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Journal of Experimental & Clinical Cancer Research

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01-12-2021 | Hepatocellular Carcinoma | Research

Identification and monitoring of mutations in circulating cell-free tumor DNA in hepatocellular carcinoma treated with lenvatinib

Authors: Yasutoshi Fujii, Atsushi Ono, C. Nelson Hayes, Hiroshi Aikata, Masami Yamauchi, Shinsuke Uchikawa, Kenichiro Kodama, Yuji Teraoka, Hatsue Fujino, Takashi Nakahara, Eisuke Murakami, Daiki Miki, Wataru Okamoto, Tomokazu Kawaoka, Masataka Tsuge, Michio Imamura, Kazuaki Chayama

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

Abstract

Background

There has been a recent surge in interest in predicting biological effects associated with genomic alterations in order to implement personalized cancer treatment strategies. However, no reports have yet evaluated the utility of profiling blood-based circulating tumor DNA (ctDNA) in hepatocellular carcinoma (HCC) patients treated with lenvatinib (LEN).

Method

We retrospectively performed ctDNA next-generation sequencing (NGS) analysis in 24 patients with advanced HCC at baseline and 4 weeks after initiation of LEN. Association of the changes in variant allele frequencies (VAFs) during treatment and clinical outcome were evaluated.

Results

In total, 131 single nucleotide variants, 17 indels, and 23 copy number variations were detected as somatic alterations in 28, 6, and 12 genes, respectively in 23 of 24 patients. The most frequently altered genes were TP53 (54%), CTNNB1 (42%), TERT (42%), ATM (25%), and ARID1A (13%). The reduction in the mean frequency of variants (VAF_mean) following 4 weeks of LEN treatment was associated with longer progression-free survival. The specificity and sensitivity of the reduction of VAF_mean for predicting partial response were 0.67 and 1.0, respectively, which were higher than those of serum α-fetoprotein level (0.10 and 0.93, respectively). No association between the mutation status at baseline and the effectiveness of LEN was observed.

Conclusion

Our study demonstrated that somatic alterations could be detected in the majority of advanced HCC patients by ctDNA profiling and that ctDNA-kinetics during LEN treatment was a useful marker of disease progression. These results suggest that ctDNA profiling is a promising method that provides valuable information in clinical practice.

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Abubakar II, Tillmann T, Banerjee A. Global, regional, and national age-sex specific all-cause and cause-specific mortality for 240 causes of death, 1990–2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet. 2015;385(9963):117–71.CrossRef

Kudo M. Lenvatinib may drastically change the treatment landscape of hepatocellular carcinoma. Liver Cancer. 2018;7(1):1–19. https://doi.org/10.1159/000487148.CrossRefPubMedPubMedCentral

Kudo M, Finn RS, Qin S, Han KH, Ikeda K, Piscaglia F, 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):1163–73. https://doi.org/10.1016/S0140-6736(18)30207-1.CrossRefPubMed

Finn RS, Qin S, Ikeda M, Galle PR, Ducreux M, Kim TY, et al. Atezolizumab plus Bevacizumab in Unresectable Hepatocellular Carcinoma. N Engl J Med. 2020;382(20):1894–905. https://doi.org/10.1056/NEJMoa1915745.CrossRefPubMed

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.CrossRefPubMed

Harding JJ, Nandakumar S, Armenia J, Khalil DN, Albano M, Ly M, et al. Prospective genotyping of hepatocellular carcinoma: clinical implications of next-generation sequencing for matching patients to targeted and immune therapies. Clin Cancer Res. 2019;25(7):2116–26. https://doi.org/10.1158/1078-0432.CCR-18-2293.CrossRefPubMed

von Felden J, Craig AJ, Garcia-Lezana T, Labgaa I. Mutations in circulating tumor DNA predict primary resistance to systemic therapies in advanced hepatocellular carcinoma. Oncogene. 2021;40(1):140–51. https://doi.org/10.1038/s41388-020-01519-1.CrossRef

Fujimoto A, Totoki Y, Abe T, Boroevich KA, Hosoda F, Nguyen HH, et al. Whole-genome sequencing of liver cancers identifies etiological influences on mutation patterns and recurrent mutations in chromatin regulators. Nat Genet. 2012;44(7):760–4. https://doi.org/10.1038/ng.2291.CrossRefPubMed

Cleary SP, Jeck WR, Zhao X, Chen K, Selitsky SR, Savich GL, et al. Identification of driver genes in hepatocellular carcinoma by exome sequencing. Hepatology. 2013;58(5):1693–702. https://doi.org/10.1002/hep.26540.CrossRefPubMed

10.

