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Cholangiocarcinoma

  • Daniel H. Ahn
  • Tanios Bekaii-SaabEmail author
Chapter

Abstract

Biliary tract cancers (BTCs) are rare gastrointestinal malignancies that involve the liver and biliary tract. Despite their being uncommon, there has been an increase in their incidence, likely due to novel risk factors. In patients who are diagnosed with limited stage disease, treatment entails potential curative treatment options including surgical resection or orthotopic liver transplantation. Unfortunately, the most present with advanced or metastatic disease where treatment is limited and primarily supportive. However, with increasing knowledge about the pathogenesis and genomic variants in BTCs, the development of novel targeted agents can result in improved outcomes, with a shift in the paradigm in how this disease is treated.

Keywords

Tumor somatic variants Targeted therapies Biliary tract cancer Genomic diversity Orthotopic liver transplantation Adjuvant therapy 

References

  1. 1.
    Cardinale V, Carpino G, Reid L, Gaudio E, Alvaro D. Multiple cells of origin in cholangiocarcinoma underlie biological, epidemiological and clinical heterogeneity. World J Gastrointest Oncol. 2012;4(5):94–102.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Theise ND, Saxena R, Portmann BC, Thung SN, Yee H, Chiriboga L, et al. The canals of hering and hepatic stem cells in humans. Hepatology. 1999;30(6):1425–33.CrossRefPubMedGoogle Scholar
  3. 3.
    Cardinale V, Wang Y, Carpino G, Cui CB, Gatto M, Rossi M, et al. Multipotent stem/progenitor cells in human biliary tree give rise to hepatocytes, cholangiocytes, and pancreatic islets. Hepatology. 2011;54(6):2159–72.CrossRefPubMedGoogle Scholar
  4. 4.
    Carpino G, Cardinale V, Onori P, Franchitto A, Berloco PB, Rossi M, et al. Biliary tree stem/progenitor cells in glands of extrahepatic and intraheptic bile ducts: an anatomical in situ study yielding evidence of maturational lineages. J Anat. 2012;220(2):186–99.CrossRefPubMedGoogle Scholar
  5. 5.
    Lazaridis KN, Gores GJ. Cholangiocarcinoma. Gastroenterology. 2005;128(6):1655–67.CrossRefGoogle Scholar
  6. 6.
    Patel T. Worldwide trends in mortality from biliary tract malignancies. BMC Cancer. 2002;2:10.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Blechacz B, Komuta M, Roskams T, Gores GJ. Clinical diagnosis and staging of cholangiocarcinoma. Nat Rev Gastroenterol Hepatol. 2011;8(9):512–22.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Charbel H, Al-Kawas FH. Cholangiocarcinoma: epidemiology, risk factors, pathogenesis, and diagnosis. Curr Gastroenterol Rep. 2011;13(2):182–7.CrossRefPubMedGoogle Scholar
  9. 9.
    Dickson PV, Behrman SW. Distal cholangiocarcinoma. Surg Clin North Am. 2014;94(2):325–42.CrossRefPubMedGoogle Scholar
  10. 10.
    Razumilava N, Gores GJ. Classification, diagnosis, and management of cholangiocarcinoma. Clin Gastroenterol Hepatol. 2013;11(1):13–21.e11; quiz e13–14.CrossRefPubMedGoogle Scholar
  11. 11.
    Razumilava N, Gores GJ. Cholangiocarcinoma. Lancet (London, England). 2014;383(9935):2168–79.CrossRefGoogle Scholar
  12. 12.
    Rizvi S, Gores GJ. Pathogenesis, diagnosis, and management of cholangiocarcinoma. Gastroenterology. 2013;145(6):1215–29.CrossRefPubMedGoogle Scholar
  13. 13.
    Shaib Y, El-Serag HB. The epidemiology of cholangiocarcinoma. Semin Liver Dis. 2004;24(2):115–25.CrossRefPubMedGoogle Scholar
  14. 14.
    Tsaitas C, Semertzidou A, Sinakos E. Update on inflammatory bowel disease in patients with primary sclerosing cholangitis. World J Hepatol. 2014;6(4):178–87.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Wade TP, Prasad CN, Virgo KS, Johnson FE. Experience with distal bile duct cancers in u.S. Veterans affairs hospitals: 1987–1991. J Surg Oncol. 1997;64(3):242–5.CrossRefPubMedGoogle Scholar
  16. 16.
    de Groen PC, Gores GJ, LaRusso NF, Gunderson LL, Nagorney DM. Biliary tract cancers. N Engl J Med. 1999;341(18):1368–78.CrossRefPubMedGoogle Scholar
  17. 17.
