PubMed]

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;17:557–88. [DOI] [PubMed] [PMC]

Vicent S, Lieshout R, Saborowski A, Verstegen MMA, Raggi C, Recalcati S, et al. Experimental models to unravel the molecular pathogenesis, cell of origin and stem cell properties of cholangiocarcinoma. Liver Int. 2019;39 Suppl 1:79–97. [DOI] [PubMed]

Fan B, Malato Y, Calvisi DF, Naqvi S, Razumilava N, Ribback S, et al. Cholangiocarcinomas can originate from hepatocytes in mice. J Clin Invest. 2012;122:2911–5. [DOI] [PubMed] [PMC]

10.

Carpino G, Cardinale V, Renzi A, Hov JR, Berloco PB, Rossi M, et al. Activation of biliary tree stem cells within peribiliary glands in primary sclerosing cholangitis. J Hepatol. 2015;63:1220–8. [DOI] [PubMed]

11.

DiPaola F, Shivakumar P, Pfister J, Walters S, Sabla G, Bezerra JA. Identification of intramural epithelial networks linked to peribiliary glands that express progenitor cell markers and proliferate after injury in mice. Hepatology. 2013;58:1486–96. [DOI] [PubMed] [PMC]

12.

Lanzoni G, Cardinale V, Carpino G. The hepatic, biliary, and pancreatic network of stem/progenitor cell niches in humans: a new reference frame for disease and regeneration. Hepatology. 2016;64:277–86. [DOI] [PubMed]

13.

Hughes NR, Pairojkul C, Royce SG, Clouston A, Bhathal PS. Liver fluke-associated and sporadic cholangiocarcinoma: an immunohistochemical study of bile duct, peribiliary gland and tumour cell phenotypes. J Clin Pathol. 2006;59:1073–8. [DOI] [PubMed] [PMC]

14.

Banales JM, Cardinale V, Carpino G, Marzioni M, Andersen JB, Invernizzi P, et al. Expert consensus document: Cholangiocarcinoma: current knowledge and future perspectives consensus statement from the European Network for the Study of Cholangiocarcinoma (ENS-CCA). Nat Rev Gastroenterol Hepatol. 2016;13:261–80. [DOI] [PubMed]

15.

Blechacz B, Komuta M, Roskams T, Gores GJ. Clinical diagnosis and staging of cholangiocarcinoma. Nat Rev Gastroenterol Hepatol. 2011;8:512–22. [DOI] [PubMed] [PMC]

16.

Rizvi S, Gores GJ. Pathogenesis, diagnosis, and management of cholangiocarcinoma. Gastroenterology. 2013;145:1215–29. [DOI] [PubMed] [PMC]

17.

Moeini A, Sia D, Bardeesy N, Mazzaferro V, Llovet JM. Molecular pathogenesis and targeted therapies for intrahepatic cholangiocarcinoma. Clin Cancer Res. 2016;22:291–300. [DOI] [PubMed]

18.

Nakamura H, Arai Y, Totoki Y, Shirota T, Elzawahry A, Kato M, et al. Genomic spectra of biliary tract cancer. Nat Genet. 2015;47:1003–10. [DOI] [PubMed]

19.

de Jong MA, Oldenborg S, Bing Oei S, Griesdoorn V, Kolff MW, Koning CC, et al. Reirradiation and hyperthermia for radiation-associated sarcoma. Cancer. 2012;118:180–7. [DOI] [PubMed]

20.

Krasinskas AM. Cholangiocarcinoma. Surg Pathol Clin. 2018;11:403–29. [DOI] [PubMed]

21.

Esnaola NF, Meyer JE, Karachristos A, Maranki JL, Camp ER, Denlinger CS. Evaluation and management of intrahepatic and extrahepatic cholangiocarcinoma. Cancer. 2016;122:1349–69. [DOI] [PubMed]

22.

Yao KJ, Jabbour S, Parekh N, Lin Y, Moss RA. Increasing mortality in the United States from cholangiocarcinoma: an analysis of the National Center for Health Statistics Database. BMC Gastroenterol. 2016;16:117. [DOI] [PubMed] [PMC]

23.

Sempoux C, Jibara G, Ward SC, Fan C, Qin L, Roayaie S, et al. Intrahepatic cholangiocarcinoma: new insights in pathology. Semin Liver Dis. 2011;31:49–60. [DOI] [PubMed]

24.

Patel T, Singh P. Cholangiocarcinoma: emerging approaches to a challenging cancer. Curr Opin Gastroenterol. 2007;23:317–23. [DOI] [PubMed]

25.