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.CrossRefPubMedPubMedCentral

11.

Schulze K, Nault JC, Villanueva A. Genetic profiling of hepatocellular carcinoma using next-generation sequencing. J Hepatol. 2016;65(5):1031–42. https://doi.org/10.1016/j.jhep.2016.05.035.CrossRefPubMed

12.

Gerlinger M, Rowan AJ, Horswell S, Math M, Larkin J, Endesfelder D, et al. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med. 2012;366(10):883–92. https://doi.org/10.1056/NEJMoa1113205.CrossRefPubMedPubMedCentral

13.

Russano M, Napolitano A, Ribelli G. Liquid biopsy and tumor heterogeneity in metastatic solid tumors: the potentiality of blood samples. J Exp Clin Cancer Res. 2020;39(1):95. https://doi.org/10.1186/s13046-020-01601-2.CrossRefPubMedPubMedCentral

14.

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

15.

Chan KC, Jiang P, Zheng YW, Liao GJ, Sun H, Wong J, et al. Cancer genome scanning in plasma: detection of tumor-associated copy number aberrations, single-nucleotide variants, and tumoral heterogeneity by massively parallel sequencing. Clin Chem. 2013;59(1):211–24. https://doi.org/10.1373/clinchem.2012.196014.CrossRefPubMed

16.

Liao H, Li H. Advances in the detection technologies and clinical applications of circulating tumor DNA in metastatic breast Cancer. Cancer Manag Res. 2020;12:3547–60. https://doi.org/10.2147/CMAR.S249041.CrossRefPubMedPubMedCentral

17.

Wei J, Liu X, Li T, Xing P, Zhang C, Yang J. The new horizon of liquid biopsy in sarcoma: the potential utility of circulating tumor nucleic acids. J Cancer. 2020;11(18):5293–308. https://doi.org/10.7150/jca.42816.CrossRefPubMedPubMedCentral

18.

Ono A, Fujimoto A, Yamamoto Y, Akamatsu S, Hiraga N, Imamura M, et al. Circulating tumor DNA analysis for liver cancers and its usefulness as a liquid biopsy. Cell Mol Gastroenterol Hepatol. 2015;1(5):516–34. https://doi.org/10.1016/j.jcmgh.2015.06.009.CrossRefPubMedPubMedCentral

19.

Yamauchi M, Urabe Y, Ono A, Miki D, Ochi H, Chayama K. Serial profiling of circulating tumor DNA for optimization of anti-VEGF chemotherapy in metastatic colorectal cancer patients. Int J Cancer. 2018;142(7):1418–26. https://doi.org/10.1002/ijc.31154.CrossRefPubMed

20.

He G, Chen Y, Zhu C, Zhou J, Xie X, Fei R, et al. Application of plasma circulating cell-free DNA detection to the molecular diagnosis of hepatocellular carcinoma. Am J Transl Res. 2019;11(3):1428–45.PubMedPubMedCentral

21.

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.CrossRefPubMedPubMedCentral

22.

Ikeda S, Lim JS, Kurzrock R. Analysis of tissue and circulating tumor DNA by next-generation sequencing of hepatocellular carcinoma: implications for targeted therapeutics. Mol Cancer Ther. 2018;17(5):1114–22. https://doi.org/10.1158/1535-7163.MCT-17-0604.CrossRefPubMedPubMedCentral

23.

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.CrossRefPubMedPubMedCentral

24.

Howell J, Atkinson SR, Pinato DJ, Knapp S, Ward C, Minisini R, et al. Identification of mutations in circulating cell-free tumour DNA as a biomarker in hepatocellular carcinoma. Eur J Cancer. 2019;116:56–66. https://doi.org/10.1016/j.ejca.2019.04.014.CrossRefPubMed

25.

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.CrossRefPubMedPubMedCentral

26.

