Personalized therapy for hepatocellular carcinoma: Where are we now?

Cancer Treatment Reviews

Volumn 45, Issue , 2016, Pages 77-86

  Chan, Stephen L ^a,b   Wong, Alissa M ^a   Lee, Kirsty ^b   Wong, Nathalie ^a   Chan, Allen K C ^a,b  

^a CHINESE UNIVERSITY OF HONG KONG   (Hong Kong)

^b CHINESE UNIVERSITY OF HONG KONG   (Hong Kong)

Author keywords

Biomarker; Drug; Liver neoplasm; Targeted therapy

Indexed keywords

ANTINEOPLASTIC AGENT; EVEROLIMUS; FIBROBLAST GROWTH FACTOR RECEPTOR 4 INHIBITOR; HISTONE DEACETYLASE INHIBITOR; RAMUCIRUMAB; SCATTER FACTOR RECEPTOR INHIBITOR; SORAFENIB; TUMOR MARKER; UNCLASSIFIED DRUG;

ADVANCED CANCER; BIOPSY TECHNIQUE; CANCER CHEMOTHERAPY; CANCER EPIDEMIOLOGY; CANCER PATIENT; CANCER RESEARCH; CHROMOSOME ABERRATION; CHROMOSOME ANALYSIS; CLINICAL TRIAL (TOPIC); DNA SEQUENCE; DRUG EFFICACY; DRUG RESEARCH; DRUG SCREENING; EPIGENETICS; HUMAN; LIVER BIOPSY; LIVER CELL CARCINOMA; METHODOLOGY; MOLECULAR GENETICS; MOLECULARLY TARGETED THERAPY; NONHUMAN; PERSONALIZED MEDICINE; POINT MUTATION; RETROSPECTIVE STUDY; REVIEW; TREATMENT RESPONSE; BLOOD; CANCER STAGING; CARCINOMA, HEPATOCELLULAR; CLASSIFICATION; DRUG DEVELOPMENT; DRUG EFFECTS; GENETIC SCREENING; GENETICS; LIVER NEOPLASMS; PATHOLOGY; PROCEDURES; SIGNAL TRANSDUCTION;

ANTINEOPLASTIC AGENTS; BIOMARKERS, TUMOR; CARCINOMA, HEPATOCELLULAR; DRUG DISCOVERY; GENETIC TESTING; HUMANS; LIVER NEOPLASMS; NEOPLASM STAGING; PRECISION MEDICINE; SIGNAL TRANSDUCTION;

EID: 84960957421     PISSN: 03057372     EISSN: 15321967     Source Type: Journal    
DOI: 10.1016/j.ctrv.2016.02.008     Document Type: Review

References (131)

1. Torre L.A., Bray F., Siegel R.L., Ferlay J., Lortet-Tieulent J., Jemal A. Global cancer statistics, 2012. CA Cancer J Clin 2015, 65:87-108.
2. Mittal S., El-Serag H.B. Epidemiology of hepatocellular carcinoma: consider the population. J Clin Gastroenterol 2013, 47:S2-S6.
3. Davila J.A., El-Serag H.B. The rising incidence of hepatocellular carcinoma in the United States: an update. Gastroenterology 2012, 142:S914.
4. Chan S.L., Wong V.W., Qin S., Chan H.L. Infection and cancer: the case of hepatitis B. J Clin Oncol 2016, 34:83-90.
5. Ni Y.H., Chang M.H., Wu J.F., Hsu H.Y., Chen H.L., Chen D.S. Minimization of hepatitis B infection by a 25-year universal vaccination program. J Hepatol 2012, 57:730-735.
6. Organization WH. Immunization, vaccines and biologicals. Hepatitis B http://www.who.int/immunization/monitoring_surveillance/burden/vpd/surveillance:type/passive/hepatitis/en/.
7. Kanwal F., Hoang T., Kramer J.R., Asch S.M., Goetz M.B., Zeringue A., et al. Increasing prevalence of HCC and cirrhosis in patients with chronic hepatitis C virus infection. Gastroenterology 2011, 140(1182-1188):e1181.
8. Chalasani N., Younossi Z., Lavine J.E., Diehl A.M., Brunt E.M., Cusi K., et al. The diagnosis and management of non-alcoholic fatty liver disease: practice Guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association. Hepatology 2012, 55:2005-2023.
9. Farrell G.C., Larter C.Z. Nonalcoholic fatty liver disease: from steatosis to cirrhosis. Hepatology 2006, 43:S99-S112.
