Genomic alterations and targeted therapies in extrahepatic cholangiocarcinoma

Abstract

The global morbimortality of biliary tract cancer (BTC) is steadily increasing and accounts for ~10% of all primary liver cancer. Distinct anatomical locations of BTC have singularities in their etiopathogenesis, which are translated into differences in their molecular fingerprints and the associated therapeutic approaches. Extrahepatic cholangiocarcinoma (eCCA), arising in the large and distal bile ducts, presents recurrent activating mutations of KRAS and loss-of-function alterations in TP53, SMAD4, and CDKN2A/B. Despite being highly prevalent, no targeted therapies are yet available for these oncogenic drivers. ERBB2 mutations and amplifications, on the other hand, are the most recurrent actionable alterations for eCCA, with several clinical trials aiming to provide benefits in biomarker-enriched populations. In addition, integrative multi-omics analysis of eCCA has allowed the identification of novel molecular classes of this disease that could be therapeutically exploited. Beyond that, the highly immunosuppressive tumor microenvironment of eCCA has prevented until now the success of immune checkpoint inhibitors, recently approved in combination with cytotoxic chemotherapy. Further characterization of eCCA at the molecular level would potentially foster treating patients based on a precision oncology approach in order to increase the clinical outcomes for this challenging disease.

Keywords

Biliary tract cancer / extrahepatic cholangiocarcinoma / genetic alterations / molecular classification / targeted therapies / biomarkers

References

[1] Fitzmaurice C,Al Lami FH.Global burden of disease cancer collaborationglobal, regional, and national cancer incidence, mortality, years of life lost, years lived with disability, and disability-adjusted life-years for 29 cancer groups, 1990 to 2016: a systematic analysis for the global burden of disease study.JAMA Oncol2018;4:1553-68

[2] Everhart JE.Burden of digestive diseases in the United States part III: liver, biliary tract, and pancreas.Gastroenterology2009;136:1134-44

[3] Bertuccio P,Carioli G.Global trends in mortality from intrahepatic and extrahepatic cholangiocarcinoma.J Hepatol2019;71:104-14.

[4] Bridgewater J,Khan SA.Guidelines for the diagnosis and management of intrahepatic cholangiocarcinoma.J Hepatol2014;60:1268-89.

[5] Blechacz B,Roskams T.Clinical diagnosis and staging of cholangiocarcinoma.Nat Rev Gastroenterol Hepatol2011;8:512-22 PMCID:PMC3331791

[6] Banales JM,Carpino G.Cholangiocarcinoma: current knowledge and future perspectives consensus statement from the European Network for the Study of Cholangiocarcinoma (ENS-CCA).Nat Rev Gastroenterol Hepatol2016;13:261-80

[7] Vogel A,Edeline J.ESMO guidelines committeeBiliary tract cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up.Ann Oncol2023;34:127-40

[8] Darwish MS,Harnois DM.Efficacy of neoadjuvant chemoradiation, followed by liver transplantation, for perihilar cholangiocarcinoma at 12 US centers.Gastroenterology2012;143:88-98

[9] Primrose JN,Palmer DH.BILCAP study groupCapecitabine compared with observation in resected biliary tract cancer (BILCAP): a randomised, controlled, multicentre, phase 3 study.Lancet Oncol2019;20:663-73

[10] Valle J,Palmer DH.ABC-02 trial investigatorsCisplatin plus gemcitabine versus gemcitabine for biliary tract cancer.N Engl J Med2010;362:1273-81

[11] Oh D,Qin S.Durvalumab plus gemcitabine and cisplatin in advanced biliary tract cancer.NEJM Evidence2022;1:EVIDoa2200015

[12] Sia D,Moeini A.Massive parallel sequencing uncovers actionable FGFR2-PPHLN1 fusion and ARAF mutations in intrahepatic cholangiocarcinoma.Nat Commun2015;6:6087

[13] Abou-Alfa GK,Hollebecque A.Pemigatinib for previously treated, locally advanced or metastatic cholangiocarcinoma: a multicentre, open-label, phase 2 study.Lancet Oncol2020;21:671-84 PMCID:PMC8461541

[14] Abou-Alfa GK,Javle MM.Ivosidenib in IDH1-mutant, chemotherapy-refractory cholangiocarcinoma (ClarIDHy): a multicentre, randomised, double-blind, placebo-controlled, phase 3 study.Lancet Oncol2020;21:796-807 PMCID:PMC7523268

