Top

Journal of Experimental & Clinical Cancer Research

Published in:

01-12-2021 | Hepatocellular Carcinoma | Review

Current status of ctDNA in precision oncology for hepatocellular carcinoma

Authors: Yan Li, Yuanyuan Zheng, Liwei Wu, Jingjing Li, Jie Ji, Qiang Yu, Weiqi Dai, Jiao Feng, Jianye Wu, Chuanyong Guo

Published in: Journal of Experimental & Clinical Cancer Research | Issue 1/2021

Abstract

The conventional method used to obtain a tumor biopsy for hepatocellular carcinoma (HCC) is invasive and does not evaluate dynamic cancer progression or assess tumor heterogeneity. It is thus imperative to create a novel non-invasive diagnostic technique for improvement in cancer screening, diagnosis, treatment selection, response assessment, and predicting prognosis for HCC. Circulating tumor DNA (ctDNA) is a non-invasive liquid biopsy method that reveals cancer-specific genetic and epigenetic aberrations. Owing to the development of technology in next-generation sequencing and PCR-based assays, the detection and quantification of ctDNA have greatly improved. In this publication, we provide an overview of current technologies used to detect ctDNA, the ctDNA markers utilized, and recent advances regarding the multiple clinical applications in the field of precision medicine for HCC.

Available only for authorised users

Akinyemiju T, Abera S, Ahmed M, Alam N, Alemayohu MA, Allen C, et al. The burden of primary liver Cancer and underlying etiologies from 1990 to 2015 at the global, regional, and National Level: results from the global burden of disease study 2015. JAMA Oncol. 2017;3(12):1683–91. https://doi.org/10.1001/jamaoncol.2017.3055.

Feng J, Li J, Wu L, Yu Q, Ji J, Wu J, et al. Emerging roles and the regulation of aerobic glycolysis in hepatocellular carcinoma. J Exp Clin Cancer Res. 2020;39(1):126. https://doi.org/10.1186/s13046-020-01629-4.

EASL-EORTC clinical practice guidelines: management of hepatocellular carcinoma. J Hepatol. 2012;56(4):908–43. https://doi.org/10.1016/j.jhep.2011.12.001.

Tzartzeva K, Obi J, Rich NE, Parikh ND, Marrero JA, Yopp A, et al. Surveillance Imaging and Alpha Fetoprotein for Early Detection of Hepatocellular Carcinoma in Patients With Cirrhosis: A Meta-analysis. Gastroenterology. 2018;154:1706–18 e1701.

Wong RJ, Ahmed A, Gish RG. Elevated alpha-fetoprotein: differential diagnosis - hepatocellular carcinoma and other disorders. Clin Liver Dis. 2015;19(2):309–23. https://doi.org/10.1016/j.cld.2015.01.005.CrossRefPubMed

Corcoran RB, Chabner BA. Application of cell-free DNA analysis to Cancer treatment. N Engl J Med. 2018;379(18):1754–65. https://doi.org/10.1056/NEJMra1706174.CrossRefPubMed

Wan JCM, Massie C, Garcia-Corbacho J, Mouliere F, Brenton JD, Caldas C, et al. Liquid biopsies come of age: towards implementation of circulating tumour DNA. Nat Rev Cancer. 2017;17(4):223–38. https://doi.org/10.1038/nrc.2017.7.

Chae YK, Oh MS. Detection of minimal residual disease using ctDNA in lung Cancer: current evidence and future directions. J Thorac Oncol. 2019;14(1):16–24. https://doi.org/10.1016/j.jtho.2018.09.022.CrossRefPubMed

Clatot F. Review ctDNA and breast Cancer. Recent Results Cancer Res. 2020;215:231–52. https://doi.org/10.1007/978-3-030-26439-0_12.CrossRefPubMed

10.

Kruger S, Heinemann V, Ross C, Diehl F, Nagel D, Ormanns S, et al. Repeated mutKRAS ctDNA measurements represent a novel and promising tool for early response prediction and therapy monitoring in advanced pancreatic cancer. Ann Oncol. 2018;29(12):2348–55. https://doi.org/10.1093/annonc/mdy417.

11.

Yang JD, Liu MC, Kisiel JB. Circulating tumor DNA and hepatocellular carcinoma. Semin Liver Dis. 2019;39(4):452–62. https://doi.org/10.1055/s-0039-1688503.CrossRefPubMed

12.

Diaz LA Jr, Bardelli A. Liquid biopsies: genotyping circulating tumor DNA. J Clin Oncol. 2014;32(6):579–86. https://doi.org/10.1200/JCO.2012.45.2011.CrossRefPubMedPubMedCentral

13.

Haber DA, Velculescu VE. Blood-based analyses of cancer: circulating tumor cells and circulating tumor DNA. Cancer Discov. 2014;4(6):650–61. https://doi.org/10.1158/2159-8290.CD-13-1014.CrossRefPubMedPubMedCentral

14.

Diehl F, Schmidt K, Choti MA, Romans K, Goodman S, Li M, et al. Circulating mutant DNA to assess tumor dynamics. Nat Med. 2008;14(9):985–90. https://doi.org/10.1038/nm.1789.

15.

Franczak C, Filhine-Tresarrieu P, Gilson P, Merlin JL, Au L, Harlé A. Technical considerations for circulating tumor DNA detection in oncology. Expert Rev Mol Diagn. 2019;19(2):121–35. https://doi.org/10.1080/14737159.2019.1568873.CrossRefPubMed

16.

Gorgannezhad L, Umer M, Islam MN, Nguyen NT, Shiddiky MJA. Circulating tumor DNA and liquid biopsy: opportunities, challenges, and recent advances in detection technologies. Lab Chip. 2018;18(8):1174–96. https://doi.org/10.1039/C8LC00100F.CrossRefPubMed

17.

Gobbini E, Swalduz A, Levra MG, Ortiz-Cuaran S, Toffart AC, Pérol M, et al. Implementing ctDNA analysis in the clinic: challenges and opportunities in non-small cell lung cancer. Cancers (Basel). 2020;12(11). https://doi.org/10.3390/cancers12113112.

18.

Zavridou M, Mastoraki S, Strati A, Tzanikou E, Chimonidou M, Lianidou E. Evaluation of preanalytical conditions and implementation of quality control steps for reliable gene expression and DNA methylation analyses in liquid biopsies. Clin Chem. 2018;64(10):1522–33. https://doi.org/10.1373/clinchem.2018.292318.CrossRefPubMed

19.