    Jarnagin WR, Ruo L, Little SA, Klimstra D, D’Angelica M, DeMatteo RP, et al. Patterns of initial disease recurrence after resection of gallbladder carcinoma and hilar cholangiocarcinoma: implications for adjuvant therapeutic strategies. Cancer. 2003;98(8):1689–700.CrossRefPubMedGoogle Scholar
  18. 18.
    Oettle H, Neuhaus P, Hochhaus A, Hartmann JT, Gellert K, Ridwelski K, et al. Adjuvant chemotherapy with gemcitabine and long-term outcomes among patients with resected pancreatic cancer: the conko-001 randomized trial. JAMA. 2013;310(14):1473–81.CrossRefGoogle Scholar
  19. 19.
    Andre T, Boni C, Mounedji-Boudiaf L, Navarro M, Tabernero J, Hickish T, et al. Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. N Engl J Med. 2004;350(23):2343–51.CrossRefPubMedGoogle Scholar
  20. 20.
    de Jong MC, Nathan H, Sotiropoulos GC, Paul A, Alexandrescu S, Marques H, et al. Intrahepatic cholangiocarcinoma: an international multi-institutional analysis of prognostic factors and lymph node assessment. J Clin Oncol. 2011;29(23):3140–5.CrossRefGoogle Scholar
  21. 21.
    Horgan AM, Amir E, Walter T, Knox JJ. Adjuvant therapy in the treatment of biliary tract cancer: a systematic review and meta-analysis. J Clin Oncol. 2012;30(16):1934–40.CrossRefGoogle Scholar
  22. 22.
    Ben-Josef E, Guthrie KA, El-Khoueiry AB, Corless CL, Zalupski MM, Lowy AM, et al. Swog s0809: a phase ii intergroup trial of adjuvant capecitabine and gemcitabine followed by radiotherapy and concurrent capecitabine in extrahepatic cholangiocarcinoma and gallbladder carcinoma. J Clin Oncol. 2015;33(24):2617–22.CrossRefPubMedGoogle Scholar
  23. 23.
    Iwatsuki S, Todo S, Marsh JW, Madariaga JR, Lee RG, Dvorchik I, et al. Treatment of hilar cholangiocarcinoma (klatskin tumors) with hepatic resection or transplantation. J Am Coll Surg. 1998;187(4):358–64.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    De Vreede I, Steers JL, Burch PA, Rosen CB, Gunderson LL, Haddock MG, et al. Prolonged disease-free survival after orthotopic liver transplantation plus adjuvant chemoirradiation for cholangiocarcinoma. Liver Transpl. 2000;6(3):309–16.CrossRefPubMedGoogle Scholar
  25. 25.
    Gu J, Bai J, Shi X, Zhou J, Qiu Y, Wu Y, et al. Efficacy and safety of liver transplantation in patients with cholangiocarcinoma: a systematic review and meta-analysis. Int J Cancer. 2012;130(9):2155–63.CrossRefPubMedGoogle Scholar
  26. 26.
    Darwish Murad S, Kim WR, Harnois DM, Douglas DD, Burton J, Kulik LM, et al. Efficacy of neoadjuvant chemoradiation, followed by liver transplantation, for perihilar cholangiocarcinoma at 12 us centers. Gastroenterology. 2012;143(1):88–98 e83; quiz e14.CrossRefPubMedGoogle Scholar
  27. 27.
    Rea DJ, Heimbach JK, Rosen CB, Haddock MG, Alberts SR, Kremers WK, et al. Liver transplantation with neoadjuvant chemoradiation is more effective than resection for hilar cholangiocarcinoma. Ann Surg. 2005;242(3):451–8; discussion 458–461.PubMedPubMedCentralGoogle Scholar
  28. 28.
    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(14):1273–81.CrossRefGoogle Scholar
  29. 29.
    He S, Shen J, Sun X, Liu L, Dong J. A phase ii folfox-4 regimen as second-line treatment in advanced biliary tract cancer refractory to gemcitabine/cisplatin. J Chemother. 2014;26(4):243–7.CrossRefPubMedGoogle Scholar
  30. 30.