Silverman IM, Hollebecque A, Friboulet L, Owens S, Newton RC, Zhen H, et al. Clinicogenomic analysis of FGFR2-rearranged cholangiocarcinoma identifies correlates of response and mechanisms of resistance to pemigatinib. Cancer Discov. 2021;11:326–39. [DOI] [PubMed]

26.

Javle MM, Murugesan K, Shroff RT, Borad MJ, Abdel-Wahab R, Schrock AB, et al. Profiling of 3,634 cholangiocarcinomas (CCA) to identify genomic alterations (GA), tumor mutational burden (TMB), and genomic loss of heterozygosity (gLOH) [abstract]. J Clin Oncol. 2019;37:4087. [DOI]

27.

Lowery MA, Ptashkin R, Jordan E, Berger MF, Zehir A, Capanu M, et al. Comprehensive molecular profiling of intrahepatic and extrahepatic cholangiocarcinomas: potential targets for intervention. Clin Cancer Res. 2018;24:4154–61. [DOI] [PubMed] [PMC]

28.

Romanidou O, Kotoula V, Fountzilas G. Bridging cancer biology with the clinic: comprehending and exploiting IDH gene mutations in gliomas. Cancer Genomics Proteomics. 2018;15:421–36. [DOI] [PubMed] [PMC]

29.

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;122:3838–47. [DOI] [PubMed]

30.

Grassian AR, Pagliarini R, Chiang DY. Mutations of isocitrate dehydrogenase 1 and 2 in intrahepatic cholangiocarcinoma. Curr Opin Gastroenterol. 2014;30:295–302. [DOI] [PubMed]

31.

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;10:751–65. [DOI] [PubMed] [PMC]

32.

Goyal L, Govindan A, Sheth RA, Nardi V, Blaszkowsky LS, Faris JE, et al. Prognosis and clinicopathologic features of patients with advanced stage isocitrate dehydrogenase (IDH) mutant and IDH wild-type intrahepatic cholangiocarcinoma. Oncologist. 2015;20:1019–27. [DOI] [PubMed] [PMC]

33.

Chan-On W, Nairismagi ML, Ong CK, Lim WK, Dima S, Pairojkul C, et al. Exome sequencing identifies distinct mutational patterns in liver fluke-related and non-infection-related bile duct cancers. Nat Genet. 2013;45:1474–8. [DOI] [PubMed]

34.

Lowery MA, Ptashkin R, Jordan E, Berger MF, Zehir A, Kemeny NE, et al. Comprehensive molecular profiling and analysis of mutual exclusivity of genetic aberrations (MEGA) of intra- and extrahepatic cholangiocarcinomas (IHC and EHC) evaluation of prognostic features and potential targets for intervention [abstract]. J Clin Oncol. 2016;34:4088. [DOI]

35.

Pak LM, Goldman D, Gonen M, Allen PJ, Balachandran VP, D’Angelica MI, et al. Mutational profiling of resected intrahepatic cholangiocarcinoma [abstract]. J Clin Oncol. 2017;35:e15675. [DOI]

36.

Pawlik TM, Borger DR, Kim Y, Cosgrove D, Alexandrescu S, Groeschl RT, et al. Genomic profiling of intrahepatic cholangiocarcinoma: refining prognostic determinants and identifying therapeutic targets [abstract]. J Clin Oncol. 2014;32:201. [DOI]

37.

Ruzzenente A, Fassan M, Conci S, Simbolo M, Lawlor RT, Pedrazzani C, et al. Cholangiocarcinoma heterogeneity revealed by multigene mutational profiling: clinical and prognostic relevance in surgically resected patients. Ann Surg Oncol. 2016;23:1699–707. [DOI] [PubMed]

38.

Wang P, Dong Q, Zhang C, Kuan PF, Liu Y, Jeck WR, et al. Mutations in isocitrate dehydrogenase 1 and 2 occur frequently in intrahepatic cholangiocarcinomas and share hypermethylation targets with glioblastomas. Oncogene. 2013;32:3091–100. [DOI] [PubMed] [PMC]

39.

Zhu AX, Borger DR, Kim Y, Cosgrove D, Ejaz A, Alexandrescu S, et al. Genomic profiling of intrahepatic cholangiocarcinoma: refining prognosis and identifying therapeutic targets. Ann Surg Oncol. 2014;21:3827–34. [DOI] [PubMed] [PMC]

40.

Churi CR, Shroff R, Wang Y, Rashid A, Kang HC, Weatherly J, et al. Mutation profiling in cholangiocarcinoma: prognostic and therapeutic implications. PLoS One. 2014;9:e115383. [DOI] [PubMed] [PMC]

41.