Diefenbach RJ, Lee JH, Kefford RF, Rizos H. Evaluation of commercial kits for purification of circulating free DNA. Cancer Genet. 2018;228-229:21–7. https://doi.org/10.1016/j.cancergen.2018.08.005.CrossRefPubMed

20.

Sonnenberg A, Marciniak JY, Rassenti L, Ghia EM, Skowronski EA, Manouchehri S, et al. Rapid electrokinetic isolation of cancer-related circulating cell-free DNA directly from blood. Clin Chem. 2014;60(3):500–9. https://doi.org/10.1373/clinchem.2013.214874.

21.

Lee H, Jeon S, Seo JS, Goh SH, Han JY, Cho Y. A novel strategy for highly efficient isolation and analysis of circulating tumor-specific cell-free DNA from lung cancer patients using a reusable conducting polymer nanostructure. Biomaterials. 2016;101:251–7. https://doi.org/10.1016/j.biomaterials.2016.06.003.CrossRefPubMed

22.

Gilson P. Enrichment and analysis of ctDNA. Recent Results Cancer Res. 2020;215:181–211. https://doi.org/10.1007/978-3-030-26439-0_10.CrossRefPubMed

23.

Soda N, Rehm BHA, Sonar P, Nguyen NT, Shiddiky MJA. Advanced liquid biopsy technologies for circulating biomarker detection. J Mater Chem B. 2019;7(43):6670–704. https://doi.org/10.1039/C9TB01490J.CrossRefPubMed

24.

Keppens C, Palma JF, Das PM, Scudder S, Wen W, Normanno N, et al. Detection of EGFR variants in plasma: a multilaboratory comparison of a real-time PCR EGFR mutation test in Europe. J Mol Diagn. 2018;20(4):483–94. https://doi.org/10.1016/j.jmoldx.2018.03.006.

25.

Mauger F, How-Kit A, Tost J. COLD-PCR technologies in the area of personalized medicine: methodology and applications. Mol Diagn Ther. 2017;21(3):269–83. https://doi.org/10.1007/s40291-016-0254-8.CrossRefPubMed

26.

Madic J, Piperno-Neumann S, Servois V, Rampanou A, Milder M, Trouiller B, et al. Pyrophosphorolysis-activated polymerization detects circulating tumor DNA in metastatic uveal melanoma. Clin Cancer Res. 2012;18(14):3934–41. https://doi.org/10.1158/1078-0432.CCR-12-0309.

27.

Thierry AR, Mouliere F, El Messaoudi S, Mollevi C, Lopez-Crapez E, Rolet F, et al. Clinical validation of the detection of KRAS and BRAF mutations from circulating tumor DNA. Nat Med. 2014;20(4):430–5. https://doi.org/10.1038/nm.3511.

28.

Thierry AR. A targeted Q-PCR-based method for point mutation testing by analyzing circulating DNA for cancer management care. Methods Mol Biol. 2016;1392:1–16. https://doi.org/10.1007/978-1-4939-3360-0_1.CrossRefPubMed

29.

Kerachian MA, Azghandi M, Javadmanesh A, Ghaffarzadegan K, Mozaffari-Jovin S. Selective capture of plasma cell-free tumor DNA on magnetic beads: a sensitive and versatile tool for liquid biopsy. Cell Oncol (Dordr). 2020;43(5):949–56. https://doi.org/10.1007/s13402-020-00536-2.CrossRef

30.

Perkins G, Lu H, Garlan F, Taly V. Droplet-based digital PCR: application in Cancer research. Adv Clin Chem. 2017;79:43–91. https://doi.org/10.1016/bs.acc.2016.10.001.CrossRefPubMed

31.

Zhang Y, Xu Y, Zhong W, Zhao J, Chen M, Zhang L, et al. Total DNA input is a crucial determinant of the sensitivity of plasma cell-free DNA EGFR mutation detection using droplet digital PCR. Oncotarget. 2017;8(4):5861–73. https://doi.org/10.18632/oncotarget.14390.

32.

Diehl F, Schmidt K, Durkee KH, Moore KJ, Goodman SN, Shuber AP, et al. Analysis of mutations in DNA isolated from plasma and stool of colorectal cancer patients. Gastroenterology. 2008;135(2):489–98. https://doi.org/10.1053/j.gastro.2008.05.039.

33.

Ilié M, Hofman P. Pros: can tissue biopsy be replaced by liquid biopsy? Transl Lung Cancer Res. 2016;5(4):420–3. https://doi.org/10.21037/tlcr.2016.08.06.CrossRefPubMedPubMedCentral

34.

O'Leary B, Hrebien S, Beaney M, Fribbens C, Garcia-Murillas I, Jiang J, et al. Comparison of BEAMing and droplet digital PCR for circulating tumor DNA analysis. Clin Chem. 2019;65(11):1405–13. https://doi.org/10.1373/clinchem.2019.305805.

35.

Rowe SP, Luber B, Makell M, Brothers P, Santmyer J, Schollenberger MD, et al. From validity to clinical utility: the influence of circulating tumor DNA on melanoma patient management in a real-world setting. Mol Oncol. 2018;12(10):1661–72. https://doi.org/10.1002/1878-0261.12373.

36.

Newman AM, Bratman SV, To J, Wynne JF, Eclov NC, Modlin LA, et al. An ultrasensitive method for quantitating circulating tumor DNA with broad patient coverage. Nat Med. 2014;20(5):548–54. https://doi.org/10.1038/nm.3519.

37.

Forshew T, Murtaza M, Parkinson C, Gale D, Tsui DW, Kaper F, et al. Noninvasive identification and monitoring of cancer mutations by targeted deep sequencing of plasma DNA. Sci Transl Med. 2012;4:136ra168.

38.

Tie J, Kinde I, Wang Y, Wong HL, Roebert J, Christie M, et al. Circulating tumor DNA as an early marker of therapeutic response in patients with metastatic colorectal cancer. Ann Oncol. 2015;26(8):1715–22. https://doi.org/10.1093/annonc/mdv177.

39.

Newman AM, Lovejoy AF, Klass DM, Kurtz DM, Chabon JJ, Scherer F, et al. Integrated digital error suppression for improved detection of circulating tumor DNA. Nat Biotechnol. 2016;34(5):547–55. https://doi.org/10.1038/nbt.3520.