    Paule B, Herelle MO, Rage E, Ducreux M, Adam R, Guettier C, et al. Cetuximab plus gemcitabine-oxaliplatin (gemox) in patients with refractory advanced intrahepatic cholangiocarcinomas. Oncology. 2007;72(1–2):105–10.CrossRefPubMedGoogle Scholar
  31. 31.
    Suzuki E, Ikeda M, Okusaka T, Nakamori S, Ohkawa S, Nagakawa T, et al. A multicenter phase ii study of s-1 for gemcitabine-refractory biliary tract cancer. Cancer Chemother Pharmacol. 2013;71(5):1141–6.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Bridgewater J, Palmer D, Cunningham D, Iveson T, Gillmore R, Waters J, et al. Outcome of second-line chemotherapy for biliary tract cancer. Eur J Cancer. 2013;49(6):1511.CrossRefPubMedGoogle Scholar
  33. 33.
    Croitoru A, Gramaticu I, Dinu I, Gheorghe L, Alexandrescu S, Buica F, et al. Fluoropyrimidines plus cisplatin versus gemcitabine/gemcitabine plus cisplatin in locally advanced and metastatic biliary tract carcinoma – a retrospective study. J Gastrointest Liver Dis: JGLD. 2012;21(3):277–84.Google Scholar
  34. 34.
    Fornaro L, Vivaldi C, Cereda S, Leone F, Aprile G, Lonardi S, et al. Second-line chemotherapy in advanced biliary cancer progressed to first-line platinum-gemcitabine combination: a multicenter survey and pooled analysis with published data. J Exp Clin Cancer Res: CR. 2015;34(1):156.CrossRefPubMedGoogle Scholar
  35. 35.
    Sasaki T, Isayama H, Nakai Y, Takahara N, Satoh Y, Takai D, et al. A pilot study of salvage irinotecan monotherapy for advanced biliary tract cancer. Anticancer Res. 2013;33(6):2619–22.PubMedGoogle Scholar
  36. 36.
    Bekaii-Saab T, Phelps MA, Li X, Saji M, Goff L, Kauh JS, et al. Multi-institutional phase ii study of selumetinib in patients with metastatic biliary cancers. J Clin Oncol. 2011;29(17):2357–63.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Peck J, Wei L, Zalupski M, O’Neil B, Villalona Calero M, Bekaii-Saab T. Her2/neu may not be an interesting target in biliary cancers: results of an early phase ii study with lapatinib. Oncology. 2012;82(3):175–9.CrossRefPubMedGoogle Scholar
  38. 38.
    Finn RS, Ahn DH, Javle MM, Tan BR Jr, Weekes CD, Bendell JC, Patnaik A, Khan GN, Laheru D, Chavira R, Christy-Bittel J, Barrett E, Sawyer MB, Bekaii-Saab TS. Phase 1b investigation of the MEK inhibitor binimetinib in patients with advanced or metastatic biliary tract cancer. Invest New Drugs. 2018;36(6):1037–43. https://doi.org/10.1007/s10637-018-0600-2. Epub 2018 May 22.CrossRefPubMedGoogle Scholar
  39. 39.
    Ahn DH, Li J, Wei L, Doyle A, Marshall JL, Schaaf LJ, et al. Results of an abbreviated phase-ii study with the akt inhibitor mk-2206 in patients with advanced biliary cancer. Sci Rep. 2015;5:12122.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Ramanathan RK, Belani CP, Singh DA, Tanaka M, Lenz HJ, Yen Y, et al. A phase ii study of lapatinib in patients with advanced biliary tree and hepatocellular cancer. Cancer Chemother Pharmacol. 2009;64(4):777–83.CrossRefPubMedGoogle Scholar
  41. 41.
    Philip PA, Mahoney MR, Allmer C, Thomas J, Pitot HC, Kim G, et al. Phase ii study of erlotinib in patients with advanced biliary cancer. J Clin Oncol. 2006;24(19):3069–74.CrossRefPubMedGoogle Scholar
  42. 42.