[15] Razumilava N.Cholangiocarcinoma.Lancet2014;383:2168-79

[16] Clements O,Kim JU,Khan SA.Risk factors for intrahepatic and extrahepatic cholangiocarcinoma: a systematic review and meta-analysis.J Hepatol2020;72:95-103

[17] Palmer WC.Are common factors involved in the pathogenesis of primary liver cancers? A meta-analysis of risk factors for intrahepatic cholangiocarcinoma.J Hepatol2012;57:69-76 PMCID:PMC3804834

[18] Tyson GL.Risk factors for cholangiocarcinoma.Hepatology2011;54:173-84 PMCID:PMC3125451

[19] Valle JW,Nervi B,Zhu AX.Biliary tract cancer.Lancet2021;397:428-44

[20] Haswell-Elkins MR,Tsuda M.Liver fluke infection and cholangiocarcinoma: model of endogenous nitric oxide and extragastric nitrosation in human carcinogenesis.Mutat Res1994;305:241-52

[21] Carpino G,Renzi A.Activation of biliary tree stem cells within peribiliary glands in primary sclerosing cholangitis.J Hepatol2015;63:1220-8

[22] Rizvi S.Pathogenesis, diagnosis, and management of cholangiocarcinoma.Gastroenterology2013;145:1215-29 PMCID:PMC3862291

[23] Moeini A,Bardeesy N,Llovet JM.Molecular pathogenesis and targeted therapies for intrahepatic cholangiocarcinoma.Clin Cancer Res2016;22:291-300

[24] Banales JM,Lamarca A.Cholangiocarcinoma 2020: the next horizon in mechanisms and management.Nat Rev Gastroenterol Hepatol2020;17:557-88 PMCID:PMC7447603

[25] Brindley PJ,Ilyas SI.Cholangiocarcinoma.Nat Rev Dis Primers2021;7:65 PMCID:PMC9246479

[26] Servais FA,Hamdorf M.Modulation of the IL-6-Signaling pathway in liver cells by miRNAs targeting gp130, JAK1, and/or STAT3.Mol Ther Nucleic Acids2019;16:419-33

[27] Clapéron A,Nguyen Ho-Bouldoires TH.EGF/EGFR axis contributes to the progression of cholangiocarcinoma through the induction of an epithelial-mesenchymal transition.J Hepatol2014;61:325-32

[28] Pant K,Peixoto E.Role of glucose metabolism reprogramming in the pathogenesis of cholangiocarcinoma.Front Med2020;7:113 PMCID:PMC7146077

[29] Tang L,Jiang BG.The prognostic significance and therapeutic potential of hedgehog signaling in intrahepatic cholangiocellular carcinoma.Clin Cancer Res2013;19:2014-24

[30] Boulter L,Kendall TJ.WNT signaling drives cholangiocarcinoma growth and can be pharmacologically inhibited.J Clin Invest2015;125:1269-85 PMCID:PMC4362247

[31] Guest RV,Dwyer BJ.Notch3 drives development and progression of cholangiocarcinoma.Proc Natl Acad Sci U S A2016;113:12250-5 PMCID:PMC5086988

[32] Valle JW,Goyal L,Zhu AX.New horizons for precision medicine in biliary tract cancers.Cancer Discov2017;7:943-62 PMCID:PMC5586506

[33] Nakamura H,Totoki Y.Genomic spectra of biliary tract cancer.Nat Genet2015;47:1003-10

[34] Homayounfar K,Cameron S.Pattern of chromosomal aberrations in primary liver cancers identified by comparative genomic hybridization.Hum Pathol2009;40:834-42

[35] Deenonpoe R,Watcharadetwittaya S.Fluorescence in situ hybridization detection of chromosome 7 and/or 17 polysomy as a prognostic marker for cholangiocarcinoma.Sci Rep2022;12:8441 PMCID:PMC9119972

[36] Jusakul A,Yong CH.Whole-Genome and epigenomic landscapes of etiologically distinct subtypes of cholangiocarcinoma.Cancer Discov2017;7:1116-35 PMCID:PMC5628134

