Promising Novel Biomarkers for Hepatocellular Carcinoma: Diagnostic and Prognostic Insights

References

• Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA. 2021;71(3):209–249. doi:10.3322/caac.21660
   Web of Science ®Google Scholar
• Colagrande S, Inghilesi AL, Aburas S, Taliani GG, Nardi C, Marra F. Challenges of advanced hepatocellular carcinoma. World J Gastroenterol. 2016;22(34):7645–7659. doi:10.3748/wjg.v22.i34.7645
   PubMed Web of Science ®Google Scholar
• Ronot M, Bouattour M, Wassermann J, et al. Alternative response criteria (Choi, European Association for the study of the liver, and modified Response Evaluation Criteria in Solid Tumors [RECIST]) versus RECIST 1.1 in patients with advanced hepatocellular carcinoma treated with sorafenib. Oncologist. 2014;19(4):394–402. doi:10.1634/theoncologist.2013-0114
   PubMed Web of Science ®Google Scholar
• 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(2):723–750. doi:10.1002/hep.29913
   PubMed Web of Science ®Google Scholar
• Galle PR, Forner A, Llovet JM, et al. EASL clinical practice guidelines: management of hepatocellular carcinoma. J Hepatol. 2018;69(1):182–236. doi:10.1016/j.jhep.2018.03.019
   PubMed Web of Science ®Google Scholar
• Finn RS, Qin S, Ikeda M, et al. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. N Engl J Med. 2020;382(20):1894–1905. doi:10.1056/NEJMoa1915745
   PubMed Web of Science ®Google Scholar
• Pfister D, Nunez NG, Pinyol R, et al. NASH limits anti-tumour surveillance in immunotherapy-treated HCC. Nature. 2021;592(7854). doi:10.1038/s41586-021-03362-0
   Web of Science ®Google Scholar
• Bruix J, Raoul JL, Sherman M, et al. Efficacy and safety of sorafenib in patients with advanced hepatocellular carcinoma: subanalyses of a phase III trial. J Hepatol. 2012;57(4):821–829. doi:10.1016/j.jhep.2012.06.014
   PubMed Web of Science ®Google Scholar
• Jackson R, Psarelli EE, Berhane S, Khan H, Johnson PJ. Impact of viral status on survival in patients receiving sorafenib for advanced hepatocellular cancer: a meta-analysis of randomized phase III trials. J Clin Oncol. 2017;35(6):622–628. doi:10.1200/JCO.2016.69.5197
   PubMed Web of Science ®Google Scholar
• Zhu AX, Kang YK, Yen CJ, et al. Ramucirumab after sorafenib in patients with advanced hepatocellular carcinoma and increased α-fetoprotein concentrations (REACH-2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2019;20(2):282–296. doi:10.1016/S1470-2045(18)30937-9
   PubMed Web of Science ®Google Scholar
• Pepe MS, Etzioni R, Feng Z, et al. Phases of biomarker development for early detection of cancer. JNCI. 2001;93(14):1054–1061. doi:10.1093/jnci/93.14.1054
   PubMed Web of Science ®Google Scholar
• Singal AG, Hoshida Y, Pinato DJ, et al. International Liver Cancer Association (ILCA) white paper on biomarker development for hepatocellular carcinoma. Gastroenterology. 2021;160(7):2572–2584. doi:10.1053/j.gastro.2021.01.233
   PubMed Web of Science ®Google Scholar
• Omata M, Cheng AL, Kokudo N, et al. Asia–Pacific clinical practice guidelines on the management of hepatocellular carcinoma: a 2017 update. Hepatol Int. 2017;11(4):317–370. doi:10.1007/s12072-017-9799-9
   PubMed Web of Science ®Google Scholar
• Singal AG, Pillai A, Tiro J. Early detection, curative treatment, and survival rates for hepatocellular carcinoma surveillance in patients with cirrhosis: a meta-analysis. PLoS Med. 2014;11(4):e1001624. doi:10.1371/journal.pmed.1001624
   PubMed Web of Science ®Google Scholar
• Singal A, Volk ML, Waljee A, et al. Meta-analysis: surveillance with ultrasound for early-stage hepatocellular carcinoma in patients with cirrhosis. Aliment Pharmacol Ther. 2009;30(1):37–47. doi:10.1111/j.1365-2036.2009.04014.x
   PubMed Web of Science ®Google Scholar
• Colli A, Fraquelli M, Casazza G, et al. Accuracy of ultrasonography, spiral CT, magnetic resonance, and alpha-fetoprotein in diagnosing hepatocellular carcinoma: a systematic review. Am J Gastroenterol. 2006;101(3):513–523. doi:10.1111/j.1572-0241.2006.00467.x
   PubMed Web of Science ®Google Scholar
• Kim JU, Shariff MIF, Crossey MME, et al. Hepatocellular carcinoma: review of disease and tumor biomarkers. World J Hepatol. 2016;8(10):471–484. doi:10.4254/wjh.v8.i10.471
   PubMed Web of Science ®Google Scholar