    Lubner SJ, Mahoney MR, Kolesar JL, Loconte NK, Kim GP, Pitot HC, et al. Report of a multicenter phase ii trial testing a combination of biweekly bevacizumab and daily erlotinib in patients with unresectable biliary cancer: a phase ii consortium study. J Clin Oncol. 2010;28(21):3491–7.CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    El-Khoueiry AB, Rankin C, Siegel AB, Iqbal S, Gong IY, Micetich KC, et al. S0941: a phase 2 swog study of sorafenib and erlotinib in patients with advanced gallbladder carcinoma or cholangiocarcinoma. Br J Cancer. 2014;110(4):882–7.CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    El-Khoueiry AB, Rankin CJ, Ben-Josef E, Lenz HJ, Gold PJ, Hamilton RD, et al. Swog 0514: a phase ii study of sorafenib in patients with unresectable or metastatic gallbladder carcinoma and cholangiocarcinoma. Invest New Drugs. 2012;30(4):1646–51.CrossRefPubMedGoogle Scholar
  45. 45.
    Bengala C, Bertolini F, Malavasi N, Boni C, Aitini E, Dealis C, et al. Sorafenib in patients with advanced biliary tract carcinoma: a phase ii trial. Br J Cancer. 2010;102(1):68–72.CrossRefPubMedGoogle Scholar
  46. 46.
    Yi JH, Thongprasert S, Lee J, Doval DC, Park SH, Park JO, et al. A phase ii study of sunitinib as a second-line treatment in advanced biliary tract carcinoma: a multicentre, multinational study. Eur J Cancer. 2012;48(2):196–201.CrossRefPubMedGoogle Scholar
  47. 47.
    Buzzoni R, Pusceddu S, Bajetta E, De Braud F, Platania M, Iannacone C, et al. Activity and safety of rad001 (everolimus) in patients affected by biliary tract cancer progressing after prior chemotherapy: a phase ii itmo study. Ann Oncol. 2014;25(8):1597–603.CrossRefPubMedGoogle Scholar
  48. 48.
    Santoro A, Gebbia V, Pressiani T, Testa A, Personeni N, Arrivas Bajardi E, et al. A randomized, multicenter, phase ii study of vandetanib monotherapy versus vandetanib in combination with gemcitabine versus gemcitabine plus placebo in subjects with advanced biliary tract cancer: the vangogh study. Ann Oncol. 2015;26(3):542–7.CrossRefPubMedGoogle Scholar
  49. 49.
    Goel HL, Mercurio AM. Vegf targets the tumour cell. Nat Rev Cancer. 2013;13(12):871–82.CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Quan ZW, Wu K, Wang J, Shi W, Zhang Z, Merrell RC. Association of p53, p16, and vascular endothelial growth factor protein expressions with the prognosis and metastasis of gallbladder cancer. J Am Coll Surg. 2001;193(4):380–3.CrossRefPubMedGoogle Scholar
  51. 51.
    Gordon MS, Margolin K, Talpaz M, Sledge GW Jr, Holmgren E, Benjamin R, et al. Phase i safety and pharmacokinetic study of recombinant human anti-vascular endothelial growth factor in patients with advanced cancer. J Clin Oncol. 2001;19(3):843–50.CrossRefPubMedGoogle Scholar
  52. 52.
    Margolin K, Gordon MS, Holmgren E, Gaudreault J, Novotny W, Fyfe G, et al. Phase ib trial of intravenous recombinant humanized monoclonal antibody to vascular endothelial growth factor in combination with chemotherapy in patients with advanced cancer: pharmacologic and long-term safety data. J Clin Oncol. 2001;19(3):851–6.CrossRefPubMedGoogle Scholar
  53. 53.
    Zhu AX, Meyerhardt JA, Blaszkowsky LS, Kambadakone AR, Muzikansky A, Zheng H, et al. Efficacy and safety of gemcitabine, oxaliplatin, and bevacizumab in advanced biliary-tract cancers and correlation of changes in 18-fluorodeoxyglucose pet with clinical outcome: a phase 2 study. Lancet Oncol. 2010;11(1):48–54.CrossRefPubMedGoogle Scholar
  54. 54.
    Benckert C, Jonas S, Cramer T, Von Marschall Z, Schafer G, Peters M, et al. Transforming growth factor beta 1 stimulates vascular endothelial growth factor gene transcription in human cholangiocellular carcinoma cells. Cancer Res. 2003;63(5):1083–92.PubMedGoogle Scholar
  55. 55.