De Luca A, Esposito Abate R, Rachiglio AM, Maiello MR, Esposito C, Schettino C, et al. FGFR fusions in cancer: from diagnostic approaches to therapeutic intervention. Int J Mol Sci. 2020;21:6856. [DOI] [PubMed] [PMC]

42.

Chen L, Zhang Y, Yin L, Cai B, Huang P, Li X, et al. Fibroblast growth factor receptor fusions in cancer: opportunities and challenges. J Exp Clin Cancer Res. 2021;40:345. [DOI] [PubMed] [PMC]

43.

Parker BC, Engels M, Annala M, Zhang W. Emergence of FGFR family gene fusions as therapeutic targets in a wide spectrum of solid tumours. J Pathol. 2014;232:4–15. [DOI] [PubMed]

44.

Turner N, Grose R. Fibroblast growth factor signalling: from development to cancer. Nat Rev Cancer. 2010;10:116–29. [DOI] [PubMed]

45.

Chioni AM, Grose RP. Biological significance and targeting of the FGFR axis in cancer. Cancers (Basel). 2021;13:5681. [DOI] [PubMed] [PMC]

46.

Saborowski A, Lehmann U, Vogel A. FGFR inhibitors in cholangiocarcinoma: what’s now and what’s next? Ther Adv Med Oncol. 2020;12:1758835920953293. [DOI] [PubMed] [PMC]

47.

Arai Y, Totoki Y, Hosoda F, Shirota T, Hama N, Nakamura H, et al. Fibroblast growth factor receptor 2 tyrosine kinase fusions define a unique molecular subtype of cholangiocarcinoma. Hepatology. 2014;59:1427–34. [DOI] [PubMed]

48.

Ross JS, Wang K, Gay L, Al-Rohil R, Rand JV, Jones DM, et al. New routes to targeted therapy of intrahepatic cholangiocarcinomas revealed by next-generation sequencing. Oncologist. 2014;19:235–42. [DOI] [PubMed] [PMC]

49.

Jain A, Borad MJ, Kelley RK, Wang Y, Abdel-Wahab R, Meric-Bernstam F, et al. Cholangiocarcinoma with FGFR genetic aberrations: a unique clinical phenotype. JCO Precis Oncol. 2018;2:1–12. [DOI] [PubMed]

50.

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. [DOI] [PubMed] [PMC]

51.

Sia D, Losic B, Moeini A, Cabellos L, Hao K, Revill K, et al. Massive parallel sequencing uncovers actionable FGFR2-PPHLN1 fusion and ARAF mutations in intrahepatic cholangiocarcinoma. Nat Commun. 2015;6:6087. [DOI] [PubMed]

52.

Wu YM, Su F, Kalyana-Sundaram S, Khazanov N, Ateeq B, Cao X, et al. Identification of targetable FGFR gene fusions in diverse cancers. Cancer Discov. 2013;3:636–47. [DOI] [PubMed] [PMC]

53.

Tanizaki J, Ercan D, Capelletti M, Dodge M, Xu C, Bahcall M, et al. Identification of oncogenic and drug-sensitizing mutations in the extracellular domain of FGFR2. Cancer Res. 2015;75:3139–46. [DOI] [PubMed]

54.

Czauderna C, Kirstein MM, Tews HC, Vogel A, Marquardt JU. Molecular subtypes and precision oncology in intrahepatic cholangiocarcinoma. J Clin Med. 2021;10:2803. [DOI] [PubMed] [PMC]

55.

Graham RP, Barr Fritcher EG, Pestova E, Schulz J, Sitailo LA, Vasmatzis G, et al. Fibroblast growth factor receptor 2 translocations in intrahepatic cholangiocarcinoma. Hum Pathol. 2014;45:1630–8. [DOI] [PubMed]

56.

Kongpetch S, Jusakul A, Lim JQ, Ng CCY, Chan JY, Rajasegaran V, et al. Lack of targetable FGFR2 fusions in endemic fluke-associated cholangiocarcinoma. JCO Glob Oncol. 2020;6:628–38. [DOI] [PubMed] [PMC]

57.

Vasen HF, Möslein G, Alonso A, Bernstein I, Bertario L, Blanco I, et al. Guidelines for the clinical management of Lynch syndrome (hereditary non-polyposis cancer). J Med Genet. 2007;44:353–62. [DOI] [PubMed] [PMC]

58.

