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Current and Emerging Medical Therapies for Advanced Disease in Intrahepatic Cholangiocarcinoma

  • Aileen Deng
  • Steven CohenEmail author
Chapter

Abstract

Biliary tract cancers are rare cancers with traditionally dismal clinical outcomes. Systemic chemotherapy remains the mainstay of treatment for patients with advanced disease. Combination therapy with cisplatin and gemcitabine is the current standard of care. Recent advancements in genomic profiling and next-generation sequencing technologies have led to a growing understanding of the true heterogeneity within this disease. Large mutational profiling studies have identified key genomic differences among intrahepatic and extrahepatic cholangiocarcinoma and gallbladder carcinoma. Understanding these genomic alterations and identifying targetable mutations will be critical to developing effective biomarker and targeted therapy options. In this chapter, we will review current and emerging systemic treatment options for cholangiocarcinoma.

Keywords

Cholangiocarcinoma Biliary tract cancer Gallbladder cancer Chemotherapy Targeted therapy Immunotherapy Genomic alteration Genomic profiling 

References

  1. 1.
    Edge SB, American Joint Committee on Cancer, American Cancer Society, editors. AJCC cancer staging handbook: from the AJCC cancer staging manual. 7th ed. New York: Springer; 2010. 718 p.Google Scholar
  2. 2.
    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(5):261–80.CrossRefGoogle Scholar
  3. 3.
    Abou-Alfa GK, Andersen JB, Chapman W, Choti M, Forbes SJ, Gores GJ, et al. Advances in cholangiocarcinoma research: report from the third cholangiocarcinoma foundation annual conference. J Gastrointest Oncol. 2016;7(6):819–27.PubMedPubMedCentralCrossRefGoogle Scholar
  4. 4.
    Chong DQ, Zhu AX, Chong DQ, Zhu AX. The landscape of targeted therapies for cholangiocarcinoma: current status and emerging targets. Oncotarget. 2016;7(29):46750–67.PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    Anderson CD, Pinson CW, Berlin J, Chari RS. Diagnosis and treatment of cholangiocarcinoma. Oncologist. 2004;9(1):43–57.CrossRefGoogle Scholar
  6. 6.
    Anand MGAC, Purl CP, Dhar BA. The value of molecular biomarkers in biliary tract cancer in the era of targeted therapy. J Clin Exp Hepatol. 2011;1(1):2.PubMedPubMedCentralCrossRefGoogle Scholar
  7. 7.
    Park J, Kim M-H, Kim K, Park DH, Moon S-H, Song TJ, et al. Natural history and prognostic factors of advanced cholangiocarcinoma without surgery, chemotherapy, or radiotherapy: a large-scale observational study. Gut Liver. 2009;3(4):298–305.PubMedPubMedCentralCrossRefGoogle Scholar
  8. 8.
    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.PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Glimelius B, Hoffman K, Sjödén P-O, Jacobsson G, Sellström H, Enander L-K, et al. Chemotherapy improves survival and quality of life in advanced pancreatic and biliary cancer. Ann Oncol. 1996;7(6):593–600.PubMedCrossRefGoogle Scholar
  10. 10.
    Benson AB, D’Angelica MI, Abrams TA, Are C, Bloomston PM, Chang DT, et al. Hepatobiliary cancers, version 2.2014. J Natl Compr Cancer Netw. 2014;12(8):1152–82.CrossRefGoogle Scholar
  11. 11.
    Okusaka T, Nakachi K, Fukutomi A, Mizuno N, Ohkawa S, Funakoshi A, et al. Gemcitabine alone or in combination with cisplatin in patients with biliary tract cancer: a comparative multicentre study in Japan. Br J Cancer. 2010;103(4):469–74.PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Valle JW, Furuse J, Jitlal M, Beare S, Mizuno N, Wasan H, et al. Cisplatin and gemcitabine for advanced biliary tract cancer: a meta-analysis of two randomised trials. Ann Oncol. 2014;25(2):391–8.CrossRefGoogle Scholar
  13. 13.
    Ulahannan SV, Rahma OE, Duffy AG, Makarova-Rusher OV, Kurtoglu M, Liewehr DJ, et al. Identification of active chemotherapy regimens in advanced biliary tract carcinoma: a review of chemotherapy trials in the past two decades. Hepatic Oncol. 2015;2(1):39.CrossRefGoogle Scholar
  14. 14.