40.

Namløs HM, Boye K, Mishkin SJ, Barøy T, Lorenz S, Bjerkehagen B, et al. Noninvasive detection of ctDNA reveals intratumor heterogeneity and is associated with tumor burden in gastrointestinal stromal tumor. Mol Cancer Ther. 2018;17(11):2473–80. https://doi.org/10.1158/1535-7163.MCT-18-0174.

41.

Manier S, Park J, Capelletti M, Bustoros M, Freeman SS, Ha G, et al. Whole-exome sequencing of cell-free DNA and circulating tumor cells in multiple myeloma. Nat Commun. 2018;9(1):1691. https://doi.org/10.1038/s41467-018-04001-5.

42.

Ulz P, Thallinger GG, Auer M, Graf R, Kashofer K, Jahn SW, et al. Inferring expressed genes by whole-genome sequencing of plasma DNA. Nat Genet. 2016;48(10):1273–8. https://doi.org/10.1038/ng.3648.

43.

Garrett-Bakelman FE, Sheridan CK, Kacmarczyk TJ, Ishii J, Betel D, Alonso A, et al. Enhanced reduced representation bisulfite sequencing for assessment of DNA methylation at base pair resolution. J Vis Exp. 2015:e52246. https://doi.org/10.3791/52246.

44.

Sun Z, Vaisvila R, Hussong LM, Yan B, Baum C, Saleh L, et al. Nondestructive enzymatic deamination enables single-molecule long-read amplicon sequencing for the determination of 5-methylcytosine and 5-hydroxymethylcytosine at single-base resolution. Genome Res. 2021;31(2):291–300. https://doi.org/10.1101/gr.265306.120.

45.

Pantel K, Alix-Panabières C. Liquid biopsy and minimal residual disease - latest advances and implications for cure. Nat Rev Clin Oncol. 2019;16(7):409–24. https://doi.org/10.1038/s41571-019-0187-3.CrossRefPubMed

46.

Leary RJ, 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.

47.

Zhang Y, Mi X, Tan X, Xiang R. Recent progress on liquid biopsy analysis using surface-enhanced Raman spectroscopy. Theranostics. 2019;9(2):491–525. https://doi.org/10.7150/thno.29875.CrossRefPubMedPubMedCentral

48.

Lyu N, Rajendran VK, Diefenbach RJ, Charles K, Clarke SJ, Engel A, et al. Multiplex detection of ctDNA mutations in plasma of colorectal cancer patients by PCR/SERS assay. Nanotheranostics. 2020;4(4):224–32. https://doi.org/10.7150/ntno.48905.

49.

Lamy PJ, van der Leest P, Lozano N, Becht C, Duboeuf F, Groen HJM, et al. Mass spectrometry as a highly sensitive method for specific circulating tumor DNA analysis in NSCLC: a comparison study. Cancers (Basel). 2020;12(10). https://doi.org/10.3390/cancers12103002.

50.

Campuzano S, Serafín V, Gamella M, Pedrero M, Yáñez-Sedeño P, Pingarrón JM. Opportunities, challenges, and prospects in electrochemical biosensing of circulating tumor DNA and its specific features. Sensors (Basel). 2019;19(17). https://doi.org/10.3390/s19173762.

51.

Rodda AE, Parker BJ, Spencer A, Corrie SR. Extending circulating tumor DNA analysis to ultralow abundance mutations: techniques and challenges. ACS Sens. 2018;3(3):540–60. https://doi.org/10.1021/acssensors.7b00953.CrossRefPubMed

52.

Merker JD, Oxnard GR, Compton C, Diehn M, Hurley P, Lazar AJ, et al. Circulating tumor DNA analysis in patients with cancer: American Society of Clinical Oncology and College of American Pathologists Joint Review. J Clin Oncol. 2018;36(16):1631–41. https://doi.org/10.1200/JCO.2017.76.8671.

53.

Ungerer V, Bronkhorst AJ, Holdenrieder S. Preanalytical variables that affect the outcome of cell-free DNA measurements. Crit Rev Clin Lab Sci. 2020;57(7):484–507. https://doi.org/10.1080/10408363.2020.1750558.CrossRefPubMed

54.

Heeke S, Hofman V, Long-Mira E, Lespinet V, Lalvée S, Bordone O, et al. Use of the ion PGM and the GeneReader NGS systems in daily routine practice for advanced lung adenocarcinoma patients: a practical point of view reporting a comparative study and assessment of 90 patients. Cancers (Basel). 2018;10(4). https://doi.org/10.3390/cancers10040088.

55.

Hilmi M, Neuzillet C, Calderaro J, Lafdil F, Pawlotsky JM, Rousseau B. Angiogenesis and immune checkpoint inhibitors as therapies for hepatocellular carcinoma: current knowledge and future research directions. J Immunother Cancer. 2019;7(1):333. https://doi.org/10.1186/s40425-019-0824-5.CrossRefPubMedPubMedCentral

56.

Faivre S, Rimassa L, Finn RS. Molecular therapies for HCC: looking outside the box. J Hepatol. 2020;72(2):342–52. https://doi.org/10.1016/j.jhep.2019.09.010.CrossRefPubMed

57.

Wu L, Li J, Liu T, Li S, Feng J, Yu Q, et al. Quercetin shows anti-tumor effect in hepatocellular carcinoma LM3 cells by abrogating JAK2/STAT3 signaling pathway. Cancer Med. 2019;8(10):4806–20. https://doi.org/10.1002/cam4.2388.

58.

Nault JC, Martin Y, Caruso S, Hirsch TZ, Bayard Q, Calderaro J, et al. Clinical impact of genomic diversity from early to advanced hepatocellular carcinoma. Hepatology. 2020;71(1):164–82. https://doi.org/10.1002/hep.30811.

59.

Huang A, Zhang X, Zhou SL, Cao Y, Huang XW, Fan J, et al. Detecting circulating tumor DNA in hepatocellular carcinoma patients using droplet digital PCR is feasible and reflects Intratumoral heterogeneity. J Cancer. 2016;7(13):1907–14. https://doi.org/10.7150/jca.15823.

60.

von Felden J, Craig AJ, Garcia-Lezana T, Labgaa I, Haber PK, D'Avola D, et al. Mutations in circulating tumor DNA predict primary resistance to systemic therapies in advanced hepatocellular carcinoma. Oncogene. 2020;40:140–51. https://doi.org/10.1038/s41388-020-01519-1.