• Bader D, Riskin A, Vafsi O, et al. Alpha-fetoprotein in the early neonatal period—a large study and review of the literature. Clin Chim Acta. 2004;349(1):15–23. doi:10.1016/j.cccn.2004.06.020
   PubMed Web of Science ®Google Scholar
• Mizejewski GJ. Alpha-fetoprotein structure and function: relevance to isoforms, epitopes, and conformational variants. Exp Biol Med. 2001;226(5):377–408. doi:10.1177/153537020122600503
   PubMed Web of Science ®Google Scholar
• Wong RJ, Ahmed A, Gish RG. Elevated alpha-fetoprotein: differential diagnosis - hepatocellular carcinoma and other disorders. Clin Liver Dis. 2015;19(2):309–323. doi:10.1016/j.cld.2015.01.005
   PubMed Web of Science ®Google Scholar
• Shen WF, Zhong W, Xu F, et al. Clinicopathological and prognostic analysis of 429 patients with intrahepatic cholangiocarcinoma. World J Gastroenterol. 2009;15(47):5976–5982. doi:10.3748/wjg.15.5976
   PubMed Web of Science ®Google Scholar
• Adachi Y, Tsuchihashi J, Shiraishi N, Yasuda K, Etoh T, Kitano S. AFP-producing gastric carcinoma: multivariate analysis of prognostic factors in 270 patients. Oncology. 2003;65(2):95–101. doi:10.1159/000072332
   PubMed Web of Science ®Google Scholar
• Di Bisceglie AM, Sterling RK, Chung RT, et al. Serum alpha-fetoprotein levels in patients with advanced hepatitis C: results from the HALT-C trial. J Hepatol. 2005;43(3):434–441. doi:10.1016/j.jhep.2005.03.019
   PubMed Web of Science ®Google Scholar
• Piñero F, Dirchwolf M, Pessôa MG. Biomarkers in hepatocellular carcinoma: diagnosis, prognosis and treatment response assessment. Cells. 2020;9(6):E1370. doi:10.3390/cells9061370
   PubMed Web of Science ®Google Scholar
• Tzartzeva K, Obi J, Rich NE, et al. Surveillance imaging and alpha fetoprotein for early detection of hepatocellular carcinoma in patients with cirrhosis: a meta-analysis. Gastroenterology. 2018;154(6):1706–1718.e1. doi:10.1053/j.gastro.2018.01.064
   PubMed Web of Science ®Google Scholar
• Zhang BH, Yang BH, Tang ZY. Randomized controlled trial of screening for hepatocellular carcinoma. J Cancer Res Clin Oncol. 2004;130(7):417–422. doi:10.1007/s00432-004-0552-0
   PubMed Web of Science ®Google Scholar
• Chen JG, Parkin DM, Chen QG, et al. Screening for liver cancer: results of a randomised controlled trial in Qidong, China. J Med Screen. 2003;10(4):204–209. doi:10.1258/096914103771773320
   PubMed Web of Science ®Google Scholar
• Taketa K, Sekiya C, Namiki M, et al. Lectin-reactive profiles of alpha-fetoprotein characterizing hepatocellular carcinoma and related conditions. Gastroenterology. 1990;99(2):508–518. doi:10.1016/0016-5085(90)91034-4
   PubMed Web of Science ®Google Scholar
• Hanif H, Ali MJ, Susheela AT, et al. Update on the applications and limitations of alpha-fetoprotein for hepatocellular carcinoma. World J Gastroenterol. 2022;28(2):216–229. doi:10.3748/wjg.v28.i2.216
   PubMed Web of Science ®Google Scholar
• 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(5):1114–1121. doi:10.1053/jhep.2003.50195
   PubMed Web of Science ®Google Scholar
• Yu R, Tan Z, Xiang X, Dan Y, Deng G. Effectiveness of PIVKA-II in the detection of hepatocellular carcinoma based on real-world clinical data. BMC Cancer. 2017;17(1):608. doi:10.1186/s12885-017-3609-6
   PubMedGoogle Scholar
• Shiraki K, Takase K, Tameda Y, Hamada M, Kosaka Y, Nakano T. A clinical study of lectin-reactive alpha-fetoprotein as an early indicator of hepatocellular carcinoma in the follow-up of cirrhotic patients. Hepatology. 1995;22(3):802–807. doi:10.1002/hep.1840220317
   PubMed Web of Science ®Google Scholar
• Lok AS, Sterling RK, Everhart JE, et al. Des-gamma-carboxy prothrombin and alpha-fetoprotein as biomarkers for the early detection of hepatocellular carcinoma. Gastroenterology. 2010;138(2):493–502. doi:10.1053/j.gastro.2009.10.031
   PubMed Web of Science ®Google Scholar
• Choi J, Kim GA, Han S, Lee W, Chun S, Lim YS. Longitudinal assessment of three serum biomarkers to detect very early-stage hepatocellular carcinoma. Hepatology. 2019;69(5):1983–1994. doi:10.1002/hep.30233
   PubMed Web of Science ®Google Scholar
• Johnson PJ, Pirrie SJ, Cox TF, et al. The detection of hepatocellular carcinoma using a prospectively developed and validated model based on serological biomarkers. Cancer Epidemiol Biomarkers Prev. 2014;23(1):144–153. doi:10.1158/1055-9965.EPI-13-0870
   PubMed Web of Science ®Google Scholar