O'Leary B, Hrebien S, Morden JP, Beaney M, Fribbens C, Huang X, et al. Early circulating tumor DNA dynamics and clonal selection with palbociclib and fulvestrant for breast cancer. Nat Commun. 2018;9(1):896. https://doi.org/10.1038/s41467-018-03215-x.CrossRefPubMedPubMedCentral

27.

Raja R, Kuziora M, Brohawn PZ, Higgs BW, Gupta A, Dennis PA, et al. Early reduction in ctDNA predicts survival in patients with lung and bladder Cancer treated with Durvalumab. Clin Cancer Res. 2018;24(24):6212–22. https://doi.org/10.1158/1078-0432.CCR-18-0386.CrossRefPubMed

28.

World Medical Association Declaration of Helsinki. Ethical principles for medical research involving human subjects. JAMA. 2013;310(20):2191–4.CrossRef

29.

Lencioni R, Llovet JM. Modified RECIST (mRECIST) assessment for hepatocellular carcinoma. Semin Liver Dis. 2010;30(1):52–60. https://doi.org/10.1055/s-0030-1247132.CrossRefPubMed

30.

Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228–47. https://doi.org/10.1016/j.ejca.2008.10.026.CrossRefPubMed

31.

Lanman RB, Mortimer SA, Zill OA, Sebisanovic D, Lopez R, Blau S, et al. Analytical and clinical validation of a digital sequencing panel for quantitative, highly accurate evaluation of cell-free circulating tumor DNA. PLoS One. 2015;10(10):e0140712. https://doi.org/10.1371/journal.pone.0140712.CrossRefPubMedPubMedCentral

32.

Zill OA, Banks KC, Fairclough SR, Mortimer SA, Vowles JV, Mokhtari R, et al. The landscape of actionable genomic alterations in cell-free circulating tumor DNA from 21,807 advanced Cancer patients. Clin Cancer Res. 2018;24(15):3528–38. https://doi.org/10.1158/1078-0432.CCR-17-3837.CrossRefPubMed

33.

Odegaard JI, Vincent JJ, Mortimer S, Vowles JV, Ulrich BC, Banks KC, et al. Validation of a plasma-based comprehensive Cancer genotyping assay utilizing orthogonal tissue- and plasma-based methodologies. Clin Cancer Res. 2018;24(15):3539–49. https://doi.org/10.1158/1078-0432.CCR-17-3831.CrossRefPubMed

34.

Chakravarty D, Gao J, Phillips SM, Kundra R, Zhang H, Wang J, et al. OncoKB: A Precision Oncology Knowledge Base. JCO Precis Oncol. 2017;1:1–6 PO.17.00011.

35.

Landrum MJ, Lee JM, Riley GR, Jang W, Rubinstein WS, Church DM, et al. ClinVar: public archive of relationships among sequence variation and human phenotype. Nucleic Acids Res. 2014;42(Database issue):D980–5. https://doi.org/10.1093/nar/gkt1113.CrossRefPubMed

36.

Tate JG, Bamford S, Jubb HC, Sondka Z, Beare DM, Bindal N, et al. COSMIC: the catalogue of somatic mutations in Cancer. Nucleic Acids Res. 2019;47(D1):D941–d7. https://doi.org/10.1093/nar/gky1015.CrossRefPubMed

37.

Li Q, Wang K. InterVar: clinical interpretation of genetic variants by the 2015 ACMG-AMP guidelines. Am J Hum Genet. 2017;100(2):267–80. https://doi.org/10.1016/j.ajhg.2017.01.004.CrossRefPubMedPubMedCentral

38.

Griffith M, Spies NC, Krysiak K, McMichael JF, Coffman AC, Danos AM, et al. CIViC is a community knowledgebase for expert crowdsourcing the clinical interpretation of variants in cancer. Nat Genet. 2017;49(2):170–4. https://doi.org/10.1038/ng.3774.CrossRefPubMedPubMedCentral

39.

Tamborero D, Rubio-Perez C, Deu-Pons J, Schroeder MP, Vivancos A, Rovira A, et al. Cancer genome interpreter annotates the biological and clinical relevance of tumor alterations. Genome Med. 2018;10(1):25. https://doi.org/10.1186/s13073-018-0531-8.CrossRefPubMedPubMedCentral

40.

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.CrossRefPubMedPubMedCentral

41.