Winkelmann R, Schneider M, Hartmann S, Schnitzbauer AA, Zeuzem S, Peveling-Oberhag J, et al. Microsatellite instability occurs rarely in patients with cholangiocarcinoma: a retrospective study from a German tertiary care hospital. Int J Mol Sci. 2018;19:1421. [DOI] [PubMed] [PMC]

59.

Suto T, Habano W, Sugai T, Uesugi N, Kanno S, Saito K, et al. Infrequent microsatellite instability in biliary tract cancer. J Surg Oncol. 2001;76:121–6. [DOI] [PubMed]

60.

Liengswangwong U, Nitta T, Kashiwagi H, Kikukawa H, Kawamoto T, Todoroki T, et al. Infrequent microsatellite instability in liver fluke infection-associated intrahepatic cholangiocarcinomas from Thailand. Int J Cancer. 2003;107:375–80. [DOI] [PubMed]

61.

Sirica AE. Role of ErbB family receptor tyrosine kinases in intrahepatic cholangiocarcinoma. World J Gastroenterol. 2008;14:7033–58. [DOI] [PubMed] [PMC]

62.

Endo K, Yoon BI, Pairojkul C, Demetris AJ, Sirica AE. ERBB-2 overexpression and cyclooxygenase-2 up-regulation in human cholangiocarcinoma and risk conditions. Hepatology. 2002;36:439–50. [DOI] [PubMed]

63.

Andersen JB, Thorgeirsson SS. Genetic profiling of intrahepatic cholangiocarcinoma. Curr Opin Gastroenterol. 2012;28:266–72. [DOI] [PubMed] [PMC]

64.

Moinzadeh P, Breuhahn K, Stutzer H, Schirmacher P. Chromosome alterations in human hepatocellular carcinomas correlate with aetiology and histological grade--results of an explorative CGH meta-analysis. Br J Cancer. 2005;92:935–41. [DOI] [PubMed] [PMC]

65.

Shiraishi K, Okita K, Harada T, Kusano N, Furui T, Kondoh S, et al. Comparative genomic hybridization analysis of genetic aberrations associated with development and progression of biliary tract carcinomas. Cancer. 2001;91:570–7. [DOI] [PubMed]

66.

Miller G, Socci ND, Dhall D, D’Angelica M, DeMatteo RP, Allen PJ, et al. Genome wide analysis and clinical correlation of chromosomal and transcriptional mutations in cancers of the biliary tract. J Exp Clin Cancer Res. 2009;28:62. [DOI] [PubMed] [PMC]

67.

McKay SC, Unger K, Pericleous S, Stamp G, Thomas G, Hutchins RR, et al. Array comparative genomic hybridization identifies novel potential therapeutic targets in cholangiocarcinoma. HPB (Oxford). 2011;13:309–19. [DOI] [PubMed] [PMC]

68.

Wong N, Li L, Tsang K, Lai PB, To KF, Johnson PJ. Frequent loss of chromosome 3p and hypermethylation of RASSF1A in cholangiocarcinoma. J Hepatol. 2002;37:633–9. [DOI] [PubMed]

69.

Uhm KO, Park YN, Lee JY, Yoon DS, Park SH. Chromosomal imbalances in Korean intrahepatic cholangiocarcinoma by comparative genomic hybridization. Cancer Genet Cytogenet. 2005;157:37–41. [DOI] [PubMed]

70.

Lee JY, Park YN, Uhm KO, Park SY, Park SH. Genetic alterations in intrahepatic cholangiocarcinoma as revealed by degenerate oligonucleotide primed PCR-comparative genomic hybridization. J Korean Med Sci. 2004;19:682–7. [DOI] [PubMed] [PMC]

71.

Goeppert B, Frauenschuh L, Renner M, Roessler S, Stenzinger A, Klauschen F, et al. BRAF V600E-specific immunohistochemistry reveals low mutation rates in biliary tract cancer and restriction to intrahepatic cholangiocarcinoma. Mod Pathol. 2014;27:1028–34. [DOI] [PubMed]

72.

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;5:2839–52. [DOI] [PubMed] [PMC]

73.

Goldenberg D, Rosenbaum E, Argani P, Wistuba II, Sidransky D, Thuluvath PJ, et al. The V599E BRAF mutation is uncommon in biliary tract cancers. Mod Pathol. 2004;17:1386–91. [DOI] [PubMed]

74.

Riener MO, Bawohl M, Clavien PA, Jochum W. Rare PIK3CA hotspot mutations in carcinomas of the biliary tract. Genes Chromosomes Cancer. 2008;47:363–7. [DOI] [PubMed]

75.