61.

Mocan T, Simão AL, Castro RE, Rodrigues CMP, Słomka A, Wang B, et al. Liquid biopsies in hepatocellular carcinoma: are we winning? J Clin Med. 2020;9(5). https://doi.org/10.3390/jcm9051541.

62.

Wheler JJ, Janku F, Naing A, Li Y, Stephen B, Zinner R, et al. TP53 alterations correlate with response to VEGF/VEGFR inhibitors: implications for targeted therapeutics. Mol Cancer Ther. 2016;15(10):2475–85. https://doi.org/10.1158/1535-7163.MCT-16-0196.

63.

Janku F, Kaseb AO, Tsimberidou AM, Wolff RA, Kurzrock R. Identification of novel therapeutic targets in the PI3K/AKT/mTOR pathway in hepatocellular carcinoma using targeted next generation sequencing. Oncotarget. 2014;5(10):3012–22. https://doi.org/10.18632/oncotarget.1687.CrossRefPubMedPubMedCentral

64.

Kogiso T, Nagahara H, Hashimoto E, Ariizumi S, Yamamoto M, Shiratori K. Efficient induction of apoptosis by wee1 kinase inhibition in hepatocellular carcinoma cells. PLoS One. 2014;9(6):e100495. https://doi.org/10.1371/journal.pone.0100495.CrossRefPubMedPubMedCentral

65.

Berardinelli F, Coluzzi E, Sgura A, Antoccia A. Targeting telomerase and telomeres to enhance ionizing radiation effects in in vitro and in vivo cancer models. Mutat Res. 2017;773:204–19. https://doi.org/10.1016/j.mrrev.2017.02.004.CrossRef

66.

Tang M, Li Y, Zhang Y, Chen Y, Huang W, Wang D, et al. Disease mutant analysis identifies a new function of DAXX in telomerase regulation and telomere maintenance. J Cell Sci. 2015;128(2):331–41. https://doi.org/10.1242/jcs.159467.

67.

Ozcan M, Altay O, Lam S, Turkez H, Aksoy Y, Nielsen J, et al. Improvement in the current therapies for hepatocellular carcinoma using a systems medicine approach. Adv Biosyst. 2020;4:e2000030.

68.

He S, Tang S. WNT/β-catenin signaling in the development of liver cancers. Biomed Pharmacother. 2020;132:110851. https://doi.org/10.1016/j.biopha.2020.110851.CrossRefPubMed

69.

Khemlina G, Ikeda S, Kurzrock R. The biology of hepatocellular carcinoma: implications for genomic and immune therapies. Mol Cancer. 2017;16(1):149. https://doi.org/10.1186/s12943-017-0712-x.CrossRefPubMedPubMedCentral

70.

Digiacomo G, Fumarola C, La Monica S, Bonelli MA, Cretella D, Alfieri R, et al. Simultaneous combination of the CDK4/6 inhibitor palbociclib with regorafenib induces enhanced anti-tumor effects in hepatocarcinoma cell lines. Front Oncol. 2020;10:563249. https://doi.org/10.3389/fonc.2020.563249.

71.

Huang A, Zhao X, Yang XR, Li FQ, Zhou XL, Wu K, et al. Circumventing intratumoral heterogeneity to identify potential therapeutic targets in hepatocellular carcinoma. J Hepatol. 2017;67(2):293–301. https://doi.org/10.1016/j.jhep.2017.03.005.

72.

Mezzalira S, De Mattia E, Guardascione M, Dalle Fratte C, Cecchin E, Toffoli G. Circulating-free DNA analysis in hepatocellular carcinoma: a promising strategy to improve Patients' Management and therapy outcomes. Int J Mol Sci. 2019;20(21). https://doi.org/10.3390/ijms20215498.

73.

Oussalah A, Rischer S, Bensenane M, Conroy G, Filhine-Tresarrieu P, Debard R, et al. Plasma mSEPT9: a novel circulating cell-free DNA-based epigenetic biomarker to diagnose hepatocellular carcinoma. EBioMedicine. 2018;30:138–47. https://doi.org/10.1016/j.ebiom.2018.03.029.

74.

Kaseb AO, Sánchez NS, Sen S, Kelley RK, Tan B, Bocobo AG, et al. Molecular profiling of hepatocellular carcinoma using circulating cell-free DNA. Clin Cancer Res. 2019;25(20):6107–18. https://doi.org/10.1158/1078-0432.CCR-18-3341.

75.

Cohen JD, Li L, Wang Y, Thoburn C, Afsari B, Danilova L, et al. Detection and localization of surgically resectable cancers with a multi-analyte blood test. Science. 2018;359(6378):926–30. https://doi.org/10.1126/science.aar3247.

76.

Marchio A, Amougou Atsama M, Béré A, Komas NP, Noah Noah D, Atangana PJA, et al. Droplet digital PCR detects high rate of TP53 R249S mutants in cell-free DNA of middle African patients with hepatocellular carcinoma. Clin Exp Med. 2018;18(3):421–31. https://doi.org/10.1007/s10238-018-0502-9.

77.

Shen T, Li SF, Wang JL, Zhang T, Zhang S, Chen HT, et al. TP53 R249S mutation detected in circulating tumour DNA is associated with prognosis of hepatocellular carcinoma patients with or without hepatectomy. Liver Int. 2020;40(11):2834–47. https://doi.org/10.1111/liv.14581.

78.

Nault JC, Zucman-Rossi J. TERT promoter mutations in primary liver tumors. Clin Res Hepatol Gastroenterol. 2016;40(1):9–14. https://doi.org/10.1016/j.clinre.2015.07.006.CrossRefPubMed

79.

In der Stroth L, Tharehalli U, Günes C, Lechel A. Telomeres and telomerase in the development of liver cancer. Cancers (Basel). 2020;12. https://doi.org/10.3390/cancers12082048.

80.

Kim YJ, Yoo JE, Jeon Y, Chong JU, Choi GH, Song DG, et al. Suppression of PROX1-mediated TERT expression in hepatitis B viral hepatocellular carcinoma. Int J Cancer. 2018;143(12):3155–68. https://doi.org/10.1002/ijc.31731.

81.