10. Farrell G.C., Wong V.W., Chitturi S. NAFLD in Asia-as common and important as in the West. Nat Rev Gastroenterol Hepatol 2013, 10:307-318.
11. Rinella M.E. Nonalcoholic fatty liver disease: a systematic review. JAMA 2015, 313:2263-2273.
12. Global, regional, and national age-sex specific all-cause and cause-specific mortality for 240 causes of death, 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet 2015; 385: p. 117-171.
13. Chan S.L., Mo F.K., Johnson P.J., Liem G.S., Chan T.C., Poon M.C., et al. Prospective validation of the Chinese University Prognostic Index and comparison with other staging systems for hepatocellular carcinoma in an Asian population. J Gastroenterol Hepatol 2011, 26:340-347.
14. Chan S.L., Mo F.K., Wong V.W., Liem G.S., Wong G.L., Chan V.T., et al. Use of antiviral therapy in surveillance: impact on outcome of hepatitis B-related hepatocellular carcinoma. Liver Int 2012, 32:271-278.
15. Wong J.S., Wong G.L., Tsoi K.K., Wong V.W., Cheung S.Y., Chong C.N., et al. Meta-analysis: the efficacy of anti-viral therapy in prevention of recurrence after curative treatment of chronic hepatitis B-related hepatocellular carcinoma. Aliment Pharmacol Ther 2011, 33:1104-1112.
16. Kumar S., Jacobson I.M. Antiviral therapy with nucleotide polymerase inhibitors for chronic hepatitis C. J Hepatol 2014, 61:S91-S97.
17. Wong V.W., Chan S.L., Mo F., Chan T.C., Loong H.H., Wong G.L., et al. Clinical scoring system to predict hepatocellular carcinoma in chronic hepatitis B carriers. J Clin Oncol 2010, 28:1660-1665.
18. Yang H.I., Yuen M.F., Chan H.L., Han K.H., Chen P.J., Kim D.Y., et al. Risk estimation for hepatocellular carcinoma in chronic hepatitis B (REACH-B): development and validation of a predictive score. Lancet Oncol 2011, 12:568-574.
19. Tamaki N., Kurosaki M., Matsuda S., Muraoka M., Yasui Y., Suzuki S., et al. Non-invasive prediction of hepatocellular carcinoma development using serum fibrosis marker in chronic hepatitis C patients. J Gastroenterol 2014, 49:1495-1503.
20. Chan S.L., Mok T., Ma B.B. Management of hepatocellular carcinoma: beyond sorafenib. Curr Oncol Rep 2012, 14:257-266.
21. Yeo W., Mok T.S., Zee B., Leung T.W., Lai P.B., Lau W.Y., et al. A randomized phase III study of doxorubicin versus cisplatin/interferon alpha-2b/doxorubicin/fluorouracil (PIAF) combination chemotherapy for unresectable hepatocellular carcinoma. J Natl Cancer Inst 2005, 19(97):1532-1538.
22. Bruix J., Sherman M. Management of hepatocellular carcinoma. Hepatology 2005, 42:1208-1236.
23. Llovet J.M., Ricci S., Mazzaferro V., Hilgard P., Gane E., Blanc J.F., et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 2008, 359:378-390.
24. Cheng A.L., Kang Y.K., Chen Z., Tsao C.J., Qin S., Kim J.S., et al. Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial. Lancet Oncol 2009, 10:25-34.
25. Chan S.L., Yeo W. Development of systemic therapy for hepatocellular carcinoma at 2013: updates and insights. World J Gastroenterol 2014, 20:3135-3145.
26. El-Khoueiry A.B., Melero I., Crocenzi T.S., Welling T.H., Yau T.C., Yeo W., et al. Phase I/II safety and antitumor activity of nivolumab in patients with advanced hepatocellular carcinoma (HCC): CA209-040. J Clin Oncol 2015, 33(Suppl.). abstr LBA101.
27. Sangro B., Gomez-Martin C., de la Mata M., Inarrairaegui M., Garralda E., Barrera P., et al. A clinical trial of CTLA-4 blockade with tremelimumab in patients with hepatocellular carcinoma and chronic hepatitis C. J Hepatol 2013, 59:81-88.
28. Cheng A.L., Kang Y.K., Lin D.Y., Park J.W., Kudo M., Qin S., et al. Sunitinib versus sorafenib in advanced hepatocellular cancer: results of a randomized phase III trial. J Clin Oncol 2013, 31:4067-4075.