• Yang JD, Addissie BD, Mara KC, et al. GALAD score for hepatocellular carcinoma detection in comparison with liver ultrasound and proposal of GALADUS score. Cancer Epidemiol Biomarkers Prev. 2019;28(3):531–538. doi:10.1158/1055-9965.EPI-18-0281
   PubMed Web of Science ®Google Scholar
• Singal AG, Tayob N, Mehta A, et al. GALAD demonstrates high sensitivity for HCC surveillance in a cohort of patients with cirrhosis. Hepatology. 2022;75(3):541–549. doi:10.1002/hep.32185
   PubMed Web of Science ®Google Scholar
• Tayob N, Kanwal F, Alsarraj A, Hernaez R, El-Serag HB. The performance of AFP, AFP-3, DCP as biomarkers for detection of Hepatocellular Carcinoma (HCC): a phase 3 biomarker study in the United States. Clin Gastroenterol Hepatol. 2022;S1542–3565(22)00106–9. doi:10.1016/j.cgh.2022.01.047
   Web of Science ®Google Scholar
• Sherman M, Feld J, Yamada H, Mori Y, Janssen H. A randomized controlled trial of US vs US + biomarkers for the diagnosis of hepatocellular carcinoma: an interim report. J Hepatol. 2017;1:S13. doi:10.1016/S0168-8278(17)30288-X
   Google Scholar
• Debes JD, Romagnoli PA, Prieto J, et al. Serum biomarkers for the prediction of hepatocellular carcinoma. Cancers. 2021;13(7):1681. doi:10.3390/cancers13071681
   PubMed Web of Science ®Google Scholar
• Ye X, Li C, Zu X, et al. A large-scale multicenter study validates aldo-keto reductase family 1 member B10 as a prevalent serum marker for detection of hepatocellular carcinoma. Hepatology. 2019;69(6):2489–2501. doi:10.1002/hep.30519
   PubMed Web of Science ®Google Scholar
• Shen Q, Fan J, Yang XR, et al. Serum DKK1 as a protein biomarker for the diagnosis of hepatocellular carcinoma: a large-scale, multicentre study. Lancet Oncol. 2012;13(8):817–826. doi:10.1016/S1470-2045(12)70233-4
   PubMed Web of Science ®Google Scholar
• Xu D, Su C, Sun L, Gao Y, Li Y. Performance of serum glypican 3 in diagnosis of hepatocellular carcinoma: a meta-analysis. Ann Hepatol. 2019;18(1):58–67. doi:10.5604/01.3001.0012.7863
   PubMed Web of Science ®Google Scholar
• Z S, L M, Z X, et al. The diagnostic value of the combination of Golgi protein 73, glypican-3 and alpha-fetoprotein in hepatocellular carcinoma: a diagnostic meta-analysis. Ann Transl Med. 2020;8(8). doi:10.21037/atm.2020.02.89
   Web of Science ®Google Scholar
• Liu J, Dang H, Wang XW. The significance of intertumor and intratumor heterogeneity in liver cancer. Exp Mol Med. 2018;50(1):e416–e416. doi:10.1038/emm.2017.165
   PubMedGoogle Scholar
• Ahn JC, Teng PC, Chen PJ, et al. Detection of circulating tumor cells and their implications as a biomarker for diagnosis, prognostication, and therapeutic monitoring in hepatocellular carcinoma. Hepatology. 2021;73(1):422–436. doi:10.1002/hep.31165
   PubMed Web of Science ®Google Scholar
• Wu J, Hu S, Zhang L, et al. Tumor circulome in the liquid biopsies for cancer diagnosis and prognosis. Theranostics. 2020;10(10):4544–4556. doi:10.7150/thno.40532
   PubMed Web of Science ®Google Scholar
• Ye Q, Ling S, Zheng S, Xu X. Liquid biopsy in hepatocellular carcinoma: circulating tumor cells and circulating tumor DNA. Mol Cancer. 2019;18(1):114. doi:10.1186/s12943-019-1043-x
   PubMed Web of Science ®Google Scholar
• Wu X, Li J, Gassa A, et al. Circulating tumor DNA as an emerging liquid biopsy biomarker for early diagnosis and therapeutic monitoring in hepatocellular carcinoma. Int J Biol Sci. 2020;16(9):1551–1562. doi:10.7150/ijbs.44024
   PubMed Web of Science ®Google Scholar
• Tran NH, Kisiel J, Roberts LR. Using cell-free DNA for HCC surveillance and prognosis. JHEP Rep. 2021;3(4):100304. doi:10.1016/j.jhepr.2021.100304
   PubMedGoogle Scholar
• Yang B, Guo M, Herman JG, Clark DP. Aberrant promoter methylation profiles of tumor suppressor genes in hepatocellular carcinoma. Am J Pathol. 2003;163(3):1101–1107. doi:10.1016/S0002-9440(10)63469-4
   PubMed Web of Science ®Google Scholar
• Lewin J, Kottwitz D, Aoyama J, et al. Plasma cell free DNA methylation markers for hepatocellular carcinoma surveillance in patients with cirrhosis: a case control study. BMC Gastroenterol. 2021;21:136. doi:10.1186/s12876-021-01714-8
   PubMed Web of Science ®Google Scholar
• Chalasani NP, Porter K, Bhattacharya A, et al. Validation of a novel multitarget blood test shows high sensitivity to detect early stage hepatocellular carcinoma. Clin Gastroenterol Hepatol. 2022;20(1):173–182.e7. doi:10.1016/j.cgh.2021.08.010
