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Digestive Diseases and Sciences
Erschienen in: Digestive Diseases and Sciences 4/2019

05.03.2019 | Review

Biomarkers: What Role Do They Play (If Any) for Diagnosis, Prognosis and Tumor Response Prediction for Hepatocellular Carcinoma?

verfasst von: James J. Harding, Danny N. Khalil, Ghassan K. Abou-Alfa

Erschienen in: Digestive Diseases and Sciences | Ausgabe 4/2019

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Abstract

Background

Hepatocellular carcinoma (HCC) is a common illness that affects patients worldwide. The disease remains poorly understood though several recent advances have increased the understanding of HCC biology and treatment.

Methods

A literature review was conducted to understand the role of biomarkers in HCC clinical practice and highlight areas of critical investigation.

Results

Candidate biomarkers may include differential alterations in HCC genomics, epigenomics, gene expression and transcriptomic profiles, protein expression, cellular composition of the microenvironment, and vasculature. To date no circulating or tumor diagnostic markers have been established in this disease. Likewise, prognostication is currently adjudicated by clinicopathologic features and it remains unclear if the incorporation of any biomarkers may help enhance the prognostic understanding following curative intents like surgery, transplant, and select regional therapy or palliative treatment including embolization or systemic therapy. Predictive biomarkers are investigational and are under evaluation for molecular pathways like TOR, MET, VEGFA, and FGF19. Tumoral genomics, HLA allele diversity and tumoral immune activation as predictive markers for immune checkpoint inhibitors are key focuses of ongoing research.