29. Llovet J.M., Decaens T., Raoul J.L., Boucher E., Kudo M., Chang C., et al. Brivanib in patients with advanced hepatocellular carcinoma who were intolerant to sorafenib or for whom sorafenib failed: results from the randomized phase III BRISK-PS study. J Clin Oncol 2013, 31:3509-3516.
30. Reig M., Torres F., Rodriguez-Lope C., Forner A., LLarch N., et al. Early dermatologic adverse events predict better outcome in HCC patients treated with sorafenib. J Hepatol 2014, 61:318-324.
31. Reig M., Rimola J., Torres F., Darnell A., Rodriguez-Lope C., Forner A., et al. Postprogression survival of patients with advanced hepatocellular carcinoma: rationale for second-line trial design. Hepatology 2013, 58:2023-2031.
32. Zucman-Rossi J., Villanueva A., Nault J.C., Llovet J.M. Genetic landscape and biomarkers of hepatocellular carcinoma. Gastroenterology 2015, 149(1226-1239):e1224.
33. Llovet J.M., Villanueva A., Lachenmayer A., Finn R.S. Advances in targeted therapies for hepatocellular carcinoma in the genomic era. Nat Rev Clin Oncol 2015, 12:436.
34. Friemel J., Rechsteiner M., Frick L., Bohm F., Struckmann K., Egger M., et al. Intratumor heterogeneity in hepatocellular carcinoma. Clin Cancer Res 2015, 21:1951-1961.
35. Saeki R., Nagai H., Kaneko S., Unoura M., Yamanaka N., Okamoto E., et al. Intratumoral genomic heterogeneity in human hepatocellular carcinoma detected by restriction landmark genomic scanning. J Hepatol 2000, 33:99-105.
36. Schulze K., Imbeaud S., Letouze E., Alexandrov L.B., Calderaro J., Rebouissou S., et al. Exome sequencing of hepatocellular carcinomas identifies new mutational signatures and potential therapeutic targets. Nat Genet 2015, 47:505-511.
37. Totoki Y., Tatsuno K., Covington K.R., Ueda H., Creighton C.J., Kato M., et al. Trans-ancestry mutational landscape of hepatocellular carcinoma genomes. Nat Genet 2014, 46:1267-1273.
38. Ahn S.M., Jang S.J., Shim J.H., Kim D., Hong S.M., Sung C.O., et al. Genomic portrait of resectable hepatocellular carcinomas: implications of RB1 and FGF19 aberrations for patient stratification. Hepatology 2014, 60:1972-1982.
39. Kan Z., Zheng H., Liu X., Li S., Barber T.D., Gong Z., et al. Whole-genome sequencing identifies recurrent mutations in hepatocellular carcinoma. Genome Res 2013, 23:1422-1433.
40. Alexandrov L.B., Nik-Zainal S., Wedge D.C., Aparicio S.A., Behjati S., Biankin A.V., et al. Signatures of mutational processes in human cancer. Nature 2013, 500:415-421.
41. Fujimoto A., Totoki Y., Abe T., Boroevich K.A., Hosoda F., Nguyen H.H., et al. Whole-genome sequencing of liver cancers identifies etiological influences on mutation patterns and recurrent mutations in chromatin regulators. Nat Genet 2012, 44:760-764.
42. Huang J., Deng Q., Wang Q., Li K.Y., Dai J.H., Li N., et al. Exome sequencing of hepatitis B virus-associated hepatocellular carcinoma. Nat Genet 2012, 44:1117-1121.
43. Tateishi R., Okanoue T., Fujiwara N., Okita K., Kiyosawa K., Omata M., et al. Clinical characteristics, treatment, and prognosis of non-B, non-C hepatocellular carcinoma: a large retrospective multicenter cohort study. J Gastroenterol 2015, 50:350-360.
44. Hashimoto E., Tokushige K. Hepatocellular carcinoma in non-alcoholic steatohepatitis: growing evidence of an epidemic?. Hepatol Res 2012, 42:1-14.
45. Oda K., Uto H., Mawatari S., Ido A. Clinical features of hepatocellular carcinoma associated with nonalcoholic fatty liver disease: a review of human studies. Clin J Gastroenterol 2015, 8:1-9.
46. Hill-Baskin A.E., Markiewski M.M., Buchner D.A., Shao H., DeSantis D., Hsiao G., et al. Diet-induced hepatocellular carcinoma in genetically predisposed mice. Hum Mol Genet 2009, 18:2975-2988.