   PubMed Web of Science ®Google Scholar
• Chalasani NP, Ramasubramanian TS, Bhattacharya A, et al. A novel blood-based panel of methylated DNA and protein markers for detection of early-stage hepatocellular carcinoma. Clin Gastroenterol Hepatol. 2021;19(12):2597–2605.e4. doi:10.1016/j.cgh.2020.08.065
   PubMed Web of Science ®Google Scholar
• Xu RH, Wei W, Krawczyk M, et al. Circulating tumour DNA methylation markers for diagnosis and prognosis of hepatocellular carcinoma. Nat Mater. 2017;16(11):1155–1161. doi:10.1038/nmat4997
   PubMed Web of Science ®Google Scholar
• Roy D, Taggart D, Zheng L, et al. Abstract 837: circulating cell-free DNA methylation assay: towards early detection of multiple cancer types. Cancer Res. 2019;79(13_Supplement):837. doi:10.1158/1538-7445.AM2019-837
   Web of Science ®Google Scholar
• Alix-Panabières C, Pantel K. Circulating tumor cells: liquid biopsy of cancer. Clin Chem. 2013;59(1):110–118. doi:10.1373/clinchem.2012.194258
   PubMed Web of Science ®Google Scholar
• Kelley RK, Magbanua MJM, Butler TM, et al. Circulating tumor cells in hepatocellular carcinoma: a pilot study of detection, enumeration, and next-generation sequencing in cases and controls. BMC Cancer. 2015;15(1):206. doi:10.1186/s12885-015-1195-z
   PubMedGoogle Scholar
• Schulze K, Gasch C, Staufer K, et al. Presence of EpCAM-positive circulating tumor cells as biomarker for systemic disease strongly correlates to survival in patients with hepatocellular carcinoma. Int J Cancer. 2013;133(9):2165–2171. doi:10.1002/ijc.28230
   PubMed Web of Science ®Google Scholar
• Guo W, Yang XR, Sun YF, et al. Clinical significance of EpCAM mRNA-positive circulating tumor cells in hepatocellular carcinoma by an optimized negative enrichment and qRT-PCR–based platform. Clin Cancer Res. 2014;20(18):4794–4805. doi:10.1158/1078-0432.CCR-14-0251
   PubMed Web of Science ®Google Scholar
• Sun C, Liao W, Deng Z, et al. The diagnostic value of assays for circulating tumor cells in hepatocellular carcinoma. Medicine. 2017;96(29):e7513. doi:10.1097/MD.0000000000007513
   PubMed Web of Science ®Google Scholar
• Cui K, Ou Y, Shen Y, Li S, Sun Z. Clinical value of circulating tumor cells for the diagnosis and prognosis of hepatocellular carcinoma (HCC). Medicine. 2020;99(40):e22242. doi:10.1097/MD.0000000000022242
   PubMed Web of Science ®Google Scholar
• Court CM, Hou S, Winograd P, et al. A novel multimarker assay for the phenotypic profiling of circulating tumor cells in hepatocellular carcinoma. Liver Transplant. 2018;24(7):946–960. doi:10.1002/lt.25062
   PubMed Web of Science ®Google Scholar
• Qi LN, Xiang BD, Wu FX, et al. Circulating tumor cells undergoing EMT provide a metric for diagnosis and prognosis of patients with hepatocellular carcinoma. Cancer Res. 2018;78(16):4731–4744. doi:10.1158/0008-5472.CAN-17-2459
   PubMed Web of Science ®Google Scholar
• Shi KQ, Lin Z, Chen XJ, et al. Hepatocellular carcinoma associated microRNA expression signature: integrated bioinformatics analysis, experimental validation and clinical significance. Oncotarget. 2015;6(28):25093–25108. doi:10.18632/oncotarget.4437
   PubMedGoogle Scholar
• Zekri ARN, Youssef ASED, El-Desouky ED, et al. Serum microRNA panels as potential biomarkers for early detection of hepatocellular carcinoma on top of HCV infection. Tumor Biol. 2016;37(9):12273–12286. doi:10.1007/s13277-016-5097-8
   PubMedGoogle Scholar
• Lin XJ, Chong Y, Guo ZW, et al. A serum microRNA classifier for early detection of hepatocellular carcinoma: a multicentre, retrospective, longitudinal biomarker identification study with a nested case-control study. Lancet Oncol. 2015;16(7):804–815. doi:10.1016/S1470-2045(15)00048-0
   PubMed Web of Science ®Google Scholar
• Duvoux C, Roudot-Thoraval F, Decaens T, et al. Liver transplantation for hepatocellular carcinoma: a model including α-fetoprotein improves the performance of Milan criteria. Gastroenterology. 2012;143(4):986–994.e3; quiz e14–15. doi:10.1053/j.gastro.2012.05.052
   Web of Science ®Google Scholar
• Llovet JM, Peña CEA, Lathia CD, et al. Plasma biomarkers as predictors of outcome in patients with advanced hepatocellular carcinoma. Clin Cancer Res. 2012;18(8):2290–2300. doi:10.1158/1078-0432.CCR-11-2175
   PubMed Web of Science ®Google Scholar