Oversoe SK, Clement MS, Pedersen MH, Weber B, Aagaard NK, Villadsen GE, et al. TERT promoter mutated circulating tumor DNA as a biomarker for prognosis in hepatocellular carcinoma. Scand J Gastroenterol. 2020;55:1–8. https://doi.org/10.1080/00365521.2020.1837928.

82.

Hirai M, Kinugasa H, Nouso K, Yamamoto S, Terasawa H, Onishi Y, et al. Prediction of the prognosis of advanced hepatocellular carcinoma by TERT promoter mutations in circulating tumor DNA. J Gastroenterol Hepatol. 2020. https://doi.org/10.1111/jgh.15227.

83.

Zucman-Rossi J, Villanueva A, Nault JC, Llovet JM. Genetic Landscape and Biomarkers of Hepatocellular Carcinoma. Gastroenterology. 2015;149:1226–39 e1224.CrossRefPubMed

84.

Dai W, Xu L, Yu X, Zhang G, Guo H, Liu H, et al. OGDHL silencing promotes hepatocellular carcinoma by reprogramming glutamine metabolism. J Hepatol. 2020;72(5):909–23. https://doi.org/10.1016/j.jhep.2019.12.015.

85.

Monga SP. β-Catenin signaling and roles in liver homeostasis, injury, and tumorigenesis. Gastroenterology. 2015;148(7):1294–310. https://doi.org/10.1053/j.gastro.2015.02.056.CrossRefPubMed

86.

Wang W, Smits R, Hao H, He C. Wnt/β-catenin signaling in liver cancers. Cancers (Basel). 2019;11. https://doi.org/10.3390/cancers11070926.

87.

Kim E, Lisby A, Ma C, Lo N, Ehmer U, Hayer KE, et al. Promotion of growth factor signaling as a critical function of β-catenin during HCC progression. Nat Commun. 2019;10(1):1909. https://doi.org/10.1038/s41467-019-09780-z.

88.

Wang J, Huang A, Wang YP, Yin Y, Fu PY, Zhang X, et al. Circulating tumor DNA correlates with microvascular invasion and predicts tumor recurrence of hepatocellular carcinoma. Ann Transl Med. 2020;8(5):237. https://doi.org/10.21037/atm.2019.12.154.

89.

Ikeda S, Tsigelny IF, Skjevik ÅA, Kono Y, Mendler M, Kuo A, et al. Next-generation sequencing of circulating tumor DNA reveals frequent alterations in advanced hepatocellular carcinoma. Oncologist. 2018;23(5):586–93. https://doi.org/10.1634/theoncologist.2017-0479.

90.

Schulze K, Imbeaud S, Letouzé E, Alexandrov LB, Calderaro J, Rebouissou S, et al. Exome sequencing of hepatocellular carcinomas identifies new mutational signatures and potential therapeutic targets. Nat Genet. 2015;47(5):505–11. https://doi.org/10.1038/ng.3252.

91.

Zhou Y, Xu Q, Tao L, Chen Y, Shu Y, Wu Z, et al. Enhanced SMARCD1, a subunit of the SWI/SNF complex, promotes liver cancer growth through the mTOR pathway. Clin Sci (Lond). 2020;134(12):1457–72. https://doi.org/10.1042/CS20200244.

92.

Hu B, Lin JZ, Yang XB, Sang XT. The roles of mutated SWI/SNF complexes in the initiation and development of hepatocellular carcinoma and its regulatory effect on the immune system: a review. Cell Prolif. 2020;53:e12791.PubMedPubMedCentral

93.

Hlady RA, Zhao X, Pan X, Yang JD, Ahmed F, Antwi SO, et al. Genome-wide discovery and validation of diagnostic DNA methylation-based biomarkers for hepatocellular cancer detection in circulating cell free DNA. Theranostics. 2019;9(24):7239–50. https://doi.org/10.7150/thno.35573.

94.

Herman JG, Farooq M. Noninvasive diagnostics for early detection of lung Cancer: challenges and potential with a focus on changes in DNA methylation. Cancer Epidemiol Biomark Prev. 2020;29:2416–22. https://doi.org/10.1158/1055-9965.epi-20-0704.

95.

Holčáková J. Effect of DNA methylation on the development of Cancer. Klin Onkol. 2018;31(Suppl 2):41–5. https://doi.org/10.14735/amko20182S41.CrossRefPubMed

96.

Moran S, Martínez-Cardús A, Sayols S, Musulén E, Balañá C, Estival-Gonzalez A, et al. Epigenetic profiling to classify cancer of unknown primary: a multicentre, retrospective analysis. Lancet Oncol. 2016;17(10):1386–95. https://doi.org/10.1016/S1470-2045(16)30297-2.

97.

Dor Y, Cedar H. Principles of DNA methylation and their implications for biology and medicine. Lancet. 2018;392(10149):777–86. https://doi.org/10.1016/S0140-6736(18)31268-6.CrossRefPubMed

98.

Villanueva A, Portela A, Sayols S, Battiston C, Hoshida Y, Méndez-González J, et al. DNA methylation-based prognosis and epidrivers in hepatocellular carcinoma. Hepatology. 2015;61(6):1945–56. https://doi.org/10.1002/hep.27732.

99.

Lu CY, Chen SY, Peng HL, Kan PY, Chang WC, Yen CJ. Cell-free methylation markers with diagnostic and prognostic potential in hepatocellular carcinoma. Oncotarget. 2017;8(4):6406–18. https://doi.org/10.18632/oncotarget.14115.CrossRefPubMed

100.

Xu RH, Wei W, Krawczyk M, Wang W, Luo H, Flagg K, et al. Circulating tumour DNA methylation markers for diagnosis and prognosis of hepatocellular carcinoma. Nat Mater. 2017;16(11):1155–61. https://doi.org/10.1038/nmat4997.

101.

Kisiel JB, Dukek BA, RVSRK, Ghoz HM, Yab TC, Berger CK, et al. Hepatocellular carcinoma detection by plasma methylated DNA: discovery, phase I pilot, and phase II clinical validation. Hepatology. 2019;69(3):1180–92. https://doi.org/10.1002/hep.30244.

102.

Mudbhary R, Hoshida Y, Chernyavskaya Y, Jacob V, Villanueva A, Fiel MI, et al. UHRF1 overexpression drives DNA hypomethylation and hepatocellular carcinoma. Cancer Cell. 2014;25(2):196–209. https://doi.org/10.1016/j.ccr.2014.01.003.

103.