Xu RF, Sun JP, Zhang SR, Zhu GS, Li LB, Liao YL, et al. KRAS and PIK3CA but not BRAF genes are frequently mutated in Chinese cholangiocarcinoma patients. Biomed Pharmacother. 2011;65:22–6. [DOI] [PubMed]

76.

Tannapfel A, Sommerer F, Benicke M, Katalinic A, Uhlmann D, Witzigmann H, et al. Mutations of the BRAF gene in cholangiocarcinoma but not in hepatocellular carcinoma. Gut. 2003;52:706–12. [DOI] [PubMed] [PMC]

77.

Robertson S, Hyder O, Dodson R, Nayar SK, Poling J, Beierl K, et al. The frequency of KRAS and BRAF mutations in intrahepatic cholangiocarcinomas and their correlation with clinical outcome. Hum Pathol. 2013;44:2768–73. [DOI] [PubMed] [PMC]

78.

Gwak GY, Yoon JH, Shin CM, Ahn YJ, Chung JK, Kim YA, et al. Detection of response-predicting mutations in the kinase domain of the epidermal growth factor receptor gene in cholangiocarcinomas. J Cancer Res Clin Oncol. 2005;131:649–52. [DOI] [PubMed]

79.

Leone F, Cavalloni G, Pignochino Y, Sarotto I, Ferraris R, Piacibello W, et al. Somatic mutations of epidermal growth factor receptor in bile duct and gallbladder carcinoma. Clin Cancer Res. 2006;12:1680–5. [DOI] [PubMed]

80.

Yoshikawa D, Ojima H, Iwasaki M, Hiraoka N, Kosuge T, Kasai S, et al. Clinicopathological and prognostic significance of EGFR, VEGF, and HER2 expression in cholangiocarcinoma. Br J Cancer. 2008;98:418–25. [DOI] [PubMed] [PMC]

81.

Kayhanian H, Smyth EC, Braconi C. Emerging molecular targets and therapy for cholangiocarcinoma. World J Gastrointest Oncol. 2017;9:268–80. [DOI] [PubMed] [PMC]

82.

Normanno N, Tejpar S, Morgillo F, De Luca A, Van Cutsem E, Ciardiello F. Implications for KRAS status and EGFR-targeted therapies in metastatic CRC. Nat Rev Clin Oncol. 2009;6:519–27. [DOI] [PubMed]

83.

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;45:1470–3. [DOI] [PubMed] [PMC]

84.

Demols A, Perez-Casanova L, Rocq L, Charry M, Nève ND, Verrellen A, et al. NTRK gene fusions in bilio-pancreatic cancers. J Clin Oncol. 2020;38:e16664. [DOI]

85.

Amatu A, Sartore-Bianchi A, Bencardino K, Pizzutilo EG, Tosi F, Siena S. Tropomyosin receptor kinase (TRK) biology and the role of NTRK gene fusions in cancer. Ann Oncol. 2019;30 Suppl 8:viii5–15. [DOI] [PMC]

86.

Vaishnavi A, Le AT, Doebele RC. TRKing down an old oncogene in a new era of targeted therapy. Cancer Discov. 2015;5:25–34. [DOI] [PubMed] [PMC]

87.

Endo K, Ashida K, Miyake N, Terada T. E-cadherin gene mutations in human intrahepatic cholangiocarcinoma. J Pathol. 2001;193:310–7. [DOI] [PubMed]

88.

Tokumoto N, Ikeda S, Ishizaki Y, Kurihara T, Ozaki S, Iseki M, et al. Immunohistochemical and mutational analyses of Wnt signaling components and target genes in intrahepatic cholangiocarcinomas. Int J Oncol. 2005;27:973–80. [DOI] [PubMed]

89.

Valle J, Wasan H, Palmer DH, Cunningham D, Anthoney A, Maraveyas A, et al. Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N Engl J Med. 2010;362:1273–81. [DOI] [PubMed]

90.

Lee H, Wang K, Johnson A, Jones DM, Ali SM, Elvin JA, et al. Comprehensive genomic profiling of extrahepatic cholangiocarcinoma reveals a long tail of therapeutic targets. J Clin Pathol. 2016;69:403–8. [DOI] [PubMed]

91.

Xue L, Guo C, Zhang K, Jiang H, Pang F, Dou Y, et al. Comprehensive molecular profiling of extrahepatic cholangiocarcinoma in Chinese population and potential targets for clinical practice. Hepatobiliary Surg Nutr. 2019;8:615–22. [DOI] [PubMed] [PMC]

92.