• Raoul JL, Bruix J, Greten TF, et al. Relationship between baseline hepatic status and outcome, and effect of sorafenib on liver function: SHARP trial subanalyses. J Hepatol. 2012;56(5):1080–1088. doi:10.1016/j.jhep.2011.12.009
   PubMed Web of Science ®Google Scholar
• 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(5):999–1008. doi:10.1016/j.jhep.2017.06.026
   PubMed Web of Science ®Google Scholar
• 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(10064):56–66. doi:10.1016/S0140-6736(16)32453-9
   PubMed Web of Science ®Google Scholar
• Montal R, Andreu-Oller C, Bassaganyas L, et al. Molecular portrait of high alpha-fetoprotein in hepatocellular carcinoma: implications for biomarker-driven clinical trials. Br J Cancer. 2019;121(4):340–343. doi:10.1038/s41416-019-0513-7
   PubMed Web of Science ®Google Scholar
• Saito Y, Shimada M, Utsunomiya T, et al. Prediction of recurrence of hepatocellular carcinoma after curative hepatectomy using preoperative Lens culinaris agglutinin-reactive fraction of alpha-fetoprotein. Hepatol Res. 2012;42(9):887–894. doi:10.1111/j.1872-034X.2012.01004.x
   PubMed Web of Science ®Google Scholar
• Kiriyama S, Uchiyama K, Ueno M, et al. Triple positive tumor markers for hepatocellular carcinoma are useful predictors of poor survival. Ann Surg. 2011;254(6):984–991. doi:10.1097/SLA.0b013e3182215016
   PubMed Web of Science ®Google Scholar
• Fujiki M, Takada Y, Ogura Y, et al. Significance of des-gamma-carboxy prothrombin in selection criteria for living donor liver transplantation for hepatocellular carcinoma. Am J Transplant. 2009;9(10):2362–2371. doi:10.1111/j.1600-6143.2009.02783.x
   PubMed Web of Science ®Google Scholar
• Shindoh J, Sugawara Y, Nagata R, et al. Evaluation methods for pretransplant oncologic markers and their prognostic impacts in patient undergoing living donor liver transplantation for hepatocellular carcinoma. Transpl Int. 2014;27(4):391–398. doi:10.1111/tri.12274
   PubMed Web of Science ®Google Scholar
• Taketomi A, Sanefuji K, Soejima Y, et al. Impact of des-gamma-carboxy prothrombin and tumor size on the recurrence of hepatocellular carcinoma after living donor liver transplantation. Transplantation. 2009;87(4):531–537. doi:10.1097/TP.0b013e3181943bee
   PubMed Web of Science ®Google Scholar
• Carr BI, Kanke F, Wise M, Satomura S. Clinical evaluation of lens culinaris agglutinin-reactive α-fetoprotein and des-γ-carboxy prothrombin in histologically proven hepatocellular carcinoma in the United States. Dig Dis Sci. 2007;52(3):776–782. doi:10.1007/s10620-006-9541-2
   PubMed Web of Science ®Google Scholar
• Toyoda H, Kumada T, Osaki Y, et al. Staging hepatocellular carcinoma by a novel scoring system (BALAD score) based on serum markers. Clin Gastroenterol Hepatol. 2006;4(12):1528–1536. doi:10.1016/j.cgh.2006.09.021
   PubMed Web of Science ®Google Scholar
• Fox R, Berhane S, Teng M, et al. Biomarker-based prognosis in hepatocellular carcinoma: validation and extension of the BALAD model. Br J Cancer. 2014;110(8):2090–2098. doi:10.1038/bjc.2014.130
   PubMed Web of Science ®Google Scholar
• Toyoda H, Tada T, Johnson PJ, et al. Validation of serological models for staging and prognostication of HCC in patients from a Japanese nationwide survey. J Gastroenterol. 2017;52(10):1112–1121. doi:10.1007/s00535-017-1321-6
   PubMed Web of Science ®Google Scholar
• Berhane S, Toyoda H, Tada T, et al. Role of the GALAD and BALAD-2 serologic models in diagnosis of hepatocellular carcinoma and prediction of survival in patients. Clin Gastroenterol Hepatol. 2016;14(6):875–886.e6. doi:10.1016/j.cgh.2015.12.042
   PubMed Web of Science ®Google Scholar
• Wongjarupong N, Negron-Ocasio GM, Mara KC, et al. BALAD and BALAD-2 predict survival of hepatocellular carcinoma patients: a North American cohort study. HPB. 2021;23(5):762–769. doi:10.1016/j.hpb.2020.09.014
   PubMed Web of Science ®Google Scholar
• Finn RS, Kudo M, Cheng AL, et al. Pharmacodynamic biomarkers predictive of survival benefit with lenvatinib in unresectable hepatocellular carcinoma: from the phase III REFLECT study. Clin Cancer Res. 2021;27(17):4848–4858. doi:10.1158/1078-0432.CCR-20-4219
   PubMed Web of Science ®Google Scholar
• Llovet JM, Singal AG, Villanueva A, et al. Prognostic and predictive factors in patients with advanced HCC and elevated alpha-fetoprotein treated with ramucirumab in two randomized phase III trials. Clin Cancer Res. 2022;28(11):2297–2305. doi:10.1158/1078-0432.CCR-21-4000