47. Nakagawa H. Recent advances in mouse models of obesity- and nonalcoholic steatohepatitis-associated hepatocarcinogenesis. World J Hepatol 2015, 7:2110-2118.
48. Yu J., Shen J., Sun T.T., Zhang X., Wong N. Obesity, insulin resistance, NASH and hepatocellular carcinoma. Semin Cancer Biol 2013, 23:483-491.
49. Reid D.T., Eksteen B. Murine models provide insight to the development of non-alcoholic fatty liver disease. Nutr Res Rev 2015, 1-10.
50. Berkers C.R., Maddocks O.D., Cheung E.C., Mor I., Vousden K.H. Metabolic regulation by p53 family members. Cell Metab 2013, 18:617-633.
51. Liu H., Fergusson M.M., Wu J.J., Rovira I.I., Liu J., Gavrilova O., et al. Wnt signaling regulates hepatic metabolism. Sci Signal 2011, 4(ra6).
52. Sherwood V. WNT signaling: an emerging mediator of cancer cell metabolism?. Mol Cell Biol 2015, 35:2-10.
53. Monga S.P. Beta-catenin signaling and roles in liver homeostasis, injury, and tumorigenesis. Gastroenterology 2015, 148:1294-1310.
54. Vousden K.H., Ryan K.M. P53 and metabolism. Nat Rev Cancer 2009, 9:691-700.
55. Spratlin J.L., Cohen R.B., Eadens M., Gore L., Camidge D.R., Diab S., et al. Phase I pharmacologic and biologic study of ramucirumab (IMC-1121B), a fully human immunoglobulin G1 monoclonal antibody targeting the vascular endothelial growth factor receptor-2. J Clin Oncol 2010, 28:780-787.
56. Zhu A.X., Park J.O., Ryoo B.Y., Yen C.J., Poon R., Pastorelli D., et al. Ramucirumab versus placebo as second-line treatment in patients with advanced hepatocellular carcinoma following first-line therapy with sorafenib (REACH): a randomised, double-blind, multicentre, phase 3 trial. Lancet Oncol 2015, 16:859-870.
57. Chan S.L., Chan A.T., Yeo W. Role of alpha-fetoprotein in hepatocellular carcinoma: prognostication, treatment monitoring or both?. Future Oncol 2009, 5:889-899.
58. Hoshida Y., Nijman S.M., Kobayashi M., Chan J.A., Brunet J.P., Chiang D.Y., et al. Integrative transcriptome analysis reveals common molecular subclasses of human hepatocellular carcinoma. Cancer Res 2009, 69:7385-7392.
59. Shan Y.F., Huang Y.L., Xie Y.K., Tan Y.H., Chen B.C., Zhou M.T., et al. Angiogenesis and clinicopathologic characteristics in different hepatocellular carcinoma subtypes defined by EpCAM and alpha-fetoprotein expression status. Med Oncol 2011, 28:1012-1016.
60. Huang J., Zhang X., Tang Q., Zhang F., Li Y., Feng Z., et al. Prognostic significance and potential therapeutic target of VEGFR2 in hepatocellular carcinoma. J Clin Pathol 2011, 64:343-348.
61. Yamashita T., Forgues M., Wang W., Kim J.W., Ye Q., Jia H., et al. EpCAM and alpha-fetoprotein expression defines novel prognostic subtypes of hepatocellular carcinoma. Cancer Res 2008, 68:1451-1461.
62. Sahin F., Kannangai R., Adegbola O., Wang J., Su G., Torbenson M. MTOR and P70 S6 kinase expression in primary liver neoplasms. Clin Cancer Res 2004, 10:8421-8425.
63. Villanueva A., Chiang D.Y., Newell P., Peix J., Thung S., Alsinet C., et al. Pivotal role of mTOR signaling in hepatocellular carcinoma. Gastroenterology 2008, 135:1972-1983.
64. Yeo W., Chan S.L., Mok F.K., Chu C.M., Hui J.W., Tong J.H., et al. Phase I/II study of temsirolimus for patients with unresectable Hepatocellular Carcinoma (HCC)- a correlative study to explore potential biomarkers for response. BMC Cancer 2015, 15:395.
65. Schnitzbauer A.A., Zuelke C., Graeb C., Rochon J., Bilbao I., Burra P., et al. A prospective randomised, open-labeled, trial comparing sirolimus-containing versus mTOR-inhibitor-free immunosuppression in patients undergoing liver transplantation for hepatocellular carcinoma. BMC Cancer 2010, 10:190.