    Wedge SR, Kendrew J, Hennequin LF, Valentine PJ, Barry ST, Brave SR, et al. Azd2171: a highly potent, orally bioavailable, vascular endothelial growth factor receptor-2 tyrosine kinase inhibitor for the treatment of cancer. Cancer Res. 2005;65(10):4389–400.CrossRefPubMedGoogle Scholar
  56. 56.
    Lee JK, Capanu M, O’Reilly EM, Ma J, Chou JF, Shia J, et al. A phase ii study of gemcitabine and cisplatin plus sorafenib in patients with advanced biliary adenocarcinomas. Br J Cancer. 2013;109(4):915–9.CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Moehler M, Maderer A, Schimanski C, Kanzler S, Denzer U, Kolligs FT, et al. Gemcitabine plus sorafenib versus gemcitabine alone in advanced biliary tract cancer: a double-blind placebo-controlled multicentre phase ii aio study with biomarker and serum programme. Eur J Cancer. 2014;50(18):3125–35.CrossRefPubMedGoogle Scholar
  58. 58.
    Demetri GD, van Oosterom AT, Garrett CR, Blackstein ME, Shah MH, Verweij J, et al. Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial. Lancet (London, England). 2006;368(9544):1329–38.CrossRefGoogle Scholar
  59. 59.
    Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Oudard S, et al. Overall survival and updated results for sunitinib compared with interferon alfa in patients with metastatic renal cell carcinoma. J Clin Oncol. 2009;27(22):3584–90.CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Valle JW, Wasan H, Lopes A, Backen AC, Palmer DH, Morris K, et al. Cediranib or placebo in combination with cisplatin and gemcitabine chemotherapy for patients with advanced biliary tract cancer (abc-03): a randomised phase 2 trial. Lancet Oncol. 2015;16(8):967–78.CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Xu L, Hausmann M, Dietmaier W, Kellermeier S, Pesch T, Stieber-Gunckel M, et al. Expression of growth factor receptors and targeting of egfr in cholangiocarcinoma cell lines. BMC Cancer. 2010;10:302.CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Yoon JH, Gwak GY, Lee HS, Bronk SF, Werneburg NW, Gores GJ. Enhanced epidermal growth factor receptor activation in human cholangiocarcinoma cells. J Hepatol. 2004;41(5):808–14.CrossRefPubMedGoogle Scholar
  63. 63.
    Kaufman M, Mehrotra B, Limaye S, White S, Fuchs A, Lebowicz Y, et al. Egfr expression in gallbladder carcinoma in north america. Int J Med Sci. 2008;5(5):285–91.CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    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(2):418–25.CrossRefPubMedGoogle Scholar
  65. 65.
    Zhou YM, Li YM, Cao N, Feng Y, Zeng F. Significance of expression of epidermal growth factor (egf) and its receptor (egfr) in chronic cholecystitis and gallbladder carcinoma. Ai zheng = Aizheng =Chin J Cancer. 2003;22(3):262–5.Google Scholar
  66. 66.
    Yoshikawa D, Ojima H, Kokubu A, Ochiya T, Kasai S, Hirohashi S, et al. Vandetanib (zd6474), an inhibitor of vegfr and egfr signalling, as a novel molecular-targeted therapy against cholangiocarcinoma. Br J Cancer. 2009;100(8):1257–66.CrossRefPubMedPubMedCentralGoogle Scholar
  67. 67.
    Lee J, Park SH, Chang HM, Kim JS, Choi HJ, Lee MA, et al. Gemcitabine and oxaliplatin with or without erlotinib in advanced biliary-tract cancer: a multicentre, open-label, randomised, phase 3 study. Lancet Oncol. 2012;13(2):181–8.CrossRefPubMedGoogle Scholar
  68. 68.
    Gruenberger B, Schueller J, Heubrandtner U, Wrba F, Tamandl D, Kaczirek K, et al. Cetuximab, gemcitabine, and oxaliplatin in patients with unresectable advanced or metastatic biliary tract cancer: a phase 2 study. Lancet Oncol. 2010;11(12):1142–8.CrossRefPubMedGoogle Scholar
  69. 69.
    Malka D, Cervera P, Foulon S, Trarbach T, de la Fouchardiere C, Boucher E, et al. Gemcitabine and oxaliplatin with or without cetuximab in advanced biliary-tract cancer (bingo): a randomised, open-label, non-comparative phase 2 trial. Lancet Oncol. 2014;15(8):819–28.CrossRefPubMedPubMedCentralGoogle Scholar
  70. 70.