Conclusions

Diagnostic, prognostic, and predictive tumor and circulating biomarkers for HCC have not been defined though several markers have been proposed to guide patient care.
Literatur
1.
Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68:394–424.CrossRefPubMed
2.
GK A-A, WJ, M L, et al. Liver and Bile Duct Cancer. 6th ed: Philadelphia, 2018.
3.
Mazzaferro V, Regalia E, Doci R, et al. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med. 1996;334:693–699.CrossRefPubMed
4.
Brown KT, Do RK, Gonen M, et al. Randomized trial of hepatic artery embolization for hepatocellular carcinoma using doxorubicin-eluting microspheres compared with embolization with microspheres alone. J Clin Oncol. 2016;34:2046–2053.CrossRefPubMedPubMedCentral
5.
Vilgrain V, Pereira H, Assenat E, et al. Efficacy and safety of selective internal radiotherapy with yttrium-90 resin microspheres compared with sorafenib in locally advanced and inoperable hepatocellular carcinoma (SARAH): an open-label randomised controlled phase 3 trial. Lancet Oncol. 2017;18:1624–1636.CrossRefPubMed
6.
Harding JJ, Abou-Alfa GK. Treating advanced hepatocellular carcinoma: how to get out of first gear. Cancer. 2014;120:3122–3130.CrossRefPubMed
7.
Benson AB 3rd, D’Angelica MI, Abbott DE, et al. NCCN guidelines insights: hepatobiliary cancers, version 1.2017. J Natl Compr Cancer Netw. 2017;15:563–573.CrossRef
8.
Marrero JA, Kulik LM, Sirlin CB, et al. Diagnosis, staging, and management of hepatocellular carcinoma: 2018 practice guidance by the American association for the study of liver diseases. Hepatology. 2018;68:723–750.CrossRefPubMed
9.
Llovet JM, Ricci S, Mazzaferro V, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359:378–390.CrossRefPubMed
10.
Kudo M, Finn RS, Qin S, et al. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial. Lancet. 2018;391:1163–1173.CrossRefPubMed
11.
Bruix J, Qin S, Merle P, et al. Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2017;389:56–66.CrossRefPubMed
12.
Abou-Alfa GK, Meyer T, Cheng AL, et al. Cabozantinib in patients with advanced and progressing hepatocellular carcinoma. N Engl J Med. 2018;379:54–63.CrossRefPubMedPubMedCentral
13.
Zhu AX, Kang Y-K, Yen C-J, et al. REACH-2: a randomized, double-blind, placebo-controlled phase 3 study of ramucirumab versus placebo as second-line treatment in patients with advanced hepatocellular carcinoma (HCC) and elevated baseline alpha-fetoprotein (AFP) following first-line sorafenib. J Clin Oncol. 2018;36:4003.CrossRef
14.
Zhu AX, Park JO, Ryoo BY, 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.CrossRefPubMed
15.
El-Khoueiry AB, Sangro B, Yau T, et al. Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial. Lancet. 2017;389:2492–2502.CrossRefPubMedPubMedCentral
16.
Zhu AX, Finn RS, Edeline J, et al. Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224): a non-randomised, open-label phase 2 trial. Lancet Oncol. 2018;19:940–952.CrossRefPubMed
17.
Hayes DF, Bast RC, Desch CE, et al. Tumor marker utility grading system: a framework to evaluate clinical utility of tumor markers. J Natl Cancer Inst. 1996;88:1456–1466.CrossRefPubMed
18.
Sauerbrei W, Taube SE, McShane LM, Cavenagh MM, Altman DG. Reporting recommendations for tumor marker prognostic studies (REMARK): an abridged explanation and elaboration. J Natl Cancer Inst. 2018;110:803–811.CrossRefPubMedPubMedCentral
19.
Cancer Genome Atlas Research Network. Electronic address wbe, Cancer Genome Atlas Research N. Comprehensive and integrative genomic characterization of hepatocellular carcinoma. Cell. 2017;169:1327–1341 e1323.CrossRef
20.
21.
22.
Xu RH, Wei W, Krawczyk M, et al. Circulating tumour DNA methylation markers for diagnosis and prognosis of hepatocellular carcinoma. Nat Mater. 2017;16:1155–1161.CrossRefPubMed
23.
Wu H, Tao J, Li X, et al. MicroRNA-206 prevents the pathogenesis of hepatocellular carcinoma by modulating expression of met proto-oncogene and cyclin-dependent kinase 6 in mice. Hepatology. 2017;66:1952–1967.CrossRefPubMed