Zhang H, Dong P, Guo S, Tao C, Chen W, Zhao W, et al. Hypomethylation in HBV integration regions aids non-invasive surveillance to hepatocellular carcinoma by low-pass genome-wide bisulfite sequencing. BMC Med. 2020;18(1):200. https://doi.org/10.1186/s12916-020-01667-x.

104.

Chen MM, Zhao RC, Chen KF, Huang Y, Liu ZJ, Wei YG, et al. Hypomethylation of CTCFL promoters as a noninvasive biomarker in plasma from patients with hepatocellular carcinoma. Neoplasma. 2020;67(04):909–15. https://doi.org/10.4149/neo_2020_190819N789.

105.

Hu N, Fan XP, Fan YC, Chen LY, Qiao CY, Han LY, et al. Hypomethylated ubiquitin-conjugating enzyme2 Q1 (UBE2Q1) gene promoter in the serum is a promising biomarker for hepatitis B virus-associated hepatocellular carcinoma. Tohoku J Exp Med. 2017;242(2):93–100. https://doi.org/10.1620/tjem.242.93.

106.

Yan L, Chen Y, Zhou J, Zhao H, Zhang H, Wang G. Diagnostic value of circulating cell-free DNA levels for hepatocellular carcinoma. Int J Infect Dis. 2018;67:92–7. https://doi.org/10.1016/j.ijid.2017.12.002.CrossRefPubMed

107.

Oh CR, Kong SY, Im HS, Kim HJ, Kim MK, Yoon KA, et al. Genome-wide copy number alteration and VEGFA amplification of circulating cell-free DNA as a biomarker in advanced hepatocellular carcinoma patients treated with Sorafenib. BMC Cancer. 2019;19(1):292. https://doi.org/10.1186/s12885-019-5483-x.

108.

Liao W, Yang H, Xu H, Wang Y, Ge P, Ren J, et al. Noninvasive detection of tumor-associated mutations from circulating cell-free DNA in hepatocellular carcinoma patients by targeted deep sequencing. Oncotarget. 2016;7(26):40481–90. https://doi.org/10.18632/oncotarget.9629.

109.

Hlady RA, Zhou D, Puszyk W, Roberts LR, Liu C, Robertson KD. Initiation of aberrant DNA methylation patterns and heterogeneity in precancerous lesions of human hepatocellular cancer. Epigenetics. 2017;12(3):215–25. https://doi.org/10.1080/15592294.2016.1277297.CrossRefPubMedPubMedCentral

110.

Cai Z, Chen G, Zeng Y, Dong X, Li Z, Huang Y, et al. Comprehensive liquid profiling of circulating tumor DNA and protein biomarkers in long-term follow-up patients with hepatocellular carcinoma. Clin Cancer Res. 2019;25(17):5284–94. https://doi.org/10.1158/1078-0432.CCR-18-3477.

111.

Cai J, Chen L, Zhang Z, Zhang X, Lu X, Liu W, et al. Genome-wide mapping of 5-hydroxymethylcytosines in circulating cell-free DNA as a non-invasive approach for early detection of hepatocellular carcinoma. Gut. 2019;68(12):2195–205. https://doi.org/10.1136/gutjnl-2019-318882.

112.

Chen X, Gole J, Gore A, He Q, Lu M, Min J, et al. Non-invasive early detection of cancer four years before conventional diagnosis using a blood test. Nat Commun. 2020;11(1):3475. https://doi.org/10.1038/s41467-020-17316-z.

113.

Wong IH, Lo YM, Yeo W, Lau WY, Johnson PJ. Frequent p15 promoter methylation in tumor and peripheral blood from hepatocellular carcinoma patients. Clin Cancer Res. 2000;6(9):3516–21.PubMed

114.

Mohamed NA, Swify EM, Amin NF, Soliman MM, Tag-Eldin LM, Elsherbiny NM. Is serum level of methylated RASSF1A valuable in diagnosing hepatocellular carcinoma in patients with chronic viral hepatitis C? Arab J Gastroenterol. 2012;13(3):111–5. https://doi.org/10.1016/j.ajg.2012.06.009.CrossRefPubMed

115.

Feng J, Dai W, Mao Y, Wu L, Li J, Chen K, et al. Simvastatin re-sensitizes hepatocellular carcinoma cells to sorafenib by inhibiting HIF-1α/PPAR-γ/PKM2-mediated glycolysis. J Exp Clin Cancer Res. 2020;39(1):24. https://doi.org/10.1186/s13046-020-1528-x.

116.

Tornesello ML, Buonaguro L, Izzo F, Buonaguro FM. Molecular alterations in hepatocellular carcinoma associated with hepatitis B and hepatitis C infections. Oncotarget. 2016;7(18):25087–102. https://doi.org/10.18632/oncotarget.7837.CrossRefPubMedPubMedCentral

117.

Mathew S, Abdel-Hafiz H, Raza A, Fatima K, Qadri I. Host nucleotide polymorphism in hepatitis B virus-associated hepatocellular carcinoma. World J Hepatol. 2016;8(10):485–98. https://doi.org/10.4254/wjh.v8.i10.485.CrossRefPubMedPubMedCentral

118.

Zhang W, He H, Zang M, Wu Q, Zhao H, Lu LL, et al. Genetic features of aflatoxin-associated hepatocellular carcinoma. Gastroenterology. 2017;153:249–62 e242.

119.

Nahon P, Nault JC. Constitutional and functional genetics of human alcohol-related hepatocellular carcinoma. Liver Int. 2017;37(11):1591–601. https://doi.org/10.1111/liv.13419.CrossRefPubMed

120.

Li X, Wang H, Li T, Wang L, Wu X, Liu J, et al. Circulating tumor DNA/circulating tumor cells and the applicability in different causes induced hepatocellular carcinoma. Curr Probl Cancer. 2020;44(2):100516. https://doi.org/10.1016/j.currproblcancer.2019.100516.

121.

Jiao J, Watt GP, Stevenson HL, Calderone TL, Fisher-Hoch SP, Ye Y, et al. Telomerase reverse transcriptase mutations in plasma DNA in patients with hepatocellular carcinoma or cirrhosis: prevalence and risk factors. Hepatol Commun. 2018;2(6):718–31. https://doi.org/10.1002/hep4.1187.

122.