    Liu H, Zhang Q-D, Li Z-H, Zhang Q-Q, Lu L-G. Efficacy and safety of gemcitabine-based chemotherapies in biliary tract cancer: a meta-analysis. World J Gastroenterol. 2014;20(47):18001–12.PubMedPubMedCentralCrossRefGoogle Scholar
  15. 15.
    Brieau B, Dahan L, De Rycke Y, Boussaha T, Vasseur P, Tougeron D, et al. Second-line chemotherapy for advanced biliary tract cancer after failure of the gemcitabine-platinum combination: a large multicenter study by the Association des Gastro-Entérologues Oncologues. Cancer. 2015;121(18):3290–7.PubMedCrossRefGoogle Scholar
  16. 16.
    Lamarca A, Hubner RA, Ryder WD, Valle JW. Second-line chemotherapy in advanced biliary cancer: a systematic review. Ann Oncol. 2014;25(12):2328–38.PubMedCrossRefGoogle Scholar
  17. 17.
    Walter T, Horgan AM, McNamara M, McKeever L, Min T, Hedley D, et al. Feasibility and benefits of second-line chemotherapy in advanced biliary tract cancer: a large retrospective study. Eur J Cancer. 2013;49(2):329–35.PubMedCrossRefGoogle Scholar
  18. 18.
    Mansour JC, Aloia TA, Crane CH, Heimbach JK, Nagino M, Vauthey J-N. Hilar cholangiocarcinoma: expert consensus statement. HPB. 2015;17(8):691–9.PubMedPubMedCentralCrossRefGoogle Scholar
  19. 19.
    Mavros MN, Economopoulos KP, Alexiou VG, Pawlik TM. Treatment and prognosis for patients with intrahepatic cholangiocarcinoma: systematic review and meta-analysis. JAMA Surg. 2014;149(6):565–74.CrossRefGoogle Scholar
  20. 20.
    Takada T, Amano H, Yasuda H, Nimura Y, Matsushiro T, Kato H, et al. Is postoperative adjuvant chemotherapy useful for gallbladder carcinoma? A phase III multicenter prospective randomized controlled trial in patients with resected pancreaticobiliary carcinoma. Cancer. 2002;95(8):1685–95.PubMedCrossRefGoogle Scholar
  21. 21.
    Neoptolemos JP, Moore MJ, Cox TF, Valle JW, Palmer DH, McDonald AC, et al. Effect of adjuvant chemotherapy with fluorouracil plus folinic acid or gemcitabine vs observation on survival in patients with resected periampullary adenocarcinoma: the ESPAC-3 periampullary cancer randomized trial. JAMA. 2012;308(2):147–56.CrossRefGoogle Scholar
  22. 22.
    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
  23. 23.
    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 Off J Am Soc Clin Oncol. 2015;33(24):2617–22.CrossRefGoogle Scholar
  24. 24.
    Stein A, Arnold D, Bridgewater J, Goldstein D, Jensen LH, Klümpen H-J, et al. Adjuvant chemotherapy with gemcitabine and cisplatin compared to observation after curative intent resection of cholangiocarcinoma and muscle invasive gallbladder carcinoma (ACTICCA-1 trial)—a randomized, multidisciplinary, multinational phase III trial. BMC Cancer. 2015;15:564. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4520064/PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    Andersen JB. Molecular pathogenesis of intrahepatic cholangiocarcinoma. J Hepatobiliary Pancreat Sci. 2015;22(2):101–13.PubMedCrossRefGoogle Scholar
  26. 26.
    Yoo KH, Kim NKD, Kwon WI, Lee C, Kim SY, Jang J, et al. Genomic alterations in biliary tract cancer using targeted sequencing. Transl Oncol. 2016;9(3):173.PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    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(12):e115383. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4275227/PubMedPubMedCentralCrossRefGoogle Scholar
  28. 28.
    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.PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Lee H, Ross JS. The potential role of comprehensive genomic profiling to guide targeted therapy for patients with biliary cancer. Therap Adv Gastroenterol. 2017;10(6):507–20.  https://doi.org/10.1177/1756283X17698090.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Jain A, Javle M. Molecular profiling of biliary tract cancer: a target rich disease. J Gastrointest Oncol. 2016;7(5):797.PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    Jain A, Kwong LN, Javle M. Genomic profiling of biliary tract cancers and implications for clinical practice. Curr Treat Options in Oncol. 2016;17(11):58.CrossRefGoogle Scholar
  32. 32.