    Douillard JY, Oliner KS, Siena S, Tabernero J, Burkes R, Barugel M, et al. Panitumumab-folfox4 treatment and ras mutations in colorectal cancer. N Engl J Med. 2013;369(11):1023–34.CrossRefPubMedGoogle Scholar
  71. 71.
    Heinemann V, von Weikersthal LF, Decker T, Kiani A, Vehling-Kaiser U, Al-Batran SE, et al. Folfiri plus cetuximab versus folfiri plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer (fire-3): a randomised, open-label, phase 3 trial. Lancet Oncol. 2014;15(10):1065–75.CrossRefPubMedGoogle Scholar
  72. 72.
    Schwartzberg LS, Rivera F, Karthaus M, Fasola G, Canon JL, Hecht JR, et al. Peak: A randomized, multicenter phase ii study of panitumumab plus modified fluorouracil, leucovorin, and oxaliplatin (mfolfox6) or bevacizumab plus mfolfox6 in patients with previously untreated, unresectable, wild-type kras exon 2 metastatic colorectal cancer. J Clin Oncol. 2014;32(21):2240–7.CrossRefPubMedGoogle Scholar
  73. 73.
    Tadlock L, Yamagiwa Y, Marienfeld C, Patel T. Double-stranded rna activates a p38 mapk-dependent cell survival program in biliary epithelia. Am J Physiol Gastrointest Liver Physiol. 2003;284(6):G924–32.CrossRefPubMedGoogle Scholar
  74. 74.
    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(5):706–12.CrossRefPubMedPubMedCentralGoogle Scholar
  75. 75.
    Finn RSJM, Tan BR, Weekes CD, et al. A phase i study of mek inhibitor mek162 (arry-438162) in patients with biliary tract cancer. J Clin Oncol. 2012;30:4s.. (suppl; abstr 220).CrossRefGoogle Scholar
  76. 76.
    Schmitz KJ, Lang H, Wohlschlaeger J, Sotiropoulos GC, Reis H, Schmid KW, et al. Akt and erk1/2 signaling in intrahepatic cholangiocarcinoma. World J Gastroenterol. 2007;13(48):6470–7.CrossRefPubMedPubMedCentralGoogle Scholar
  77. 77.
    Chung JY, Hong SM, Choi BY, Cho H, Yu E, Hewitt SM. The expression of phospho-akt, phospho-mtor, and pten in extrahepatic cholangiocarcinoma. Clin Cancer Res. 2009;15(2):660–7.CrossRefPubMedGoogle Scholar
  78. 78.
    Deshpande V, Nduaguba A, Zimmerman SM, Kehoe SM, Macconaill LE, Lauwers GY, et al. Mutational profiling reveals pik3ca mutations in gallbladder carcinoma. BMC Cancer. 2011;11:60.CrossRefPubMedPubMedCentralGoogle Scholar
  79. 79.
    Li Q, Yang Z. Expression of phospho-erk1/2 and pi3-k in benign and malignant gallbladder lesions and its clinical and pathological correlations. J Exp Clin Cancer Res: CR. 2009;28:65.CrossRefPubMedGoogle Scholar
  80. 80.
    Tanno S, Yanagawa N, Habiro A, Koizumi K, Nakano Y, Osanai M, et al. Serine/threonine kinase akt is frequently activated in human bile duct cancer and is associated with increased radioresistance. Cancer Res. 2004;64(10):3486–90.CrossRefPubMedGoogle Scholar
  81. 81.
    Yoon H, Min JK, Lee JW, Kim DG, Hong HJ. Acquisition of chemoresistance in intrahepatic cholangiocarcinoma cells by activation of akt and extracellular signal-regulated kinase (erk)1/2. Biochem Biophys Res Commun. 2011;405(3):333–7.CrossRefPubMedGoogle Scholar
  82. 82.
    Verma S, Miles D, Gianni L, Krop IE, Welslau M, Baselga J, et al. Trastuzumab emtansine for her2-positive advanced breast cancer. N Engl J Med. 2012;367(19):1783–91.CrossRefPubMedPubMedCentralGoogle Scholar
  83. 83.