Spizzo G, Puccini A, Xiu J, Goldberg RM, Grothey A, Shields AF, et al. Molecular profile of BRCA-mutated biliary tract cancers. ESMO Open. 2020;5:e000682. [DOI] [PubMed] [PMC]

93.

Tella SH, Kommalapati A, Borad MJ, Mahipal A. Second-line therapies in advanced biliary tract cancers. Lancet Oncol. 2020;21:e29–41. [DOI] [PubMed]

94.

Montal R, Sia D, Montironi C, Leow WQ, Esteban-Fabro R, Pinyol R, et al. Molecular classification and therapeutic targets in extrahepatic cholangiocarcinoma. J Hepatol. 2020;73:315–27. [DOI] [PubMed] [PMC]

95.

Cheng DT, Mitchell TN, Zehir A, Shah RH, Benayed R, Syed A, et al. Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT): a hybridization capture-based next-generation sequencing clinical assay for solid tumor molecular oncology. J Mol Diagn. 2015;17:251–64. [DOI] [PubMed] [PMC]

96.

Ellison G, Zhu G, Moulis A, Dearden S, Speake G, McCormack R. EGFR mutation testing in lung cancer: a review of available methods and their use for analysis of tumour tissue and cytology samples. J Clin Pathol. 2013;66:79–89. [DOI] [PubMed] [PMC]

97.

Inamura K. Update on immunohistochemistry for the diagnosis of lung cancer. Cancers (Basel). 2018;10:72. [DOI] [PubMed] [PMC]

98.

Pilotto S, Gkountakos A, Carbognin L, Scarpa A, Tortora G, Bria E. MET exon 14 juxtamembrane splicing mutations: clinical and therapeutical perspectives for cancer therapy. Ann Transl Med. 2017;5:2. [DOI] [PubMed] [PMC]

99.

Moncur JT, Bartley AN, Bridge JA, Kamel-Reid S, Lazar AJ, Lindeman NI, et al. Performance comparison of different analytic methods in proficiency testing for mutations in the BRAF, EGFR, and KRAS Genes: a study of the college of American pathologists molecular oncology committee. Arch Pathol Lab Med. 2019;143:1203–11. [DOI] [PubMed]

100.

Bartley AN, Washington MK, Ventura CB, Ismaila N, Colasacco C, Benson AB 3rd, et al. HER2 testing and clinical decision making in gastroesophageal adenocarcinoma: guideline from the college of American pathologists, American society for clinical pathology, and American society of clinical oncology. Am J Clin Pathol. 2016;146:647–69. [DOI] [PubMed] [PMC]

101.

Chrzanowska NM, Kowalewski J, Lewandowska MA. Use of fluorescence in situ hybridization (FISH) in diagnosis and tailored therapies in solid tumors. Molecules. 2020;25:1864. [DOI] [PubMed] [PMC]

102.

Maruki Y, Morizane C, Arai Y, Ikeda M, Ueno M, Ioka T, et al. Correction to: Molecular detection and clinicopathological characteristics of advanced/recurrent biliary tract carcinomas harboring the FGFR2 rearrangements: a prospective observational study (PRELUDE Study). J Gastroenterol. 2021;56:297. Erratum in: J Gastroenterol. 2021;56:250–60. [DOI] [PubMed] [PMC]

103.

Hollebecque A, Silverman I, Owens S, Féliz L, Lihou C, Zhen H, et al. Comprehensive genomic profiling and clinical outcomes in patients (pts) with fibroblast growth factor receptor rearrangement-positive (FGFR2+) cholangiocarcinoma (CCA) treated with pemigatinib in the fight-202 trial [abstract]. Ann Oncol. 2019;30:v276. [DOI]

104.

Vogel A, Sahai V, Hollebecque A, Vaccaro G, Melisi D, Al-Rajabi R, et al. FIGHT-202: a phase 2 study of pemigatinib in patients (pts) with previously treated locally advanced or metastatic cholangiocarcinoma (CCA) [abstract]. Ann Oncol. 2019;30:v876. [DOI]

105.

Cheng L, Lopez-Beltran A, Massari F, MacLennan GT, Montironi R. Molecular testing for BRAF mutations to inform melanoma treatment decisions: a move toward precision medicine. Mod Pathol. 2018;31:24–38. [DOI] [PubMed] [PMC]

106.

Alvarez-Garcia V, Bartos C, Keraite I, Trivedi U, Brennan PM, Kersaudy-Kerhoas M, et al. A simple and robust real-time qPCR method for the detection of PIK3CA mutations. Sci Rep. 2018;8:4290. [DOI] [PubMed] [PMC]

107.