    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(5):403–8.PubMedCrossRefGoogle Scholar
  33. 33.
    Fisher SB, Fisher KE, Maithel SK. Molecular targeted therapy for biliary tract malignancy: defining the target. Hepatobiliary Surg Nutr. 2012;1(1):53.PubMedPubMedCentralGoogle Scholar
  34. 34.
    Sirica AE. Role of ErbB family receptor tyrosine kinases in intrahepatic cholangiocarcinoma. World J Gastroenterol. 2008;14(46):7033.PubMedPubMedCentralCrossRefGoogle Scholar
  35. 35.
    Merla A, Liu KG, Rajdev L. Targeted therapy in biliary tract cancers. Curr Treat Options in Oncol. 2015;16(10):48.CrossRefGoogle Scholar
  36. 36.
    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.PubMedCrossRefGoogle Scholar
  37. 37.
    Nakamura H, Arai Y, Totoki Y, Shirota T, Elzawahry A, Kato M, et al. Genomic spectra of biliary tract cancer. Nat Genet. 2015;47(9):1003–10.PubMedCrossRefGoogle Scholar
  38. 38.
    Malka D, Cervera P, Foulon S, Trarbach T, de la Fouchardière 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.PubMedCrossRefGoogle Scholar
  39. 39.
    Chen L-T, Chen J-S, Chao Y, Tsai C-S, Shan Y-S, Hsu C, et al. KRAS mutation status-stratified randomized phase II trial of GEMOX with and without cetuximab in advanced biliary tract cancer (ABTC): the TCOG T1210 trial. J Clin Oncol. 2013;31(Suppl; abstr):4018. http://meetinglibrary.asco.org/content/116810-132Google Scholar
  40. 40.
    Lee J, Park SH, Chang H-M, 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.PubMedCrossRefGoogle Scholar
  41. 41.
    Leone F, Marino D, Cereda S, Filippi R, Belli C, Spadi R, et al. Panitumumab in combination with gemcitabine and oxaliplatin does not prolong survival in wild-type KRAS advanced biliary tract cancer: a randomized phase 2 trial (Vecti-BIL study). Cancer. 2016;122(4):574–81.PubMedCrossRefGoogle Scholar
  42. 42.
    Yokoyama M, Ohnishi H, Ohtsuka K, Matsushima S, Ohkura Y, Furuse J, et al. KRAS mutation as a potential prognostic biomarker of biliary tract cancers. Jpn Clin Med. 2016;7:33–9.PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    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(24):3838–47.PubMedCrossRefGoogle Scholar
  44. 44.
    Chen JS, Hsu C, Chiang NJ, Tsai CS, Tsou HH, Huang SF, et al. A KRAS mutation status-stratified randomized phase II trial of gemcitabine and oxaliplatin alone or in combination with cetuximab in advanced biliary tract cancer. Ann Oncol. 2015;26(5):943–9.PubMedCrossRefGoogle Scholar
  45. 45.
    Kiguchi K, Carbajal S, Chan K, Beltrán L, Ruffino L, Shen J, et al. Constitutive expression of ErbB-2 in gallbladder epithelium results in development of adenocarcinoma. Cancer Res. 2001;61(19):6971–6.PubMedGoogle Scholar
  46. 46.
    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. https://www-ncbi-nlm-nih-gov.proxy1.lib.tju.edu/pmc/articles/PMC4469402/PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    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.PubMedCrossRefGoogle Scholar
  48. 48.
    Ramanathan RK, Belani CP, Singh DA, Tanaka M, Lenz H-J, 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.PubMedCrossRefGoogle Scholar
  49. 49.
    Javle MM, Hainsworth JD, Swanton C, Burris HA, Kurzrock R, Sweeney C, et al. Pertuzumab + trastuzumab for HER2-positive metastatic biliary cancer: preliminary data from MyPathway. J Clin Oncol. 2017;35(Suppl 4S; abstract):402. http://meetinglibrary.asco.org/content/176131-195CrossRefGoogle Scholar
  50. 50.