24.
Jiang L, Cheng Q, Zhang BH, Zhang MZ. Circulating microRNAs as biomarkers in hepatocellular carcinoma screening: a validation set from China. Medicine (Baltimore). 2015;94:e603.CrossRef
25.
Lee JS, Chu IS, Heo J, et al. Classification and prediction of survival in hepatocellular carcinoma by gene expression profiling. Hepatology. 2004;40:667–676.CrossRefPubMed
26.
Hoshida Y, Nijman SM, Kobayashi M, et al. Integrative transcriptome analysis reveals common molecular subclasses of human hepatocellular carcinoma. Cancer Res. 2009;69:7385–7392.CrossRefPubMedPubMedCentral
27.
Lee JS, Thorgeirsson SS. Genome-scale profiling of gene expression in hepatocellular carcinoma: classification, survival prediction, and identification of therapeutic targets. Gastroenterology. 2004;127:S51–S55.CrossRefPubMed
28.
Sia D, Jiao Y, Martinez-Quetglas I, et al. Identification of an immune-specific class of hepatocellular carcinoma, based on molecular features. Gastroenterology. 2017;153:812–826.CrossRefPubMed
29.
Yang XR, Xu Y, Yu B, et al. High expression levels of putative hepatic stem/progenitor cell biomarkers related to tumour angiogenesis and poor prognosis of hepatocellular carcinoma. Gut. 2010;59:953–962.CrossRefPubMed
30.
Kuboki S, Shimizu H, Mitsuhashi N, et al. Angiopoietin-2 levels in the hepatic vein as a useful predictor of tumor invasiveness and prognosis in human hepatocellular carcinoma. J Gastroenterol Hepatol. 2008;23:e157–e164.CrossRefPubMed
31.
Hagel M, Miduturu C, Sheets M, et al. First selective small molecule inhibitor of FGFR4 for the treatment of hepatocellular carcinomas with an activated fgfr4 signaling pathway. Cancer Discov. 2015;5:424–437.CrossRefPubMed
32.
Joshi JJ, Coffey H, Corcoran E, et al. H3B-6527 is a potent and selective inhibitor of FGFR4 in FGF19-driven hepatocellular carcinoma. Cancer Res. 2017;77:6999–7013.CrossRefPubMed
33.
Durazo FA, Blatt LM, Corey WG, et al. Des-gamma-carboxyprothrombin, alpha-fetoprotein and AFP-L3 in patients with chronic hepatitis, cirrhosis and hepatocellular carcinoma. J Gastroenterol Hepatol. 2008;23:1541–1548.CrossRefPubMed
34.
Marrero JA, Su GL, Wei W, et al. Des-gamma carboxyprothrombin can differentiate hepatocellular carcinoma from nonmalignant chronic liver disease in american patients. Hepatology. 2003;37:1114–1121.CrossRefPubMed
35.
Nakamura S, Nouso K, Sakaguchi K, et al. Sensitivity and specificity of des-gamma-carboxy prothrombin for diagnosis of patients with hepatocellular carcinomas varies according to tumor size. Am J Gastroenterol. 2006;101:2038–2043.CrossRefPubMed
36.
Harding JJ, El Dika I, Abou-Alfa GK. Immunotherapy in hepatocellular carcinoma: primed to make a difference? Cancer. 2016;122:367–377.CrossRefPubMed
37.
El-Assal ON, Yamanoi A, Soda Y, et al. Clinical significance of microvessel density and vascular endothelial growth factor expression in hepatocellular carcinoma and surrounding liver: possible involvement of vascular endothelial growth factor in the angiogenesis of cirrhotic liver. Hepatology. 1998;27:1554–1562.CrossRefPubMed
38.
39.
Ronot M, Fouque O, Esvan M, Lebigot J, Aube C, Vilgrain V. Comparison of the accuracy of AASLD and LI-RADS criteria for the non-invasive diagnosis of HCC smaller than 3 cm. J Hepatol. 2018;68(4):715–723.CrossRefPubMed
40.
41.
Trevisani F, D’Intino PE, Morselli-Labate AM, et al. Serum alpha-fetoprotein for diagnosis of hepatocellular carcinoma in patients with chronic liver disease: influence of HBsAg and anti-HCV status. J Hepatol. 2001;34:570–575.CrossRefPubMed
42.
Soresi M, Magliarisi C, Campagna P, et al. Usefulness of alpha-fetoprotein in the diagnosis of hepatocellular carcinoma. Anticancer Res. 2003;23:1747–1753.PubMed
43.
Farinati F, Marino D, De Giorgio M, et al. Diagnostic and prognostic role of alpha-fetoprotein in hepatocellular carcinoma: both or neither? Am J Gastroenterol. 2006;101:524–532.CrossRefPubMed