Chen VL, Xu D, Wicha MS, Lok AS, Parikh ND. Utility of liquid biopsy analysis in detection of hepatocellular carcinoma, determination of prognosis, and disease monitoring: a systematic review. Clin Gastroenterol Hepatol. 2020;18(13):2879–2902.e9.CrossRefPubMedPubMedCentral

42.

Cai J, Chen L. 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.CrossRefPubMed

43.

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(10):6462–74.PubMedPubMedCentral

44.

Long G, Fang T, Su W, Mi X, Zhou L. The prognostic value of postoperative circulating cell-free DNA in operable hepatocellular carcinoma. Scand J Gastroenterol. 2020;55(12):1441–6. https://doi.org/10.1080/00365521.2020.1839127.CrossRefPubMed

45.

Bulbul A, Leal A, Husain H. Applications of cell-free circulating tumor DNA detection in EGFR mutant lung cancer. J Thorac Dis. 2020;12(5):2877–82. https://doi.org/10.21037/jtd.2020.01.66.CrossRefPubMedPubMedCentral

46.

Klein-Scory S, Wahner I, Maslova M, Al-Sewaidi Y, Pohl M, Mika T, et al. Evolution of RAS mutational status in liquid biopsies during first-line chemotherapy for metastatic colorectal Cancer. Front Oncol. 2020;10:1115. https://doi.org/10.3389/fonc.2020.01115.CrossRefPubMedPubMedCentral

47.

van Helden EJ, Angus L. RAS and BRAF mutations in cell-free DNA are predictive for outcome of cetuximab monotherapy in patients with tissue-tested RAS wild-type advanced colorectal cancer. Mol Oncol. 2019;13(11):2361–74. https://doi.org/10.1002/1878-0261.12550.CrossRefPubMedPubMedCentral

48.

Yamada T, Matsuda A, Takahashi G, Iwai T, Takeda K, Ueda K, et al. Emerging RAS, BRAF, and EGFR mutations in cell-free DNA of metastatic colorectal patients are associated with both primary and secondary resistance to first-line anti-EGFR therapy. Int J Clin Oncol. 2020;25(8):1523–32. https://doi.org/10.1007/s10147-020-01691-0.CrossRefPubMed

49.

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.CrossRefPubMedPubMedCentral

50.

Navin N, Kendall J, Troge J, Andrews P, Rodgers L, McIndoo J, et al. Tumour evolution inferred by single-cell sequencing. Nature. 2011;472(7341):90–4. https://doi.org/10.1038/nature09807.CrossRefPubMedPubMedCentral

51.

Zhang Q, Luo J, Wu S, Si H, Gao C, Xu W, et al. Prognostic and predictive impact of circulating tumor DNA in patients with advanced cancers treated with immune checkpoint blockade. Cancer Discov. 2020;10(12):1842–53. https://doi.org/10.1158/2159-8290.CD-20-0047.CrossRefPubMedPubMedCentral

52.

Wang T, Zhang KH. New blood biomarkers for the diagnosis of AFP-negative hepatocellular carcinoma. Front Oncol. 2020;10:1316. https://doi.org/10.3389/fonc.2020.01316.CrossRefPubMedPubMedCentral

53.

Gupta S, Bent S, Kohlwes J. Test characteristics of alpha-fetoprotein for detecting hepatocellular carcinoma in patients with hepatitis C. a systematic review and critical analysis. Ann Intern Med. 2003;139(1):46–50. https://doi.org/10.7326/0003-4819-139-1-200307010-00012.CrossRefPubMed

54.

Kodama K, Kawaoka T, Namba M, Uchikawa S, Ohya K, Morio K, et al. Correlation between early tumor marker response and imaging response in patients with advanced hepatocellular carcinoma treated with Lenvatinib. Oncology. 2019;97(2):75–81. https://doi.org/10.1159/000499715.CrossRefPubMed

55.

Nance T, Helman E, Artieri C, Yen J, Slavin TP, Chudova D, et al. Abstract 4272: A novel approach to differentiation of somatic vs. germline variants in liquid biopsies using a betabinomial model. Cancer Res. 2018;78(13 Supplement):4272.

56.