    Chiang N-J, Hsu C, Chen J-S, Tsou H-H, Shen Y-Y, Chao Y, et al. Expression levels of ROS1/ALK/c-MET and therapeutic efficacy of cetuximab plus chemotherapy in advanced biliary tract cancer. Sci Rep. 2016;6:25369. https://www-ncbi-nlm-nih-gov.proxy1.lib.tju.edu/pmc/articles/PMC4853728/PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    Goel S, Duda DG, Xu L, Munn LL, Boucher Y, Fukumura D, et al. Normalization of the vasculature for treatment of cancer and other diseases. Physiol Rev. 2011;91(3):1071–121.PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Oyasiji T, Zhang J, Kuvshinoff B, Iyer R, Hochwald SN. Molecular targets in biliary carcinogenesis and implications for therapy. Oncologist. 2015;20(7):742.PubMedPubMedCentralCrossRefGoogle 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.PubMedCrossRefGoogle Scholar
  54. 54.
    Iyer RV, Groman A, Ma WW, Malhotra U, Iancu D, Grande C, et al. Gemcitabine (G), capecitabine (C) and bevacizumab (BV) in patients with advanced biliary cancers (ABC): final results of a multicenter phase II study. J Clin Oncol. 2015;33(Suppl; abstr):4078. http://meetinglibrary.asco.org/content/148921-156Google Scholar
  55. 55.
    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.PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    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.PubMedCrossRefGoogle Scholar
  57. 57.
    El-Khoueiry AB, Rankin C, Siegel AB, Iqbal S, Gong I-Y, 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.PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    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.PubMedCrossRefGoogle Scholar
  59. 59.
    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.PubMedPubMedCentralCrossRefGoogle Scholar
  60. 60.
    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.PubMedCrossRefGoogle Scholar
  61. 61.
    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.PubMedCrossRefGoogle Scholar
  62. 62.
    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.PubMedPubMedCentralCrossRefGoogle Scholar
  63. 63.
    Lambrechts D, Lenz H-J, de Haas S, Carmeliet P, Scherer SJ. Markers of response for the antiangiogenic agent bevacizumab. J Clin Oncol. 2013;31(9):1219–30.PubMedCrossRefGoogle Scholar
  64. 64.
    Ang C. Role of the fibroblast growth factor receptor axis in cholangiocarcinoma. J Gastroenterol Hepatol. 2015;30(7):1116–22.PubMedCrossRefGoogle Scholar
  65. 65.
    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.PubMedCrossRefGoogle Scholar
  66. 66.
    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.PubMedPubMedCentralCrossRefGoogle Scholar
  67. 67.
    Javle MM, Shroff RT, Zhu A, Sadeghi S, Choo S, Borad MJ, et al. A phase 2 study of BGJ398 in patients (pts) with advanced or metastatic FGFR-altered cholangiocarcinoma (CCA) who failed or are intolerant to platinum-based chemotherapy. J Clin Oncol. 2016;34(Suppl 4S; abstr):335. http://meetinglibrary.asco.org/content/159420-173CrossRefGoogle Scholar
  68. 68.
    Plummer R, Madi A, Jeffels M, Richly H, Nokay B, Rubin S, et al. A phase I study of pazopanib in combination with gemcitabine in patients with advanced solid tumors. Cancer Chemother Pharmacol. 2013;71(1):93–101.PubMedCrossRefGoogle Scholar
  69. 69.
    Gudernova I, Vesela I, Balek L, Buchtova M, Dosedelova H, Kunova M, et al. Multikinase activity of fibroblast growth factor receptor (FGFR) inhibitors SU5402, PD173074, AZD1480, AZD4547 and BGJ398 compromises the use of small chemicals targeting FGFR catalytic activity for therapy of short-stature syndromes. Hum Mol Genet. 2016;25(1):9–23.PubMedCrossRefGoogle Scholar
  70. 70.
    Phase I study determining the safety and tolerability of combination therapy with pazopanib, a VEGFR/PDGFR/Raf inhibitor, and GSK1120212, a MEK inhibitor, in advanced solid tumors enriched with patients with advanced differentiated thyroid cancer, soft tissue sarcoma, and cholangiocarcinoma—AdisInsight [Internet]. [cited 24 Apr 2017]. http://adisinsight.springer.com/trials/700205728#disabled
  71. 71.
    Dang L, Yen K, Attar EC. IDH mutations in cancer and progress toward development of targeted therapeutics. Ann Oncol. 2016;27(4):599–608.PubMedCrossRefGoogle Scholar
  72. 72.