    Bang YJ, Van Cutsem E, Feyereislova A, Chung HC, Shen L, Sawaki A, et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of her2-positive advanced gastric or gastro-oesophageal junction cancer (toga): a phase 3, open-label, randomised controlled trial. Lancet (London, England). 2010;376(9742):687–97.CrossRefGoogle Scholar
  84. 84.
    Janjigian YY, Werner D, Pauligk C, Steinmetz K, Kelsen DP, Jager E, et al. Prognosis of metastatic gastric and gastroesophageal junction cancer by her2 status: a european and USA international collaborative analysis. Ann Oncol. 2012;23(10):2656–62.CrossRefPubMedGoogle Scholar
  85. 85.
    Kim HJ, Yoo TW, Park DI, Park JH, Cho YK, Sohn CI, et al. Gene amplification and protein overexpression of her-2/neu in human extrahepatic cholangiocarcinoma as detected by chromogenic in situ hybridization and immunohistochemistry: its prognostic implication in node-positive patients. Ann Oncol. 2007;18(5):892–7.CrossRefPubMedGoogle Scholar
  86. 86.
    Pignochino Y, Sarotto I, Peraldo-Neia C, Penachioni JY, Cavalloni G, Migliardi G, et al. Targeting egfr/her2 pathways enhances the antiproliferative effect of gemcitabine in biliary tract and gallbladder carcinomas. BMC Cancer. 2010;10:631.CrossRefPubMedPubMedCentralGoogle Scholar
  87. 87.
    Javle M, Churi C, Kang HC, Shroff R, Janku F, Surapaneni R, et al. Her2/neu-directed therapy for biliary tract cancer. J Hematol Oncol. 2015;8:58.CrossRefPubMedPubMedCentralGoogle Scholar
  88. 88.
    Kawamoto T, Ishige K, Thomas M, Yamashita-Kashima Y, Shu S, Ishikura N, et al. Overexpression and gene amplification of egfr, her2, and her3 in biliary tract carcinomas, and the possibility for therapy with the her2-targeting antibody pertuzumab. J Gastroenterol. 2015;50(4):467–79.CrossRefPubMedGoogle Scholar
  89. 89.
    Schindler G, Capper D, Meyer J, Janzarik W, Omran H, Herold-Mende C, et al. Analysis of braf v600e mutation in 1,320 nervous system tumors reveals high mutation frequencies in pleomorphic xanthoastrocytoma, ganglioglioma and extra-cerebellar pilocytic astrocytoma. Acta Neuropathol. 2011;121(3):397–405.CrossRefPubMedGoogle Scholar
  90. 90.
    Michaloglou C, Vredeveld LC, Mooi WJ, Peeper DS. Braf(e600) in benign and malignant human tumours. Oncogene. 2008;27(7):877–95.CrossRefPubMedGoogle Scholar
  91. 91.
    Brose MS, Volpe P, Feldman M, Kumar M, Rishi I, Gerrero R, et al. Braf and ras mutations in human lung cancer and melanoma. Cancer Res. 2002;62(23):6997–7000.PubMedGoogle Scholar
  92. 92.
    Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, et al. Mutations of the braf gene in human cancer. Nature. 2002;417(6892):949–54.CrossRefGoogle Scholar
  93. 93.
    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(7):1028–34.CrossRefPubMedGoogle Scholar
  94. 94.
    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(12):2768–73.CrossRefPubMedGoogle Scholar
  95. 95.
    Kim KB, Cabanillas ME, Lazar AJ, Williams MD, Sanders DL, Ilagan JL, et al. Clinical responses to vemurafenib in patients with metastatic papillary thyroid cancer harboring braf(v600e) mutation. Thyroid. 2013;23(10):1277–83.CrossRefPubMedPubMedCentralGoogle Scholar
  96. 96.
    Dietrich S, Glimm H, Andrulis M, von Kalle C, Ho AD, Zenz T. Braf inhibition in refractory hairy-cell leukemia. N Engl J Med. 2012;366(21):2038–40.CrossRefPubMedGoogle Scholar
  97. 97.
    Hauschild A, Grob JJ, Demidov LV, Jouary T, Gutzmer R, Millward M, et al. Dabrafenib in braf-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet (London, England). 2012;380(9839):358–65.CrossRefGoogle Scholar
  98. 98.