66. Huynh H., Chow K.H., Soo K.C., Toh H.C., Choo S.P., Foo K.F., et al. RAD001 (everolimus) inhibits tumour growth in xenograft models of human hepatocellular carcinoma. J Cell Mol Med 2009, 13:1371-1380.
67. Finn R.S., Poon R.T., Yau T., Klümpen H.J., Chen L.T., Kang Y.K., et al. Phase I study investigating everolimus combined with sorafenib in patients with advanced hepatocellular carcinoma. J Hepatol 2013, 59:1271-1277.
68. Shiah H.S., Chen C.Y., Dai C.Y., Hsiao C.F., Lin Y.J., Su W.C., et al. Randomised clinical trial: comparison of two everolimus dosing schedules in patients with advanced hepatocellular carcinoma. Aliment Pharmacol Ther 2013, 37:62-73.
69. Zhu A.X., Abrams T.A., Miksad R., Blaszkowsky L.S., Meyerhardt J.A., Zheng H., et al. Phase 1/2 study of everolimus in advanced hepatocellular carcinoma. Cancer 2011, 117:5094-5102.
70. Zhu A.X., Kudo M., Assenat E., Cattan S., Kang Y.K., Lim H.Y., et al. Effect of everolimus on survival in advanced hepatocellular carcinoma after failure of sorafenib: the EVOLVE-1 randomized clinical trial. JAMA 2014, 312:57-67.
71. Huynh H., Hao H.X., Chan S.L., Chen D., Ong R., Soo K.C., et al. Loss of tuberous sclerosis complex 2 (TSC2) is frequent in hepatocellular carcinoma and predicts response to mTORC1 inhibitor everolimus. Mol Cancer Ther 2015, 14:1224-1235.
72. Yang B., Guo M., Herman J.G., Clark D.P. Aberrant promoter methylation profiles of tumor suppressor genes in hepatocellular carcinoma. Am J Pathol 2003, 163:1101-1107.
73. Zhong S., Tang M.W., Yeo W., Liu C., Lo Y.M., Johnson P.J. Silencing of GSTP1 gene by CpG island DNA hypermethylation in HBV-associated hepatocellular carcinomas. Clin Cancer Res 2002, 8:1087-1092.
74. Coradini D., Speranza A. Histone deacetylase inhibitors for treatment of hepatocellular carcinoma. Acta Pharmacol Sin 2005, 26:1025-1033.
75. Chiba T., Yokosuka O., Arai M., Tada M., Fukai K., Imazeki F., et al. Identification of genes up-regulated by histone deacetylase inhibition with cDNA microarray and exploration of epigenetic alterations on hepatoma cells. J Hepatol 2004, 41:436-445.
76. Ma B.B., Sung F., Tao Q., Poon F.F., Lui V.W., Yeo W., et al. The preclinical activity of the histone deacetylase inhibitor PXD101 (belinostat) in hepatocellular carcinoma cell lines. Invest New Drugs 2010, 28:107-114.
77. Plumb J.A., Finn P.W., Williams R.J., Bandara M.J., Romero M.R., Watkins C.J., et al. Pharmacodynamic response and inhibition of growth of human tumor xenografts by the novel histone deacetylase inhibitor PXD101. Mol Cancer Ther 2003, 2:721-728.
78. Khan O., Fotheringham S., Wood V., Stimson L., Zhang C., Pezzella F., et al. HR23B is a biomarker for tumor sensitivity to HDAC inhibitor-based therapy. Proc Natl Acad Sci USA 2010, 107:6532-6537.
79. New M., Olzscha H., Liu G., Khan O., Stimson L., McGouran J., et al. A regulatory circuit that involves HR23B and HDAC6 governs the biological response to HDAC inhibitors. Cell Death Differ 2013.
80. Fotheringham S., Epping M.T., Stimson L., Khan O., Wood V., Pezzella F., et al. Genome-wide loss-of-function screen reveals an important role for the proteasome in HDAC inhibitor-induced apoptosis. Cancer Cell 2009, 15:57-66.
81. Yeo W., Chung H.C., Chan S.L., Wang L.Z., Lim R., Picus J., et al. Epigenetic therapy using belinostat for patients with unresectable hepatocellular carcinoma: a multicenter phase I/II study with biomarker and pharmacokinetic analysis of tumors from patients in the Mayo Phase II Consortium and the Cancer Therapeutics Research Group. J Clin Oncol 2012, 30:3361-3367.