    Fujii T, Khawaja MR, DiNardo CD, Atkins JT, Janku F. Targeting isocitrate dehydrogenase (IDH) in cancer. Discov Med. 2016;21(117):373–80.PubMedGoogle Scholar
  73. 73.
    Saha SK, Parachoniak CA, Ghanta KS, Fitamant J, Ross KN, Najem MS, et al. Mutant IDH inhibits HNF-4α to block hepatocyte differentiation and promote biliary cancer. Nature. 2014;513(7516):110–4.PubMedPubMedCentralCrossRefGoogle Scholar
  74. 74.
    Borger DR, Tanabe KK, Fan KC, Lopez HU, Fantin VR, Straley KS, et al. Frequent mutation of isocitrate dehydrogenase (IDH)1 and IDH2 in cholangiocarcinoma identified through broad-based tumor genotyping. Oncologist. 2012;17(1):72–9.PubMedCrossRefGoogle Scholar
  75. 75.
    Pharmaceuticals A. Agios announces data from dose-escalation phase 1 study of AG-120 in patients with IDH1 mutant positive advanced solid tumors [Internet]. GlobeNewswire News Room. 2015 [cited 25 Apr 2017]. http://globenewswire.com/news-release/2015/11/08/784897/10155627/en/Agios-Announces-Data-from-Dose-Escalation-Phase-1-Study-of-AG-120-in-Patients-with-IDH1-Mutant-Positive-Advanced-Solid-Tumors.html
  76. 76.
    Yen KE, Bittinger MA, Su SM, Fantin VR. Cancer-associated IDH mutations: biomarker and therapeutic opportunities. Oncogene. 2010;29(49):6409–17.PubMedCrossRefGoogle Scholar
  77. 77.
    Organ SL, Tsao M-S. An overview of the c-MET signaling pathway. Ther Adv Med Oncol. 2011;3(1 Suppl):S7–19.PubMedPubMedCentralCrossRefGoogle Scholar
  78. 78.
    Socoteanu MP, Mott F, Alpini G, Frankel AE. c-Met targeted therapy of cholangiocarcinoma. World J Gastroenterol. 2008;14(19):2990.PubMedPubMedCentralCrossRefGoogle Scholar
  79. 79.
    Miyamoto M, Ojima H, Iwasaki M, Shimizu H, Kokubu A, Hiraoka N, et al. Prognostic significance of overexpression of c-Met oncoprotein in cholangiocarcinoma. Br J Cancer. 2011;105(1):131–8.PubMedPubMedCentralCrossRefGoogle Scholar
  80. 80.
  81. 81.
    Goyal L, Zheng H, Yurgelun MB, Abrams TA, Allen JN, Cleary JM, et al. A phase 2 and biomarker study of cabozantinib in patients with advanced cholangiocarcinoma. Cancer. 2017;123(11):1979–88.PubMedPubMedCentralCrossRefGoogle Scholar
  82. 82.
    Sama AR, Denlinger CS, Vogel A, He AR, Bousmans N, Zhang W, et al. Gemcitabine and cisplatin plus ramucirumab or merestinib or placebo in first-line treatment for advanced or metastatic biliary tract cancer: a double-blind, randomized phase II trial. J Clin Oncol. 2017;35(Suppl 4S; abstract):TPS509. http://meetinglibrary.asco.org/content/176544-195CrossRefGoogle Scholar
  83. 83.
    Zhang Y, Du Z, Zhang M. Biomarker development in MET-targeted therapy. Oncotarget. 2016;7(24):37370–89.PubMedPubMedCentralGoogle Scholar
  84. 84.
    Roberts PJ, Der CJ. Targeting the Raf-MEK-ERK mitogen-activated protein kinase cascade for the treatment of cancer. Oncogene. 2007;26(22):3291–310.PubMedCrossRefGoogle Scholar
  85. 85.
    McArthur G. Exploring the pathway: the RAS/RAF/MEK/ERK pathway in cancer: combination therapies and overcoming feedback [Internet]. ASCO annual meeting. 2015 [cited 27 Apr 2017]. https://am.asco.org/exploring-pathway-rasrafmekerkpathway-cancer-combination-therapies-and-overcoming-feedback
  86. 86.
    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.PubMedPubMedCentralCrossRefGoogle Scholar
  87. 87.