    Sosman JA, Kim KB, Schuchter L, Gonzalez R, Pavlick AC, Weber JS, et al. Survival in braf v600-mutant advanced melanoma treated with vemurafenib. N Engl J Med. 2012;366(8):707–14.CrossRefPubMedPubMedCentralGoogle Scholar
  99. 99.
    Saha SK, Parachoniak CA, Ghanta KS, Fitamant J, Ross KN, Najem MS, et al. Mutant idh inhibits hnf-4alpha to block hepatocyte differentiation and promote biliary cancer. Nature. 2014;513(7516):110–4.CrossRefPubMedPubMedCentralGoogle Scholar
  100. 100.
    Belov AA, Mohammadi M. Molecular mechanisms of fibroblast growth factor signaling in physiology and pathology. Cold Spring Harb Perspect Biol. 2013;5(6):1–23.CrossRefPubMedPubMedCentralGoogle Scholar
  101. 101.
    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(2):e1004135.CrossRefPubMedPubMedCentralGoogle Scholar
  102. 102.
    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(3):235–42.CrossRefPubMedPubMedCentralGoogle Scholar
  103. 103.
    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.CrossRefPubMedGoogle Scholar
  104. 104.
    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(4):1427–34.CrossRefPubMedGoogle Scholar
  105. 105.
    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(6):636–47.CrossRefPubMedPubMedCentralGoogle Scholar
  106. 106.
    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(8):1630–8.CrossRefPubMedGoogle Scholar
  107. 107.
    Kouhara H, Hadari YR, Spivak-Kroizman T, Schilling J, Bar-Sagi D, Lax I, et al. A lipid-anchored grb2-binding protein that links fgf-receptor activation to the ras/mapk signaling pathway. Cell. 1997;89(5):693–702.CrossRefPubMedGoogle Scholar
  108. 108.
    Gu TL, Deng X, Huang F, Tucker M, Crosby K, Rimkunas V, et al. Survey of tyrosine kinase signaling reveals ros kinase fusions in human cholangiocarcinoma. PLoS One. 2011;6(1):e15640.CrossRefPubMedPubMedCentralGoogle Scholar
  109. 109.
    Saborowski A, Saborowski M, Davare MA, Druker BJ, Klimstra DS, Lowe SW. Mouse model of intrahepatic cholangiocarcinoma validates fig-ros as a potent fusion oncogene and therapeutic target. Proc Natl Acad Sci U S A. 2013;110(48):19513–8.CrossRefPubMedPubMedCentralGoogle Scholar
  110. 110.
    Shaw AT, Ou SH, Bang YJ, Camidge DR, Solomon BJ, Salgia R, et al. Crizotinib in ros1-rearranged non-small-cell lung cancer. N Engl J Med. 2014;371(21):1963–71.CrossRefPubMedPubMedCentralGoogle Scholar
  111. 111.
    Zender S, Nickeleit I, Wuestefeld T, Sorensen I, Dauch D, Bozko P, et al. A critical role for notch signaling in the formation of cholangiocellular carcinomas. Cancer Cell. 2013;23(6):784–95.CrossRefPubMedGoogle Scholar
  112. 112.
    Yoon HA, Noh MH, Kim BG, Han JS, Jang JS, Choi SR, et al. Clinicopathological significance of altered notch signaling in extrahepatic cholangiocarcinoma and gallbladder carcinoma. World J Gastroenterol. 2011;17(35):4023–30.CrossRefPubMedPubMedCentralGoogle Scholar
  113. 113.
    Wu WR, Shi XD, Zhang R, Zhu MS, Xu LB, Yu XH, et al. Clinicopathological significance of aberrant notch receptors in intrahepatic cholangiocarcinoma. Int J Clin Exp Pathol. 2014;7(6):3272–9.PubMedPubMedCentralGoogle Scholar
  114. 114.
    Huntzicker EG, Hotzel K, Choy L, Che L, Ross J, Pau G, et al. Differential effects of targeting notch receptors in a mouse model of liver cancer. Hepatology. 2015;61(3):942–52.CrossRefPubMedPubMedCentralGoogle Scholar
  115. 115.
    Le DT, Uram JN, Wang H, Bartlett BR, Kemberling H, Eyring AD, et al. Pd-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med. 2015;372(26):2509–20.CrossRefPubMedPubMedCentralGoogle Scholar

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© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Division of Hematology/Medical OncologyMayo ClinicPhoenixUSA

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