82. Pediaditakis P., Lopez-Talavera J.C., Petersen B., Monga S.P., Michalopoulos G.K. The processing and utilization of hepatocyte growth factor/scatter factor following partial hepatectomy in the rat. Hepatology 2001, 34:688-693.
83. Gherardi E., Birchmeier W., Birchmeier C., Vande Woude G. Targeting MET in cancer: rationale and progress. Nat Rev Cancer 2012, 12:89-103.
84. Huh C.G., Factor V.M., Sanchez A., Uchida K., Conner E.A., Thorgeirsson S.S. Hepatocyte growth factor/c-met signaling pathway is required for efficient liver regeneration and repair. Proc Natl Acad Sci USA 2004, 101:4477-4482.
85. Giordano S., Columbano A. Met as a therapeutic target in HCC: facts and hopes. J Hepatol 2014, 60:442-452.
86. Qian F., Engst S., Yamaguchi K., Yu P., Won K.A., Mock L., et al. Inhibition of tumor cell growth, invasion, and metastasis by EXEL-2880 (XL880, GSK1363089), a novel inhibitor of HGF and VEGF receptor tyrosine kinases. Cancer Res 2009, 69:8009-8016.
87. Yakes F.M., Chen J., Tan J., Yamaguchi K., Shi Y., Yu P., et al. Cabozantinib (XL184), a novel MET and VEGFR2 inhibitor, simultaneously suppresses metastasis, angiogenesis, and tumor growth. Mol Cancer Ther 2011, 10:2298-2308.
88. You H., Ding W., Dang H., Jiang Y., Rountree C.B. c-Met represents a potential therapeutic target for personalized treatment in hepatocellular carcinoma. Hepatology 2011, 54:879-889.
89. Koeppen H., Rost S., Yauch R.L. Developing biomarkers to predict benefit from HGF/MET pathway inhibitors. J Pathol 2014, 232:210-218.
90. Chan S.L., Chan A.W., Yeo W. Novel therapeutic targets and predictive markers for hepatocellular carcinoma. Expert Opin Ther Targets 2015, 19:973-983.
91. Santoro A., Rimassa L., Borbath I., Daniele B., Salvagni S., Van Laethem J.L., et al. Tivantinib for second-line treatment of advanced hepatocellular carcinoma: a randomised, placebo-controlled phase 2 study. Lancet Oncol 2013, 14:55-63.
92. Kir S., Kliewer S.A., Mangelsdorf D.J. Roles of FGF19 in liver metabolism. Cold Spring Harb Symp Quant Biol 2011, 76:139-144.
93. Lin B.C., Wang M., Blackmore C., Desnoyers L.R. Liver-specific activities of FGF19 require Klotho beta. J Biol Chem 2007, 282:27277-27284.
94. Goetz R., Beenken A., Ibrahimi O.A., Kalinina J., Olsen S.K., Eliseenkova A.V., et al. Molecular insights into the Klotho-dependent, endocrine mode of action of fibroblast growth factor 19 subfamily members. Mol Cell Biol 2007, 27:3417-3428.
95. Liu W.Y., Xie D.M., Zhu G.Q., Huang G.Q., Lin Y.Q., Wang L.R., et al. Targeting fibroblast growth factor 19 in liver disease: a potential biomarker and therapeutic target. Expert Opin Ther Targets 2015, 19:675-685.
96. Miura S., Mitsuhashi N., Shimizu H., Kimura F., Yoshidome H., Otsuka M., et al. Fibroblast growth factor 19 expression correlates with tumor progression and poorer prognosis of hepatocellular carcinoma. BMC Cancer 2012, 12:56.
97. Zhao H., Lv F., Liang G., Huang X., Wu G., Zhang W., et al. FGF19 promotes epithelial-mesenchymal transition in hepatocellular carcinoma cells by modulating the GSK3beta/beta-catenin signaling cascade via FGFR4 activation. Oncotarget 2015.
98. Nicholes K., Guillet S., Tomlinson E., Hillan K., Wright B., Frantz G.D., et al. A mouse model of hepatocellular carcinoma: ectopic expression of fibroblast growth factor 19 in skeletal muscle of transgenic mice. Am J Pathol 2002, 160:2295-2307.
99. French D.M., Lin B.C., Wang M., Adams C., Shek T., Hotzel K., et al. Targeting FGFR4 inhibits hepatocellular carcinoma in preclinical mouse models. PLoS One 2012, 7:e36713.