    Bekaii-Saab T, Phelps MA, Li X, Saji M, Goff L, Kauh JSW, et al. Multi-institutional phase II study of selumetinib in patients with metastatic biliary cancers. J Clin Oncol Off J Am Soc Clin Oncol. 2011;29(17):2357–63.CrossRefGoogle Scholar
  88. 88.
    Bridgewater J, Lopes A, Beare S, Duggan M, Lee D, Ricamara M, et al. A phase 1b study of Selumetinib in combination with cisplatin and gemcitabine in advanced or metastatic biliary tract cancer: the ABC-04 study. BMC Cancer. 2016;16:153.PubMedPubMedCentralCrossRefGoogle Scholar
  89. 89.
    Lowery MA, O’Reilly EM, Harding JJ, Salehi E, Hollywood E, Bradley M, et al. A phase I trial of binimetinib in combination with gemcitabine (G) and cisplatin (C) patients (pts) with untreated advanced biliary cancer (ABC). J Clin Oncol. 2015;33(Suppl; abstr):e15125. http://meetinglibrary.asco.org/content/152744-156Google Scholar
  90. 90.
    Lowery MA, O’Reilly EM, Harding JJ, Yu KH, Cercek A, Hollywood E, et al. A phase I/II trial of MEK162 in combination with gemcitabine (G) and cisplatin (C) for patients (pts) with untreated advanced biliary cancer (ABC). J Clin Oncol. 2017;35(Suppl 4S; abstract):290. http://meetinglibrary.asco.org/content/177293-195CrossRefGoogle Scholar
  91. 91.
    Yuan TL, Cantley LC. PI3K pathway alterations in cancer: variations on a theme. Oncogene. 2008;27(41):5497–510.PubMedPubMedCentralCrossRefGoogle Scholar
  92. 92.
    Courtney KD, Corcoran RB, Engelman JA. The PI3K pathway as drug target in human cancer. J Clin Oncol. 2010;28(6):1075–83.PubMedPubMedCentralCrossRefGoogle Scholar
  93. 93.
    Lunardi A, Webster KA, Papa A, Padmani B, Clohessy JG, Bronson RT, et al. Role of aberrant PI3K pathway activation in gallbladder tumorigenesis. Oncotarget. 2014;5(4):894–900.PubMedPubMedCentralCrossRefGoogle Scholar
  94. 94.
    Marsh V, Davies EJ, Williams GT, Clarke AR. PTEN loss and KRAS activation cooperate in murine biliary tract malignancies. J Pathol. 2013;230(2):165–73.PubMedCrossRefGoogle Scholar
  95. 95.
    Ando Y, Inada-Inoue M, Mitsuma A, Yoshino T, Ohtsu A, Suenaga N, et al. Phase I dose-escalation study of buparlisib (BKM120), an oral pan-class I PI3K inhibitor, in Japanese patients with advanced solid tumors. Cancer Sci. 2014;105(3):347–53.PubMedPubMedCentralCrossRefGoogle Scholar
  96. 96.
    Bendell JC, Rodon J, Burris HA, de Jonge M, Verweij J, Birle D, et al. Phase I, dose-escalation study of BKM120, an oral pan-class I PI3K inhibitor, in patients with advanced solid tumors. J Clin Oncol. 2012;30(3):282–90.PubMedCrossRefGoogle Scholar
  97. 97.
    Rodon J, Braña I, Siu LL, De Jonge MJ, Homji N, Mills D, et al. Phase I dose-escalation and -expansion study of buparlisib (BKM120), an oral pan-class I PI3K inhibitor, in patients with advanced solid tumors. Investig New Drugs. 2014;32(4):670–81.CrossRefGoogle Scholar
  98. 98.
    McRee AJ, Sanoff HK, Carlson C, Ivanova A, O’Neil BH. A phase I trial of mFOLFOX6 combined with the oral PI3K inhibitor BKM120 in patients with advanced refractory solid tumors. Investig New Drugs. 2015;33(6):1225–31.CrossRefGoogle Scholar
  99. 99.
    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.PubMedCrossRefGoogle Scholar
  100. 100.
    Yeung YH, Chionh FJM, Price TJ, Scott AM, Tran H, Fang G, et al. Phase II study of everolimus monotherapy as first-line treatment in advanced biliary tract cancer: RADichol. J Clin Oncol. 2014;32(Suppl; abstr):4101. http://meetinglibrary.asco.org/content/130951-144Google Scholar
  101. 101.