   PubMed Web of Science ®Google Scholar
• Teufel M, Seidel H, Köchert K, et al. Biomarkers associated with response to regorafenib in patients with hepatocellular carcinoma. Gastroenterology. 2019;156(6):1731–1741. doi:10.1053/j.gastro.2019.01.261
   PubMed Web of Science ®Google Scholar
• Zhu AX, Abbas AR, de Galarreta MR, et al. Molecular correlates of clinical response and resistance to atezolizumab in combination with bevacizumab in advanced hepatocellular carcinoma. Nat Med. 2022;28(8):1599–1611. doi:10.1038/s41591-022-01868-2
   PubMed Web of Science ®Google Scholar
• Rimassa L, Kelley RK, Meyer T, et al. Outcomes based on plasma biomarkers for the phase 3 CELESTIAL trial of cabozantinib versus placebo in advanced hepatocellular carcinoma. Liver Cancer. 2022;11(1):38–47. doi:10.1159/000519867
   PubMed Web of Science ®Google Scholar
• 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(10088):2492–2502. doi:10.1016/S0140-6736(17)31046-2
   PubMed Web of Science ®Google Scholar
• Sangro B, Melero I, Wadhawan S, et al. Association of inflammatory biomarkers with clinical outcomes in nivolumab-treated patients with advanced hepatocellular carcinoma. J Hepatol. 2020;73(6):1460–1469. doi:10.1016/j.jhep.2020.07.026
   PubMed Web of Science ®Google Scholar
• Yau T, Kang YK, Kim TY, et al. Efficacy and safety of nivolumab plus ipilimumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib: the checkmate 040 randomized clinical trial. JAMA Oncol. 2020;6(11):e204564. doi:10.1001/jamaoncol.2020.4564
   PubMed Web of Science ®Google Scholar
• Yau T, Park JW, Finn RS, et al. Nivolumab versus sorafenib in advanced hepatocellular carcinoma (CheckMate 459): a randomised, multicentre, open-label, phase 3 trial. Lancet Oncol. 2022;23(1):77–90. doi:10.1016/S1470-2045(21)00604-5
   PubMed Web of Science ®Google Scholar
• 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(7):940–952. doi:10.1016/S1470-2045(18)30351-6
   PubMed Web of Science ®Google Scholar
• Neely J, Yao J, Kudo M, et al. Abstract 2145: genomic and transcriptomic analyses related to the clinical efficacy of first-line nivolumab in advanced hepatocellular carcinoma from the phase 3 CheckMate 459 trial. Cancer Res. 2022;82(12_Supplement):2145. doi:10.1158/1538-7445.AM2022-2145
   Web of Science ®Google Scholar
• Kaseb AO, Guan Y, Gok Yavuz B, et al. Serum IGF-1 scores and clinical outcomes in the phase III imbrave150 study of atezolizumab plus bevacizumab versus sorafenib in patients with unresectable hepatocellular carcinoma. J Hepatocell Carcinoma. 2022;9:1065–1079. doi:10.2147/JHC.S369951
   PubMed Web of Science ®Google Scholar
• Zhu AX, Dayyani F, Yen CJ, et al. Alpha-fetoprotein as a potential surrogate biomarker for atezolizumab + bevacizumab treatment of hepatocellular carcinoma. Clin Cancer Res. 2022;28(16):3537–3545. doi:10.1158/1078-0432.CCR-21-3275
   PubMed Web of Science ®Google Scholar
• Llovet JM, Ricci S, Mazzaferro V, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359(4):378–390. doi:10.1056/NEJMoa0708857
   PubMed Web of Science ®Google Scholar
• Cheng AL, Kang YK, Chen Z, 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(1):25–34. doi:10.1016/S1470-2045(08)70285-7
   PubMed Web of Science ®Google Scholar
• 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(10126):1163–1173. doi:10.1016/S0140-6736(18)30207-1
   PubMed Web of Science ®Google Scholar
• 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(7):859–870. doi:10.1016/S1470-2045(15)00050-9
   PubMed Web of Science ®Google Scholar
• Boilève A, Hilmi M, Delaye M, Tijeras-Raballand A, Neuzillet C. Biomarkers in hepatobiliary cancers: what is useful in clinical practice? Cancers. 2021;13(11):2708. doi:10.3390/cancers13112708
   PubMed Web of Science ®Google Scholar
• Abou-Alfa GK, Meyer T, Cheng AL, et al. Cabozantinib in patients with advanced and progressing hepatocellular carcinoma. N Engl J Med. 2018;379(1):54–63. doi:10.1056/NEJMoa1717002
   PubMed Web of Science ®Google Scholar
• Kelley RK, Rimassa L, Cheng AL, et al. Cabozantinib plus atezolizumab versus sorafenib for advanced hepatocellular carcinoma (COSMIC-312): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2022;23(8):995–1008. doi:10.1016/S1470-2045(22)00326-6
   PubMed Web of Science ®Google Scholar