Alunni-Fabbroni M, Rönsch K, Huber T, Cyran CC, Seidensticker M, Mayerle J, et al. Circulating DNA as prognostic biomarker in patients with advanced hepatocellular carcinoma: a translational exploratory study from the SORAMIC trial. J Transl Med. 2019;17(1):328. https://doi.org/10.1186/s12967-019-2079-9.

123.

Feng J, Wu L, Ji J, Chen K, Yu Q, Zhang J, et al. PKM2 is the target of proanthocyanidin B2 during the inhibition of hepatocellular carcinoma. J Exp Clin Cancer Res. 2019;38(1):204. https://doi.org/10.1186/s13046-019-1194-z.

124.

Lim HY, Merle P, Weiss KH, Yau T, Ross P, Mazzaferro V, et al. Phase II studies with Refametinib or Refametinib plus Sorafenib in patients with RAS-mutated hepatocellular carcinoma. Clin Cancer Res. 2018;24(19):4650–61. https://doi.org/10.1158/1078-0432.CCR-17-3588.

125.

Galle E, Thienpont B, Cappuyns S, Venken T, Busschaert P, Van Haele M, et al. DNA methylation-driven EMT is a common mechanism of resistance to various therapeutic agents in cancer. Clin Epigenetics. 2020;12(1):27. https://doi.org/10.1186/s13148-020-0821-z.

126.

Chen S, Cao Q, Wen W, Wang H. Targeted therapy for hepatocellular carcinoma: challenges and opportunities. Cancer Lett. 2019;460:1–9. https://doi.org/10.1016/j.canlet.2019.114428.CrossRefPubMed

127.

Zhu AX, Kang YK, Yen CJ, Finn RS, Galle PR, Llovet JM, 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):282–96. https://doi.org/10.1016/S1470-2045(18)30937-9.

128.

Iseda N, Itoh S, Tomiyama T, Morinaga A, Wang H, Shimagaki T, et al. Immune response on outcomes in hepatocellular carcinoma. Gan To Kagaku Ryoho. 2020;47(9):1303–6.

129.

Casak SJ, Donoghue M, Fashoyin-Aje L, Jiang X, Rodriguez L, Shen YL, et al. FDA approval summary: Atezolizumab plus bevacizumab for the treatment of patients with advanced unresectable or metastatic hepatocellular carcinoma. Clin Cancer Res. 2020;27:1836–41. https://doi.org/10.1158/1078-0432.ccr-20-3407.

130.

Singal G, Miller PG, Agarwala V, Li G, Kaushik G, Backenroth D, et al. Association of Patient Characteristics and Tumor Genomics with Clinical Outcomes among Patients with non-Small Cell Lung Cancer Using a Clinicogenomic database. Jama. 2019;321(14):1391–9. https://doi.org/10.1001/jama.2019.3241.

131.

Jensen TJ, Goodman AM, Kato S, Ellison CK, Daniels GA, Kim L, et al. Genome-wide sequencing of cell-free DNA identifies copy-number alterations that can be used for monitoring response to immunotherapy in Cancer patients. Mol Cancer Ther. 2019;18(2):448–58. https://doi.org/10.1158/1535-7163.MCT-18-0535.

132.

Goldberg SB, Narayan A, Kole AJ, Decker RH, Teysir J, Carriero NJ, et al. Early assessment of lung Cancer immunotherapy response via circulating tumor DNA. Clin Cancer Res. 2018;24(8):1872–80. https://doi.org/10.1158/1078-0432.CCR-17-1341.

133.

Ashida A, Sakaizawa K, Uhara H, Okuyama R. Circulating tumour DNA for monitoring treatment response to anti-PD-1 immunotherapy in melanoma patients. Acta Derm Venereol. 2017;97(10):1212–8. https://doi.org/10.2340/00015555-2748.CrossRefPubMed

134.

Jin Y, Chen DL, Wang F, Yang CP, Chen XX, You JQ, et al. The predicting role of circulating tumor DNA landscape in gastric cancer patients treated with immune checkpoint inhibitors. Mol Cancer. 2020;19(1):154. https://doi.org/10.1186/s12943-020-01274-7.

135.

Herbreteau G, Langlais A, Greillier L, Audigier-Valette C, Uwer L, Hureaux J, et al. Circulating tumor DNA as a prognostic determinant in small cell lung cancer patients receiving atezolizumab. J Clin Med. 2020;9(12). https://doi.org/10.3390/jcm9123861.

136.

Marsavela G, Lee J, Calapre L, Wong SQ, Pereira MR, McEvoy AC, et al. Circulating tumor DNA predicts outcome from first-, but not second-line treatment and identifies melanoma patients who may benefit from combination immunotherapy. Clin Cancer Res. 2020;26(22):5926–33. https://doi.org/10.1158/1078-0432.CCR-20-2251.

137.

Weng J, Atyah M, Zhou C, Ren N. Prospects and challenges of circulating tumor DNA in precision medicine of hepatocellular carcinoma. Clin Exp Med. 2020;20(3):329–37. https://doi.org/10.1007/s10238-020-00620-9.CrossRefPubMed

138.

Forner A, Reig M, Bruix J. Hepatocellular carcinoma. Lancet. 2018;391(10127):1301–14. https://doi.org/10.1016/S0140-6736(18)30010-2.CrossRefPubMed

139.

Vogel A, Cervantes A, Chau I, Daniele B, Llovet JM, Meyer T, et al. Hepatocellular carcinoma: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2019;30(5):871–3. https://doi.org/10.1093/annonc/mdy510.

140.

Bruix J, Sherman M. Management of hepatocellular carcinoma: an update. Hepatology. 2011;53(3):1020–2. https://doi.org/10.1002/hep.24199.CrossRefPubMed

141.

Cai ZX, Chen G, Zeng YY, Dong XQ, Lin MJ, Huang XH, et al. Circulating tumor DNA profiling reveals clonal evolution and real-time disease progression in advanced hepatocellular carcinoma. Int J Cancer. 2017;141(5):977–85. https://doi.org/10.1002/ijc.30798.

142.

Ng CKY, Di Costanzo GG, Tosti N, Paradiso V, Coto-Llerena M, Roscigno G, et al. Genetic profiling using plasma-derived cell-free DNA in therapy-naïve hepatocellular carcinoma patients: a pilot study. Ann Oncol. 2018;29(5):1286–91. https://doi.org/10.1093/annonc/mdy083.

143.