Murray JL, Hu P, Shafer DA. Seven novel probe systems for real-time PCR provide absolute single-base discrimination, higher signaling, and generic components. J Mol Diagn. 2014;16:627–38. [DOI] [PubMed] [PMC]

108.

Tuononen K, Sarhadi VK, Wirtanen A, Ronty M, Salmenkivi K, Knuuttila A, et al. Targeted resequencing reveals ALK fusions in non-small cell lung carcinomas detected by FISH, immunohistochemistry, and real-time RT-PCR: a comparison of four methods. Biomed Res Int. 2013;2013:757490. [DOI] [PubMed] [PMC]

109.

Tsongalis GJ, Peterson JD, de Abreu FB, Tunkey CD, Gallagher TL, Strausbaugh LD, et al. Routine use of the Ion Torrent AmpliSeq™ Cancer Hotspot Panel for identification of clinically actionable somatic mutations. Clin Chem Lab Med. 2014;52:707–14. [DOI] [PubMed]

110.

Frampton GM, Fichtenholtz A, Otto GA, Wang K, Downing SR, He J, et al. Development and validation of a clinical cancer genomic profiling test based on massively parallel DNA sequencing. Nat Biotechnol. 2013;31:1023–31. [DOI] [PubMed] [PMC]

111.

Zehir A, Benayed R, Shah RH, Syed A, Middha S, Kim HR, et al. Mutational landscape of metastatic cancer revealed from prospective clinical sequencing of 10,000 patients. Nat Med. 2017;23:703–13. [DOI] [PubMed] [PMC]

112.

FoundationOne®Liquid CDx [Internet]. FOUNDATION MEDICINE, INC; c2022 [cited 2022 Feb 19]. Available from: https://foundationmedicine.com/test/foundationone-liquid-cdx/

113.

MSK-IMPACT: A Targeted Test for Mutations in Both Rare and Common Cancers [Internet]. Memorial Sloan Kettering Cancer Center; c2022 [cited 2022 Feb 19]. Available from: https://www.mskcc.org/msk-impact/

114.

Oncomine™ Dx Target Test–P160045/S019 [Internet]. FDA; [updatd 2022 Nov 23; cited 2022 Feb 19]. Available from: https://www.fda.gov/medical-devices/recently-approved-devices/oncominetm-dx-target-test-p160045s019

115.

FusionPlex Solid Tumor Panel [Internet]. NCBI; [updated 2021 May 21; cited 2022 Feb 19]. Available from: https://www.ncbi.nlm.nih.gov/gtr/tests/588101/

116.

Mercer TR, Clark MB, Crawford J, Brunck ME, Gerhardt DJ, Taft RJ, et al. Targeted sequencing for gene discovery and quantification using RNA CaptureSeq. Nat Protoc. 2014;9:989–1009. [DOI] [PubMed]

117.

Kirchner M, Neumann O, Volckmar AL, Stogbauer F, Allgäuer M, Kazdal D, et al. RNA-based detection of gene fusions in formalin-fixed and paraffin-embedded solid cancer samples. Cancers (Basel). 2019;11:1309. [DOI] [PubMed] [PMC]

118.

Vendrell JA, Taviaux S, Beganton B, Godreuil S, Audran P, Grand D, et al. Detection of known and novel ALK fusion transcripts in lung cancer patients using next-generation sequencing approaches. Sci Rep. 2017;7:12510. [DOI] [PubMed] [PMC]

119.

Mosele F, Remon J, Mateo J, Westphalen CB, Barlesi F, Lolkema MP, et al. Recommendations for the use of next-generation sequencing (NGS) for patients with metastatic cancers: a report from the ESMO Precision Medicine Working Group. Ann Oncol. 2020;31:1491–505. [DOI] [PubMed]

120.

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. [DOI] [PubMed] [PMC]

121.

Pantel K, Alix-Panabieres C. Real-time liquid biopsy in cancer patients: fact or fiction? Cancer Res. 2013;73:6384–8. [DOI] [PubMed]

122.

Esposito Abate R, Pasquale R, Fenizia F, Rachiglio AM, Roma C, Bergantino F, et al. The role of circulating free DNA in the management of NSCLC. Expert Rev Anticancer Ther. 2019;19:19–28. [DOI] [PubMed]

123.

Andersen RF, Jakobsen A. Screening for circulating RAS/RAF mutations by multiplex digital PCR. Clin Chim Acta. 2016;458:138–43. [DOI] [PubMed]

124.

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;18:2780–94. [DOI] [PubMed] [PMC]

125.