• Wei F, Zhong S, Ma Z, et al. Strength of PD-1 signaling differentially affects T-cell effector functions. Proc Natl Acad Sci USA. 2013;110(27):E2480–E2489. doi:10.1073/pnas.1305394110
   PubMed Web of Science ®Google Scholar
• Elliott LA, Doherty GA, Sheahan K, Ryan EJ. Human tumor-infiltrating myeloid cells: phenotypic and functional diversity. Front Immunol. 2017;8:86. doi:10.3389/fimmu.2017.00086
   PubMed Web of Science ®Google Scholar
• Hong JY, Cho HJ, Sa JK, et al. Hepatocellular carcinoma patients with high circulating cytotoxic T cells and intra-tumoral immune signature benefit from pembrolizumab: results from a single-arm phase 2 trial. Genome Med. 2022;14(1):1. doi:10.1186/s13073-021-00995-8
   PubMed Web of Science ®Google Scholar
• Ren Z, Xu J, Bai Y, et al. Sintilimab plus a bevacizumab biosimilar (IBI305) versus sorafenib in unresectable hepatocellular carcinoma (ORIENT-32): a randomised, open-label, phase 2–3 study. Lancet Oncol. 2021;22(7):977–990. doi:10.1016/S1470-2045(21)00252-7
   PubMed Web of Science ®Google Scholar
• Abdel-Wahab R, Shehata S, Hassan MM, et al. Type I insulin-like growth factor as a liver reserve assessment tool in hepatocellular carcinoma. J Hepatocell Carcinoma. 2015;2:131–142. doi:10.2147/JHC.S81309
   PubMedGoogle Scholar
• Wang J, Huang A, Wang YP, et al. Circulating tumor DNA correlates with microvascular invasion and predicts tumor recurrence of hepatocellular carcinoma. Ann Transl Med. 2020;8(5):237. doi:10.21037/atm.2019.12.154
   PubMed Web of Science ®Google Scholar
• Zhou L, Xu Y, Wang D, et al. Perioperative circulating tumor DNA analysis to predict patient prognosis in liver cancer. JCO. 2020;38(15_suppl):4593. doi:10.1200/JCO.2020.38.15_suppl.4593
   Web of Science ®Google Scholar
• Huang A, Guo DZ, Zhang X, et al. Application of circulating tumor DNA for prediction and surveillance of tumor recurrence after liver transplantation: a pilot study. JCO. 2022;40(16_suppl):e16149–e16149. doi:10.1200/JCO.2022.40.16_suppl.e16149
   Web of Science ®Google Scholar
• Jiang N, Zeng X, Tang J, et al. Circulating tumor DNA is a potential prognostic risk factor of recurrence in patients with hepatocellular carcinoma treated by liver transplantation. JCO. 2022;40(16_suppl):e16196–e16196. doi:10.1200/JCO.2022.40.16_suppl.e16196
   Web of Science ®Google Scholar
• Zhu GQ, Liu WR, Tang Z, et al. Serial circulating tumor DNA to predict early recurrence in patients with hepatocellular carcinoma: a prospective study. Mol Oncol. 2022;16(2):549–561. doi:10.1002/1878-0261.13105
   PubMed Web of Science ®Google Scholar
• Kim SS, Eun JW, Choi JH, et al. MLH1 single-nucleotide variant in circulating tumor DNA predicts overall survival of patients with hepatocellular carcinoma. Sci Rep. 2020;10(1):17862. doi:10.1038/s41598-020-74494-y
   PubMed Web of Science ®Google Scholar
• Hsu CH, Lu S, Abbas A, et al. Longitudinal and personalized detection of circulating tumor DNA (ctDNA) for monitoring efficacy of atezolizumab plus bevacizumab in patients with unresectable hepatocellular carcinoma (HCC). JCO. 2020;38(15_suppl):3531. doi:10.1200/JCO.2020.38.15_suppl.3531
   Web of Science ®Google Scholar
• von Felden J, Craig AJ, Garcia-Lezana T, et al. Mutations in circulating tumor DNA predict primary resistance to systemic therapies in advanced hepatocellular carcinoma. Oncogene. 2021;40(1):140–151. doi:10.1038/s41388-020-01519-1
   PubMed Web of Science ®Google Scholar
• Morishita A, Oura K, Tadokoro T, Fujita K, Tani J, Masaki T. MicroRNAs in the pathogenesis of hepatocellular carcinoma: a review. Cancers. 2021;13(3):514. doi:10.3390/cancers13030514
   PubMed Web of Science ®Google Scholar
• Sorop A, Constantinescu D, Cojocaru F, Dinischiotu A, Cucu D, Dima SO. Exosomal microRNAs as biomarkers and therapeutic targets for hepatocellular carcinoma. Int J Mol Sci. 2021;22(9):4997. doi:10.3390/ijms22094997
   PubMed Web of Science ®Google Scholar
• Zhou Y, Wang B, Wu J, et al. Association of preoperative EpCAM circulating tumor cells and peripheral treg cell levels with early recurrence of hepatocellular carcinoma following radical hepatic resection. BMC Cancer. 2016;16:506. doi:10.1186/s12885-016-2526-4
   PubMed Web of Science ®Google Scholar
• Wang Z, Luo L, Cheng Y, et al. Correlation between postoperative early recurrence of hepatocellular carcinoma and mesenchymal circulating tumor cells in peripheral blood. J Gastrointest Surg. 2018;22(4):633–639. doi:10.1007/s11605-017-3619-3