    Kim ST, Lee J, Park SH, Park JO, Park YS, Kang WK, et al. Prospective phase II trial of everolimus in PIK3CA amplification/mutation and/or PTEN loss patients with advanced solid tumors refractory to standard therapy. BMC Cancer. 2017;17:211.PubMedPubMedCentralCrossRefGoogle Scholar
  102. 102.
    Marks EI, Yee NS. Immunotherapeutic approaches in biliary tract carcinoma: current status and emerging strategies. World J Gastrointest Oncol. 2015;7(11):338.PubMedPubMedCentralCrossRefGoogle Scholar
  103. 103.
    Nakakubo Y, Miyamoto M, Cho Y, Hida Y, Oshikiri T, Suzuoki M, et al. Clinical significance of immune cell infiltration within gallbladder cancer. Br J Cancer. 2003;89(9):1736–42.PubMedPubMedCentralCrossRefGoogle Scholar
  104. 104.
    Goeppert B, Frauenschuh L, Zucknick M, Stenzinger A, Andrulis M, Klauschen F, et al. Prognostic impact of tumour-infiltrating immune cells on biliary tract cancer. Br J Cancer. 2013;109(10):2665–74.PubMedPubMedCentralCrossRefGoogle Scholar
  105. 105.
    Takagi S, Miyagawa S-I, Ichikawa E, Soeda J, Miwa S, Miyagawa Y, et al. Dendritic cells, T-cell infiltration, and grp94 expression in cholangiocellular carcinoma. Hum Pathol. 2004;35(7):881–6.PubMedCrossRefGoogle Scholar
  106. 106.
    Oshikiri T, Miyamoto M, Shichinohe T, Suzuoki M, Hiraoka K, Nakakubo Y, et al. Prognostic value of intratumoral CD8+ T lymphocyte in extrahepatic bile duct carcinoma as essential immune response. J Surg Oncol. 2003;84(4):224–8.PubMedCrossRefGoogle Scholar
  107. 107.
    Pauff JM, Goff LW. Current progress in immunotherapy for the treatment of biliary cancers. J Gastrointest Cancer. 2016;47(4):351–7.PubMedCrossRefGoogle Scholar
  108. 108.
    Lepisto AJ, Moser AJ, Zeh H, Lee K, Bartlett D, McKolanis JR, et al. A phase I/II study of a MUC1 peptide pulsed autologous dendritic cell vaccine as adjuvant therapy in patients with resected pancreatic and biliary tumors. Cancer Ther. 2008;6(B):955–64.PubMedPubMedCentralGoogle Scholar
  109. 109.
    Kobayashi M, Sakabe T, Abe H, Tanii M, Takahashi H, Chiba A, et al. Dendritic cell-based immunotherapy targeting synthesized peptides for advanced biliary tract cancer. J Gastrointest Surg. 2013;17(9):1609–17.PubMedCrossRefGoogle Scholar
  110. 110.
    Tran E, Turcotte S, Gros A, Robbins PF, Lu Y-C, Dudley ME, et al. Cancer immunotherapy based on mutation-specific CD4+ T cells in a patient with epithelial cancer. Science. 2014;344(6184):641–5.PubMedCrossRefGoogle Scholar
  111. 111.
    Shimizu K, Kotera Y, Aruga A, Takeshita N, Takasaki K, Yamamoto M. Clinical utilization of postoperative dendritic cell vaccine plus activated T-cell transfer in patients with intrahepatic cholangiocarcinoma. J Hepatobiliary Pancreat Sci. 2012;19(2):171–8.CrossRefGoogle Scholar
  112. 112.
    Bang YJ, Doi T, Braud FD, Piha-Paul S, Hollebecque A, Razak ARA, et al. 525 Safety and efficacy of pembrolizumab (MK-3475) in patients (pts) with advanced biliary tract cancer: interim results of KEYNOTE-028. Eur J Cancer. 2015;51:S112.CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2018

Authors and Affiliations

  1. 1.Sidney Kimmel Cancer CenterThomas Jefferson University HospitalhPhiladelphiaUSA
  2. 2.Rosenfeld Cancer Center at Abington Jefferson HealthAbingtonUSA
  3. 3.Department of Medical Oncology, Sidney Kimmel Cancer CenterThomas Jefferson University HospitalPhiladelphiaUSA

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