44.
Song P, Bao H, Yu Y, et al. Comprehensive profiling of metastasis-related proteins in paired hepatocellular carcinoma cells with different metastasis potentials. Proteom Clin Appl. 2009;3:841–852.CrossRef
45.
Cohen JD, Li L, Wang Y, et al. Detection and localization of surgically resectable cancers with a multi-analyte blood test. Science. 2018;359:926–930.CrossRefPubMedPubMedCentral
46.
Jiang P, Sun K, Tong YK, et al. Preferred end coordinates and somatic variants as signatures of circulating tumor DNA associated with hepatocellular carcinoma. Proc Natl Acad Sci USA. 2018;115:E10925–E10933.CrossRefPubMedPubMedCentral
47.
Kuhn P, Keating SM, Baxter GT, Thomas K, Kolatkar A, Sigman CC. Lessons learned: transfer of the high-definition circulating tumor cell assay platform to development as a commercialized clinical assay platform. Clin Pharmacol Ther. 2017;102:777–785.CrossRefPubMed
48.
Sun C, Liao W, Deng Z, et al. The diagnostic value of assays for circulating tumor cells in hepatocellular carcinoma: a meta-analysis. Medicine (Baltimore). 2017;96:e7513.CrossRef
49.
Kalinich M, Bhan I, Kwan TT, et al. An RNA-based signature enables high specificity detection of circulating tumor cells in hepatocellular carcinoma. Proc Natl Acad Sci USA. 2017;114:1123–1128.CrossRefPubMedPubMedCentral
50.
Huitzil-Melendez FD, Capanu M, O’Reilly EM, et al. Advanced hepatocellular carcinoma: which staging systems best predict prognosis? J Clin Oncol. 2010;28:2889–2895.CrossRefPubMedPubMedCentral
51.
52.
Kan Z, Zheng H, Liu X, et al. Whole-genome sequencing identifies recurrent mutations in hepatocellular carcinoma. Genome Res. 2013;23:1422–1433.CrossRefPubMedPubMedCentral
53.
Schulze K, Imbeaud S, Letouze E, et al. Exome sequencing of hepatocellular carcinomas identifies new mutational signatures and potential therapeutic targets. Nat Genet. 2015;47:505–511.CrossRefPubMedPubMedCentral
54.
Xie K, Xu L, Wu H, et al. OX40 expression in hepatocellular carcinoma is associated with a distinct immune microenvironment, specific mutation signature, and poor prognosis. Oncoimmunology. 2018;7:e1404214.CrossRefPubMedPubMedCentral
55.
Kim HD, Song GW, Park S, et al. Association between expression level of PD1 by tumor-infiltrating CD8(+) T cells and features of hepatocellular carcinoma. Gastroenterology. 2018;155:1936–1950.CrossRefPubMed
56.
Zhou ZQ, Tong DN, Guan J, et al. Follicular helper T cell exhaustion induced by PD-L1 expression in hepatocellular carcinoma results in impaired cytokine expression and B cell help, and is associated with advanced tumor stages. Am J Transl Res. 2016;8:2926–2936.PubMedPubMedCentral
57.
Zheng C, Zheng L, Yoo JK, et al. Landscape of infiltrating T cells in liver cancer revealed by single-cell sequencing. Cell. 2017;169(–):1342–1356-e1316.CrossRefPubMed
58.
Llovet JM, Pena CE, Lathia CD, et al. Plasma biomarkers as predictors of outcome in patients with advanced hepatocellular carcinoma. Clin Cancer Res. 2012;18:2290–2300.CrossRefPubMed
59.
Santoro A, Rimassa L, Borbath I, et al. Tivantinib for second-line treatment of advanced hepatocellular carcinoma: a randomised, placebo-controlled phase 2 study. Lancet Oncol. 2013;14:55–63.CrossRefPubMed
60.
Rimassa L, Assenat E, Peck-Radosavljevic M, et al. Tivantinib for second-line treatment of MET-high, advanced hepatocellular carcinoma (METIV-HCC): a final analysis of a phase 3, randomised, placebo-controlled study. Lancet Oncol. 2018;19:682–693.CrossRefPubMed
61.
Sun YF, Xu Y, Yang XR, et al. Circulating stem cell-like epithelial cell adhesion molecule-positive tumor cells indicate poor prognosis of hepatocellular carcinoma after curative resection. Hepatology. 2013;57:1458–1468.CrossRefPubMed
62.
Bruix J, Cheng AL, Meinhardt G, Nakajima K, De Sanctis Y, Llovet J. Prognostic factors and predictors of sorafenib benefit in patients with hepatocellular carcinoma: analysis of two phase III studies. J Hepatol. 2017;67:999–1008.CrossRefPubMed