100. Sawey E.T., Chanrion M., Cai C., Wu G., Zhang J., Zender L., et al. Identification of a therapeutic strategy targeting amplified FGF19 in liver cancer by oncogenomic screening. Cancer Cell 2011, 19:347-358.
101. Guagnano V., Kauffmann A., Wohrle S., Stamm C., Ito M., Barys L., et al. FGFR genetic alterations predict for sensitivity to NVP-BGJ398, a selective pan-FGFR inhibitor. Cancer Discov 2012, 2:1118-1133.
102. Schmidt B., Wei L., DePeralta D.K., Hoshida Y., Tan P., Sun X., et al. Molecular subclasses of hepatocellular carcinoma predict sensitivity to fibroblast growth factor receptor inhibition. Int J Cancer 2015.
103. Chan K.C.A. Scanning for cancer genomic changes in plasma: toward an era of personalized blood-based tumor markers. Clin Chem 2013, 59:1553-1555.
104. Chan K.C.A., Chan A.T., Leung S.F., Pang J.C., Wang A.Y., Tong J.H., et al. Investigation into the origin and tumoral mass correlation of plasma Epstein-Barr virus DNA in nasopharyngeal carcinoma. Clin Chem 2005, 51:2192-2195.
105. Chan K.C.A., Zhang J., Chan A.T.C., Lei K.I.K., Leung S.F., Chan L.Y.S., et al. Molecular characterization of circulating EBV DNA in the plasma of nasopharyngeal carcinoma and lymphoma patients. Cancer Res 2003, 63:2028-2032.
106. Jiang P., Chan C.W., Chan K.C.A., Cheng S.H., Wong J., Wong V.W., et al. Lengthening and shortening of plasma DNA in hepatocellular carcinoma patients. Proc Natl Acad Sci USA 2015, 112:E1317-E1325.
107. Yung T.K.F., Chan K.C.A., Mok T.S.K., Tong J., To K.F., Lo Y.M.D. Single-molecule detection of epidermal growth factor receptor mutations in plasma by microfluidics digital PCR in non-small cell lung cancer patients. Clin Cancer Res 2009, 15:2076-2084.
108. Chan K.C.A., Jiang P., Zheng Y.W., Liao G.J., Sun H., Wong J., et al. Cancer genome scanning in plasma: detection of tumor-associated copy number aberrations, single-nucleotide variants, and tumoral heterogeneity by massively parallel sequencing. Clin Chem 2013, 59:211-224.
109. Chan K.C.A., Jiang P., Chan C.W.M., Wong J., Hui E.P., Chan A.T.C., et al. Noninvasive detection of cancer-associated genomewide hypomethylation and copy number aberrations by plasma DNA bisulfite sequencing. Proc Natl Acad Sci USA 2013, 110:18761-18768.
110. Chan K.C.A., Lai P.B.S., Mok T.S.K., Chan H.L., Ding C., Yeung S.W., et al. Quantitative analysis of circulating methylated DNA as a biomarker for hepatocellular carcinoma. Clin Chem 2008, 54:1528-1536.
111. Murtaza M., Dawson S.J., Tsui D.W., Gale D., Forshew T., Piskorz A.M., et al. Non-invasive analysis of acquired resistance to cancer therapy by sequencing of plasma DNA. Nature 2013, 497:108-112.
112. Mok T.S., Lee K., Leung L. Targeting epidermal growth factor receptor in the management of lung cancer. Semin Oncol 2014, 41:101-109.
113. Forshew T., Murtaza M., Parkinson C., Gale D., Tsui D.W., Kaper F., et al. Noninvasive identification and monitoring of cancer mutations by targeted deep sequencing of plasma DNA. Sci Transl Med 2012, 4(136ra168).
114. Garcia-Murillas I., Schiavon G., Weigelt B., Ng C., Hrebien S., Cutts R.J., et al. Mutation tracking in circulating tumor DNA predicts relapse in early breast cancer. Sci Transl Med 2015, 7(302ra133).
115. Sun K., Jiang P., Chan K.C.A., Wong J., Cheng Y.K., Liang R.H., et al. Plasma DNA tissue mapping by genome-wide methylation sequencing for noninvasive prenatal, cancer, and transplantation assessments. Proc Natl Acad Sci USA 2015, 112:E5503-E5512.
116. Wong I.H., Lo Y.M.D., Zhang J., Liew C.T., Ng M.H., Wong N., et al. Detection of aberrant p16 methylation in the plasma and serum of liver cancer patients. Cancer Res 1999, 59:71-73.