[37] Lee H,Johnson A.Comprehensive genomic profiling of extrahepatic cholangiocarcinoma reveals a long tail of therapeutic targets.J Clin Pathol2016;69:403-8

[38] Montal R,Montironi C.Molecular classification and therapeutic targets in extrahepatic cholangiocarcinoma.J Hepatol2020;73:315-27 PMCID:PMC8418904

[39] Jiao Y,Anders RA.Exome sequencing identifies frequent inactivating mutations in BAP1, ARID1A and PBRM1 in intrahepatic cholangiocarcinomas.Nat Genet2013;45:1470-3 PMCID:PMC4013720

[40] Arai Y,Hosoda F.Fibroblast growth factor receptor 2 tyrosine kinase fusions define a unique molecular subtype of cholangiocarcinoma.Hepatology2014;59:1427-34

[41] Wu YM,Kalyana-Sundaram S.Identification of targetable FGFR gene fusions in diverse cancers.Cancer Discov2013;3:636-47 PMCID:PMC3694764

[42] Farshidfar F,Gingras MC.Cancer Genome Atlas NetworkIntegrative genomic analysis of cholangiocarcinoma identifies distinct IDH-Mutant molecular profiles.Cell Rep2017;18:2780-94 PMCID:PMC5493145

[43] Saha SK,Ghanta KS.Mutant IDH inhibits HNF-4α to block hepatocyte differentiation and promote biliary cancer.Nature2014;513:110-4. PMCID:PMC4499230

[44] Galdy S,McNamara MG.HER2/HER3 pathway in biliary tract malignancies; systematic review and meta-analysis: a potential therapeutic target?.Cancer Metastasis Rev2017;36:141-57 PMCID:PMC5385197

[45] Li M,Li X.Whole-exome and targeted gene sequencing of gallbladder carcinoma identifies recurrent mutations in the ErbB pathway.Nat Genet2014;46:872-6

[46] Mateo J,Dienstmann R.A framework to rank genomic alterations as targets for cancer precision medicine: the ESMO Scale for Clinical Actionability of molecular Targets (ESCAT).Ann Oncol2018;29:1895-902. PMCID:PMC6158764

[47] Chakravarty D,Phillips SM.OncoKB: a precision oncology knowledge base.JCO Precis Oncol2017;2017 PMCID:PMC5586540

[48] Sia D,Villanueva A.Integrative molecular analysis of intrahepatic cholangiocarcinoma reveals 2 classes that have different outcomes.Gastroenterology2013;144:829-40 PMCID:PMC3624083

[49] Andersen JB,Blechacz BR.Genomic and genetic characterization of cholangiocarcinoma identifies therapeutic targets for tyrosine kinase inhibitors.Gastroenterology2012;142:1021-1031.e15 PMCID:PMC3413201

[50] Andersen JB.Genomic decoding of intrahepatic cholangiocarcinoma reveals therapeutic opportunities.Gastroenterology2013;144:687-90.

[51] Bijlsma MF,Tan P.Molecular subtypes in cancers of the gastrointestinal tract.Nat Rev Gastroenterol Hepatol2017;14:333- 42.

[52] Sirica AE.The role of cancer-associated myofibroblasts in intrahepatic cholangiocarcinoma.Nat Rev Gastroenterol Hepatol2011;9:44-54

[53] Junttila MR.Influence of tumour micro-environment heterogeneity on therapeutic response.Nature2013;501:346-54

[54] Mertens JC,Christensen JD.Therapeutic effects of deleting cancer-associated fibroblasts in cholangiocarcinoma.Cancer Res2013;73:897-907. PMCID:PMC3549008

[55] Cadamuro M,Indraccolo S.Platelet-derived growth factor-D and Rho GTPases regulate recruitment of cancer-associated fibroblasts in cholangiocarcinoma.Hepatology2013;58:1042-53 PMCID:PMC3732815

[56] Sulpice L,Desille M.Molecular profiling of stroma identifies osteopontin as an independent predictor of poor prognosis in intrahepatic cholangiocarcinoma.Hepatology2013;58:1992-2000

[57] Kasper HU,Stippel DL,Gillessen A.Liver tumor infiltrating lymphocytes: comparison of hepatocellular and cholangiolar carcinoma.World J Gastroenterol2009;15:5053-7 PMCID:PMC2768884