63.
Nomura F, Ohnishi K, Tanabe Y. Clinical features and prognosis of hepatocellular carcinoma with reference to serum alpha-fetoprotein levels. Analysis of 606 patients. Cancer. 1989;64:1700–1707.CrossRefPubMed
64.
Hashimoto K, Ikeda Y, Korenaga D, et al. The impact of preoperative serum C-reactive protein on the prognosis of patients with hepatocellular carcinoma. Cancer. 2005;103:1856–1864.CrossRefPubMed
65.
Liu YB, Ying J, Kuang SJ, et al. Elevated preoperative serum Hs-CRP level as a prognostic factor in patients who underwent resection for hepatocellular carcinoma. Medicine (Baltimore). 2015;94:e2209.CrossRef
66.
Zhang S, Ma X, Zhu C, Liu L, Wang G, Yuan X. The role of myeloid-derived suppressor cells in patients with solid tumors: a meta-analysis. PLoS ONe. 2016;11:e0164514.CrossRefPubMedPubMedCentral
67.
Chakravarty D, Gao J, Phillips SM, et al. OncoKB: a precision oncology knowledge base. JCO Precis Oncol. 2017;1:1–16.CrossRef
68.
Zehir A, Benayed R, Shah RH, et al. Mutational landscape of metastatic cancer revealed from prospective clinical sequencing of 10,000 patients. Nat Med. 2017;23:703–713.CrossRefPubMedPubMedCentral
69.
Paik PK, Drilon A, Fan PD, et al. Response to MET inhibitors in patients with stage IV lung adenocarcinomas harboring MET mutations causing exon 14 skipping. Cancer Discov. 2015;5:842–849.CrossRefPubMedPubMedCentral
70.
Horwitz E, Stein I, Andreozzi M, et al. Human and mouse VEGFA-amplified hepatocellular carcinomas are highly sensitive to sorafenib treatment. Cancer Discov. 2014;4:730–743.CrossRefPubMed
71.
Rizvi NA, Hellmann MD, Snyder A, et al. Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science. 2015;348:124–128.CrossRefPubMedPubMedCentral
72.
Patel SP, Kurzrock R. PD-L1 expression as a predictive biomarker in cancer immunotherapy. Mol Cancer Ther. 2015;14:847–856.CrossRefPubMed
73.
Zaretsky JM, Garcia-Diaz A, Shin DS, et al. Mutations associated with acquired resistance to PD-1 blockade in melanoma. N Engl J Med. 2016;375:819–829.CrossRefPubMedPubMedCentral
74.
Daud AI, Loo K, Pauli ML, et al. Tumor immune profiling predicts response to anti-PD-1 therapy in human melanoma. J Clin Invest. 2016;126:3447–3452.CrossRefPubMedPubMedCentral
75.
Chowell D, Morris LGT, Grigg CM, et al. Patient HLA class I genotype influences cancer response to checkpoint blockade immunotherapy. Science. 2018;359:582–587.CrossRefPubMed
76.
Gopalakrishnan V, Spencer CN, Nezi L, et al. Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients. Science. 2018;359:97–103.CrossRefPubMed
77.
78.
Li G, Kim YJ, Broxmeyer HE. Macrophage colony-stimulating factor drives cord blood monocyte differentiation into IL-10(high)IL-12absent dendritic cells with tolerogenic potential. J Immunol. 2005;174:4706–4717.CrossRefPubMed
79.
Rutella S, Bonanno G, Procoli A, et al. Hepatocyte growth factor favors monocyte differentiation into regulatory interleukin (IL)-10++IL-12low/neg accessory cells with dendritic-cell features. Blood. 2006;108:218–227.CrossRefPubMed
80.
Xia G, He J, Leventhal JR. Ex vivo-expanded natural CD4+ CD25+ regulatory T cells synergize with host T-cell depletion to promote long-term survival of allografts. Am J Transplant. 2008;8:298–306.CrossRefPubMed
81.
Steinman RM, Hawiger D, Nussenzweig MC. Tolerogenic dendritic cells. Annu Rev Immunol. 2003;21:685–711.CrossRefPubMed
Metadaten
Titel
Biomarkers: What Role Do They Play (If Any) for Diagnosis, Prognosis and Tumor Response Prediction for Hepatocellular Carcinoma?
verfasst von
James J. Harding
Danny N. Khalil
Ghassan K. Abou-Alfa
Publikationsdatum
05.03.2019
Verlag
Springer US
Erschienen in
Digestive Diseases and Sciences / Ausgabe 4/2019
Print ISSN: 0163-2116
Elektronische ISSN: 1573-2568
DOI
https://doi.org/10.1007/s10620-019-05517-6

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