An Y, Guan Y, Xu Y, Han Y, Wu C, Bao C, et al. The diagnostic and prognostic usage of circulating tumor DNA in operable hepatocellular carcinoma. Am J Transl Res. 2019;11:6462–74.

144.

Ma G, Ge Y, Gu D, Du M, Chu H, Chen J, et al. Functional annotation of colorectal cancer susceptibility loci identifies MLH1 rs1800734 associated with MSI patients. Gut. 2016;65(7):1227–8. https://doi.org/10.1136/gutjnl-2016-311543.

145.

Kim SS, Eun JW, Choi JH, Woo HG, Cho HJ, Ahn HR, et al. MLH1 single-nucleotide variant in circulating tumor DNA predicts overall survival of patients with hepatocellular carcinoma. Sci Rep. 2020;10(1):17862. https://doi.org/10.1038/s41598-020-74494-y.

146.

Li F, Qiao CY, Gao S, Fan YC, Chen LY, Wang K. Circulating cell-free DNA of methylated insulin-like growth factor-binding protein 7 predicts a poor prognosis in hepatitis B virus-associated hepatocellular carcinoma after hepatectomy. Free Radic Res. 2018;52(4):455–64. https://doi.org/10.1080/10715762.2018.1443448.CrossRefPubMed

147.

Yang YC, Wang D, Jin L, Yao HW, Zhang JH, Wang J, et al. Circulating tumor DNA detectable in early- and late-stage colorectal cancer patients. Biosci Rep. 2018;38(4). https://doi.org/10.1042/BSR20180322.

148.

Sundaresan TK, Sequist LV, Heymach JV, Riely GJ, Jänne PA, Koch WH, et al. Detection of T790M, the acquired resistance EGFR mutation, by tumor biopsy versus noninvasive blood-based analyses. Clin Cancer Res. 2016;22(5):1103–10. https://doi.org/10.1158/1078-0432.CCR-15-1031.

149.

Liu HE, Vuppalapaty M, Wilkerson C, Renier C, Chiu M, Lemaire C, et al. Detection of EGFR mutations in cfDNA and CTCs, and comparison to tumor tissue in non-small-cell-lung-cancer (NSCLC) patients. Front Oncol. 2020;10:572895. https://doi.org/10.3389/fonc.2020.572895.

150.

Takeda K, Yamada T, Takahashi G, Iwai T, Ueda K, Kuriyama S, et al. Analysis of colorectal cancer-related mutations by liquid biopsy: utility of circulating cell-free DNA and circulating tumor cells. Cancer Sci. 2019;110(11):3497–509. https://doi.org/10.1111/cas.14186.

151.

Freidin MB, Freydina DV, Leung M, Montero Fernandez A, Nicholson AG, Lim E. Circulating tumor DNA outperforms circulating tumor cells for KRAS mutation detection in thoracic malignancies. Clin Chem. 2015;61(10):1299–304. https://doi.org/10.1373/clinchem.2015.242453.CrossRefPubMed

152.

Hodara E, Morrison G, Cunha A, Zainfeld D, Xu T, Xu Y, et al. Multiparametric liquid biopsy analysis in metastatic prostate cancer. JCI Insight. 2019;4(5). https://doi.org/10.1172/jci.insight.125529.

153.

Kelley RK, Magbanua MJ, Butler TM, Collisson EA, Hwang J, Sidiropoulos N, 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. https://doi.org/10.1186/s12885-015-1195-z.

154.

Lin VTG, Yang ES. The pros and cons of incorporating transcriptomics in the age of precision oncology. J Natl Cancer Inst. 2019;111(10):1016–22. https://doi.org/10.1093/jnci/djz114.CrossRefPubMedPubMedCentral

155.

Huang X, Liu S, Wu L, Jiang M, Hou Y. High throughput single cell RNA sequencing, bioinformatics analysis and applications. Adv Exp Med Biol. 2018;1068:33–43. https://doi.org/10.1007/978-981-13-0502-3_4.CrossRefPubMed

156.

Jan YJ, Yoon J, Chen JF, Teng PC, Yao N, Cheng S, et al. A circulating tumor cell-RNA assay for assessment of androgen receptor signaling inhibitor sensitivity in metastatic castration-resistant prostate cancer. Theranostics. 2019;9(10):2812–26. https://doi.org/10.7150/thno.34485.

157.

Rodon J, Soria JC, Berger R, Miller WH, Rubin E, Kugel A, et al. Genomic and transcriptomic profiling expands precision cancer medicine: the WINTHER trial. Nat Med. 2019;25(5):751–8. https://doi.org/10.1038/s41591-019-0424-4.

158.

Tuxen IV, Rohrberg KS, Oestrup O, Ahlborn LB, Schmidt AY, Spanggaard I, et al. Copenhagen prospective personalized oncology (CoPPO)-clinical utility of using molecular profiling to select patients to phase I trials. Clin Cancer Res. 2019;25(4):1239–47. https://doi.org/10.1158/1078-0432.CCR-18-1780.

Title: Current status of ctDNA in precision oncology for hepatocellular carcinoma
Authors: Yan Li
Yuanyuan Zheng
Liwei Wu
Jingjing Li
Jie Ji
Qiang Yu
Weiqi Dai
Jiao Feng
Jianye Wu
Chuanyong Guo
Publication date: 01-12-2021
Publisher: BioMed Central
Keywords: Hepatocellular Carcinoma
Hepatocellular Carcinoma
Published in: Journal of Experimental & Clinical Cancer Research / Issue 1/2021
Electronic ISSN: 1756-9966
DOI: https://doi.org/10.1186/s13046-021-01940-8

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 1/2021

Super-enhancers: a new frontier for epigenetic modifiers in cancer chemoresistance

What are the applications of single-cell RNA sequencing in cancer research: a systematic review

Circulating tumor DNA tracking through driver mutations as a liquid biopsy-based biomarker for uveal melanoma

Long non-coding RNA SLC2A1-AS1 induced by GLI3 promotes aerobic glycolysis and progression in esophageal squamous cell carcinoma by sponging miR-378a-3p to enhance Glut1 expression

Preclinical models of pancreatic ductal adenocarcinoma: challenges and opportunities in the era of precision medicine

PFKFB4 is overexpressed in clear-cell renal cell carcinoma promoting pentose phosphate pathway that mediates Sunitinib resistance

Keynote webinar | Spotlight on antibody–drug conjugates in cancer