[58] Ayers M,Nebozhyn M.IFN-γ-related mRNA profile predicts clinical response to PD-1 blockade.J Clin Invest2017;127:2930-40 PMCID:PMC5531419

[59] Kraehenbuehl L,Eghbali S,Merghoub T.Enhancing immunotherapy in cancer by targeting emerging immunomodulatory pathways.Nat Rev Clin Oncol2022;19:37-50

[60] Buzzoni R,Bajetta E.Activity and safety of RAD001 (everolimus) in patients affected by biliary tract cancer progressing after prior chemotherapy: a phase II ITMO study.Ann Oncol2014;25:1597-603

[61] Bekaii-Saab T,Li X.Multi-institutional phase II study of selumetinib in patients with metastatic biliary cancers.J Clin Oncol2011;29:2357-63 PMCID:PMC3107751

[62] Philip PA,Allmer C.Phase II study of erlotinib in patients with advanced biliary cancer.J Clin Oncol2006;24:3069-74

[63] Javle M,Shroff RT.Phase II study of BGJ398 in patients with FGFR-Altered advanced cholangiocarcinoma.J Clin Oncol2018;36:276-82 PMCID:PMC6075847

[64] Goyal L,Liu LY.Polyclonal secondary FGFR2 mutations drive acquired resistance to FGFR inhibition in patients with FGFR2 fusion-positive cholangiocarcinoma.Cancer Discov2017;7:252-63 PMCID:PMC5433349

[65] Hainsworth JD,Swanton C.Targeted therapy for advanced solid tumors on the basis of molecular profiles: results from mypathway, an open-label, phase IIa multiple basket study.J Clin Oncol2018;36:536-42

[66] Hyman DM,Won H.HER kinase inhibition in patients with HER2- and HER3-mutant cancers.Nature2018;554:189-94

[67] Subbiah V,Élez E.Dabrafenib plus trametinib in patients with BRAF(V600E)-mutated biliary tract cancer (ROAR): a phase 2, open-label, single-arm, multicentre basket trial.Lancet Oncol2020;21:1234-43

[68] Hallin J,Calinisan A.Anti-tumor efficacy of a potent and selective non-covalent KRAS(G12D) inhibitor.Nat Med2022;28:2171-82

[69] Mariotti V,Cadamuro M,Strazzabosco M.New insights on the role of vascular endothelial growth factor in biliary pathophysiology.JHEP Rep2021;3:100251 PMCID:PMC8189933

[70] Marabelle A,Ascierto PA.Efficacy of pembrolizumab in patients with noncolorectal high microsatellite instability/mismatch repair-deficient cancer: results from the phase II KEYNOTE-158 study.J Clin Oncol2020;38:1-10.

[71] Piha-Paul SA,Ueno M.Efficacy and safety of pembrolizumab for the treatment of advanced biliary cancer: results from the KEYNOTE-158 and KEYNOTE-028 studies.Int J Cancer2020;147:2190-8

[72] Corcoran RB.Application of cell-free DNA analysis to cancer treatment.N Engl J Med2018;379:1754-65

[73] Ho WJ,Zheng L.The tumour microenvironment in pancreatic cancer - clinical challenges and opportunities.Nat Rev Clin Oncol2020;17:527-40. PMCID:PMC7442729

[74] Karamitopoulou E.Tumour microenvironment of pancreatic cancer: immune landscape is dictated by molecular and histopathological features.Br J Cancer2019;121:5-14 PMCID:PMC6738327

[75] Finn RS,Ikeda M.IMbrave150 InvestigatorsAtezolizumab plus bevacizumab in unresectable hepatocellular carcinoma.N Engl J Med2020;382:1894-905

[76] Hyman DM,Baselga J.Implementing genome-driven oncology.Cell2017;168:584-99 PMCID:PMC5463457

[77] Canon J,Saiki AY.The clinical KRAS(G12C) inhibitor AMG 510 drives anti-tumour immunity.Nature2019;575:217-23

[78] Song G,Meng L.Single-cell transcriptomic analysis suggests two molecularly distinct subtypes of intrahepatic cholangiocarcinoma.Nat Commun2022;13:1642

[79] Collins DC,Lim JSJ.Towards precision medicine in the clinic: from biomarker discovery to novel therapeutics.Trends Pharmacol Sci2017;38:25-40