Mody K, Cleary SP. A review of circulating tumor DNA in hepatobiliary malignancies. Front Oncol. 2018;8:212. [DOI] [PubMed] [PMC]

126.

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;148:702–12. [DOI] [PubMed] [PMC]

127.

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

128.

Nakamura Y, Taniguchi H, Ikeda M, Bando H, Kato K, Morizane C, et al. Clinical utility of circulating tumor DNA sequencing in advanced gastrointestinal cancer: SCRUM-Japan GI-SCREEN and GOZILA studies. Nat Med. 2020;26:1859–64. [DOI] [PubMed]

129.

Goyal L, Saha SK, Liu LY, Siravegna G, Leshchiner I, Ahronian LG, et al. Polyclonal secondary FGFR2 mutations drive acquired resistance to FGFR inhibition in patients with FGFR2 fusion-positive cholangiocarcinoma. Cancer Discov. 2017;7:252–63. [DOI] [PubMed] [PMC]

130.

Lowery MA, Burris HA 3rd, Janku F, Shroff RT, Cleary JM, Azad NS, et al. Safety and activity of ivosidenib in patients with IDH1-mutant advanced cholangiocarcinoma: a phase 1 study. Lancet Gastroenterol Hepatol. 2019;4:711–20. [DOI] [PubMed] [PMC]

131.

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;21:671–84. [DOI] [PubMed] [PMC]

132.

Eder JP, Doroshow DB, Do KT, Keedy VL, Sklar JS, Glazer P, et al. Clinical efficacy of olaparib in IDH1/IDH2-mutant mesenchymal sarcomas. JCO Precis Oncol. 2021;5:466–72. [DOI] [PubMed]

133.

Bekaii-Saab TS, Valle JW, Van Cutsem E, Rimassa L, Furuse J, Ioka T, et al. FIGHT-302: first-line pemigatinib vs gemcitabine plus cisplatin for advanced cholangiocarcinoma with FGFR2 rearrangements. Future Oncol. 2020;16:2385–99. [DOI] [PubMed]

134.

Javle M, Lowery M, Shroff RT, Weiss KH, Springfeld C, Borad MJ, et al. Phase II study of BGJ398 in patients with FGFR-altered advanced cholangiocarcinoma. J Clin Oncol. 2018;36:276–82. [DOI] [PubMed] [PMC]

135.

Mazzaferro V, El-Rayes BF, Droz Dit Busset M, Cotsoglou C, Harris WP, Damjanov N, et al. Derazantinib (ARQ 087) in advanced or inoperable FGFR2 gene fusion-positive intrahepatic cholangiocarcinoma. Br J Cancer. 2019;120:165–71. [DOI] [PubMed] [PMC]

136.

Goyal L, Shi L, Liu LY, Fece de la Cruz F, 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;9:1064–79. [DOI] [PubMed] [PMC]

137.

Marchiò C, Scaltriti M, Ladanyi M, Iafrate AJ, Bibeau F, Dietel M, et al. ESMO recommendations on the standard methods to detect NTRK fusions in daily practice and clinical research. Ann Oncol. 2019;30:1417–27. [DOI] [PubMed]

138.

Malka D, Siebenhüner AR, Mertens JC, Schirmacher P. The importance of molecular testing in the treatment of cholangiocarcinoma. EMJ Oncol. 2020;8:82–94.

139.

Subbiah V, Lassen U, Elez E, Italiano A, Curigliano G, Javle M, et al. Dabrafenib plus trametinib in patients with BRAF(V600E)-mutated biliary tract cancer (ROAR): a phase 2, open-label, single-arm, multicentre basket trial. Lancet Oncol. 2020;21:1234–43. [DOI] [PubMed]

140.

Normanno N, Apostolidis K, Akkermans M, Al Dieri R, Bedard Pfeiffer C, Cattaneo I, et al. Improving cancer care through broader access to quality biomarker testing: an IQN Path, ECPC and EFPIA initiative [abstract]. Ann Oncol. 2021;32:S1103–4. [DOI]

141.

Rachiglio AM, Fenizia F, Piccirillo MC, Galetta D, Crinò L, Vincenzi B, et al. The presence of concomitant mutations affects the activity of EGFR tyrosine kinase inhibitors in EGFR-mutant non-small cell lung cancer (NSCLC) patients. Cancers (Basel). 2019;11:341. [DOI] [PubMed] [PMC]

142.

Chen G, Cai Z, Dong X, Zhao J, Lin S, Hu X, et al. Genomic and transcriptomic landscape of tumor clonal evolution in cholangiocarcinoma. Front Genet. 2020;11:195. [DOI] [PubMed] [PMC]