   PubMed Web of Science ®Google Scholar
• Ou H, Huang Y, Xiang L, et al. Circulating tumor cell phenotype indicates poor survival and recurrence after surgery for hepatocellular carcinoma. Dig Dis Sci. 2018;63(9):2373–2380. doi:10.1007/s10620-018-5124-2
   PubMed Web of Science ®Google Scholar
• Altman DG, McShane LM, Sauerbrei W, Taube SE. Reporting recommendations for tumor marker prognostic studies (REMARK): explanation and elaboration. BMC Med. 2012;10(1):51. doi:10.1186/1741-7015-10-51
   PubMedGoogle Scholar
• Borges KA, Dai J, Parikh ND, et al. Rationale and design of the hepatocellular carcinoma early detection strategy study: a multi-center longitudinal initiative of the national cancer institute’s early detection research network. Contemp Clin Trials. 2019;76:49–54. doi:10.1016/j.cct.2018.11.008
   PubMed Web of Science ®Google Scholar
• Feng Z, Marrero JA, Khaderi S, et al. Design of the Texas hepatocellular carcinoma consortium cohort study. Am J Gastroenterol. 2019;114(3):530–532. doi:10.14309/ajg.0000000000000068
   PubMed Web of Science ®Google Scholar
• Tsuchiya N, Sawada Y, Endo I, Saito K, Uemura Y, Nakatsura T. Biomarkers for the early diagnosis of hepatocellular carcinoma. World J Gastroenterol. 2015;21(37):10573–10583. doi:10.3748/wjg.v21.i37.10573
   PubMed Web of Science ®Google Scholar
• Kim BK, Cheon J, Kim H, et al. Atezolizumab/bevacizumab vs. lenvatinib as first-line therapy for unresectable hepatocellular carcinoma: a real-world, multi-center study. Cancers. 2022;14(7):1747. doi:10.3390/cancers14071747
   PubMed Web of Science ®Google Scholar
• Rimini M, Rimassa L, Ueshima K, et al. Atezolizumab plus bevacizumab versus lenvatinib or sorafenib in non-viral unresectable hepatocellular carcinoma: an international propensity score matching analysis. ESMO Open. 2022;7(6):100591. doi:10.1016/j.esmoop.2022.100591
   PubMed Web of Science ®Google Scholar
• Fang JH, Xu L, Shang LR, et al. Vessels That Encapsulate Tumor Clusters (VETC) pattern is a predictor of sorafenib benefit in patients with hepatocellular carcinoma. Hepatology. 2019;70(3):824–839. doi:10.1002/hep.30366
   PubMed Web of Science ®Google Scholar
• Chin RI, Chen K, Usmani A, et al. Detection of solid tumor Molecular Residual Disease (MRD) using Circulating Tumor DNA (ctDNA). Mol Diagn Ther. 2019;23(3):311–331. doi:10.1007/s40291-019-00390-5
   PubMed Web of Science ®Google Scholar
• Tie J, Wang Y, Tomasetti C, et al. Circulating tumor DNA analysis detects minimal residual disease and predicts recurrence in patients with stage II colon cancer. Sci Transl Med. 2016;8(346):346ra92. doi:10.1126/scitranslmed.aaf6219
   PubMed Web of Science ®Google Scholar
• Powles T, Assaf ZJ, Davarpanah N, et al. ctDNA guiding adjuvant immunotherapy in urothelial carcinoma. Nature. 2021;595(7867):432–437. doi:10.1038/s41586-021-03642-9
   PubMed Web of Science ®Google Scholar
• Kudo M, Ueshima K, Nakahira S, et al. Final results of adjuvant nivolumab for hepatocellular carcinoma (HCC) after surgical resection (SR) or radiofrequency ablation (RFA) (NIVOLVE): a phase 2 prospective multicenter single-arm trial and exploratory biomarker analysis. JCO. 2022;40(4_suppl):416. doi:10.1200/JCO.2022.40.4_suppl.416
   Web of Science ®Google Scholar
• Xia Y, Tang W, Qian X, et al. Efficacy and safety of camrelizumab plus apatinib during the perioperative period in resectable hepatocellular carcinoma: a single-arm, open label, phase II clinical trial. J Immunother Cancer. 2022;10(4):e004656. doi:10.1136/jitc-2022-004656
   PubMed Web of Science ®Google Scholar
• Natera. Natera launches initiative to transform the management of cancer patients in organ transplantation; 2020. Available from: https://www.natera.com/company/news/natera-launches-initiative-to-transform-the-management-of-cancer-patients-in-organ-transplantation-2/. Accessed July 7, 2023.
   Google Scholar
• Chow P, Chen M, Cheng AL, et al. Abstract CT003: iMbrave050: phase 3 study of adjuvant atezolizumab + bevacizumab versus active surveillance in patients with hepatocellular carcinoma (HCC) at high risk of disease recurrence following resection or ablation. Cancer Res. 2023;83(8_Supplement):CT003. doi:10.1158/1538-7445.AM2023-CT003
   Google Scholar