117. McBride D.J., Orpana A.K., Sotiriou C., Joensuu H., Stephens P.J., Mudie L.J., et al. Use of cancer-specific genomic rearrangements to quantify disease burden in plasma from patients with solid tumors. Genes Chromosomes Cancer 2010, 49:1062-1069.
118. Leary R.J., Kinde I., Diehl F., Schmidt K., Clouser C., Duncan C., et al. Development of personalized tumor biomarkers using massively parallel sequencing. Sci Transl Med 2010, 2(20ra14).
119. Leary R.J., Sausen M., Kinde I., Papadopoulos N., Carpten J.D., Craig D., et al. Detection of chromosomal alterations in the circulation of cancer patients with whole-genome sequencing. Sci Transl Med 2012, 4(162ra154).
120. Xu H., Zhu X., Xu Z., Hu Y., Bo S., Xing T., et al. Non-invasive analysis of genomic copy number variation in patients with hepatocellular carcinoma by next generation DNA sequencing. J Cancer 2015, 6:247-253.
121. Kim E.S., Herbst R.S., Wistuba I.I., Lee J.J., Blumenschein G.R., Tsao A., et al. The BATTLE trial: personalizing therapy for lung cancer. Cancer Discov 2011, 1:44-53.
122. Johnson P.J., Qin S., Park J.W., Poon R.T., Raoul J.L., Philip P.A., et al. Brivanib versus sorafenib as first-line therapy in patients with unresectable, advanced hepatocellular carcinoma: results from the randomized phase III BRISK-FL study. J Clin Oncol 2013, 31:3517-3524.
123. Cainap C., Qin S., Huang W.T., Chung I.J., Pan H., Cheng Y., et al. Linifanib versus Sorafenib in patients with advanced hepatocellular carcinoma: results of a randomized phase III trial. J Clin Oncol 2015, 33:172-179.
124. Cheng A.L., Thongprasert S., Lim H.Y., Sukeepaisarnjaroen W., Yang T.S., Wu C.C., et al. Phase II study of front-line dovitinib (TKI258) versus sorafenib in patients (Pts) with advanced hepatocellular carcinoma (HCC). J Clin Oncol 2015, 33.
125. Hsu C., Yang T.S., Huo T.I., Hsieh R.K., Yu C.W., Hwang W.S., et al. Vandetanib in patients with inoperable hepatocellular carcinoma: a phase II, randomized, double-blind, placebo-controlled study. J Hepatol 2012, 56:1097-1103.
126. Cheng A.L., Yen C.J., Kim T.Y., Feng Y.H., Chao Y., Lin D.Y., et al. Efficacy and safety of nintedanib versus sorafenib in Asian patients with advanced hepatocellular carcinoma (HCC): a randomized phase II trial. J Clin Oncol 2015, 33.
127. Zhu A.X., Rosmorduc O., Evans T.R., Ross P.J., Santoro A., Carrilho F.J., et al. SEARCH: a phase III, randomized, double-blind, placebo-controlled trial of sorafenib plus erlotinib in patients with advanced hepatocellular carcinoma. J Clin Oncol 2015, 33:559-566.
128. Abou-Alfa G.K., Johnson P., Knox J.J., Capanu M., Davidenko I., Lacava J., et al. Doxorubicin plus sorafenib vs doxorubicin alone in patients with advanced hepatocellular carcinoma: a randomized trial. JAMA 2010, 304:2154-2160.
129. Kang Y.K., Yau T., Park J.W., Lim H.Y., Lee T.Y., Obi S., et al. Randomized phase II study of axitinib versus placebo plus best supportive care in second-line treatment of advanced hepatocellular carcinoma. Ann Oncol 2015, 26:2457-2463.
130. Yen C.J., Daniele B., Kudo M., Merie P., Park J.W., Ross P.J., et al. Randomized phase II trial of intravenous RO5137382/GC33 at 1600 mg every other week and placebo in previously treated patients with unresectable advanced hepatocellular carcinoma. J Clin Oncol 2014, 32(Suppl.). abstr 4102.
131. Cheng A.L., Kang Y.K., He A.R., Lim H.Y., Ryoo B.Y., Hung C.H., et al. Safety and efficacy of tigatuzumab plus sorafenib as first-line therapy in subjects with advanced hepatocellular carcinoma: a phase 2 randomized study. J Hepatol 2015, 63:896-904.