Nakamura Y, Taniguchi H. Clinical utility of circulating tumor DNA sequencing in advanced gastrointestinal cancer: SCRUM-Japan GI-SCREEN and GOZILA studies. Nat Med. 2020;26(12):1859–64. https://doi.org/10.1038/s41591-020-1063-5.CrossRefPubMed

57.

Totoki Y, Tatsuno K, Covington KR, Ueda H, Creighton CJ, Kato M, et al. Trans-ancestry mutational landscape of hepatocellular carcinoma genomes. Nat Genet. 2014;46(12):1267–73. https://doi.org/10.1038/ng.3126.CrossRefPubMed

58.

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

59.

Brunner SF, Roberts ND, Wylie LA, Moore L, Aitken SJ, Davies SE, et al. Somatic mutations and clonal dynamics in healthy and cirrhotic human liver. Nature. 2019;574(7779):538–42. https://doi.org/10.1038/s41586-019-1670-9.CrossRefPubMedPubMedCentral

60.

Lombardo D, Saitta C, Giosa D, Di Tocco FC, Musolino C, Caminiti G, et al. Frequency of somatic mutations in TERT promoter, TP53 and CTNNB1 genes in patients with hepatocellular carcinoma from southern Italy. Oncol Lett. 2020;19(3):2368–74. https://doi.org/10.3892/ol.2020.11332.CrossRefPubMedPubMedCentral

61.

Nault JC, Mallet M, Pilati C, Calderaro J, Bioulac-Sage P, Laurent C, et al. High frequency of telomerase reverse-transcriptase promoter somatic mutations in hepatocellular carcinoma and preneoplastic lesions. Nat Commun. 2013;4(1):2218. https://doi.org/10.1038/ncomms3218.CrossRefPubMed

62.

Amirouchene-Angelozzi N, Swanton C, Bardelli A. Tumor evolution as a therapeutic target. Cancer Discov. 2017;7(8):805–17. https://doi.org/10.1158/2159-8290.CD-17-0343.CrossRef

63.

Si H, Kuziora M, Quinn KJ, Helman E, Ye J, Liu F, et al. A blood-based assay for assessment of tumor mutational burden in first-line metastatic NSCLC treatment: results from the MYSTIC study. Clin Cancer Res. 2021;27(6):1631–40. https://doi.org/10.1158/1078-0432.CCR-20-3771.CrossRefPubMed

64.

Carausu M, Melaabi S. ESR1 mutation detection and dynamics in meningeal Carcinomatosis in breast Cancer. J Breast Cancer. 2020;23(2):218–23. https://doi.org/10.4048/jbc.2020.23.e4.CrossRefPubMed

65.

Robinson DR, Wu YM, Vats P, Su F, Lonigro RJ, Cao X, et al. Activating ESR1 mutations in hormone-resistant metastatic breast cancer. Nat Genet. 2013;45(12):1446–51. https://doi.org/10.1038/ng.2823.CrossRefPubMedPubMedCentral

66.

Ongusaha PP, Kim JI, Fang L, Wong TW, Yancopoulos GD, Aaronson SA, et al. p53 induction and activation of DDR1 kinase counteract p53-mediated apoptosis and influence p53 regulation through a positive feedback loop. EMBO J. 2003;22(6):1289–301. https://doi.org/10.1093/emboj/cdg129.CrossRefPubMedPubMedCentral

67.

Ambrogio C, Gómez-López G, Falcone M, Vidal A, Nadal E, Crosetto N, et al. Combined inhibition of DDR1 and notch signaling is a therapeutic strategy for KRAS-driven lung adenocarcinoma. Nat Med. 2016;22(3):270–7. https://doi.org/10.1038/nm.4041.CrossRefPubMed

68.

Ambrogio C, Nadal E, Villanueva A, Gómez-López G, Cash TP, Barbacid M, et al. KRAS-driven lung adenocarcinoma: combined DDR1/notch inhibition as an effective therapy. ESMO Open. 2016;1(5):e000076. https://doi.org/10.1136/esmoopen-2016-000076.CrossRefPubMedPubMedCentral

69.

Das S, Ongusaha PP, Yang YS, Park JM, Aaronson SA, Lee SW. Discoidin domain receptor 1 receptor tyrosine kinase induces cyclooxygenase-2 and promotes chemoresistance through nuclear factor-kappaB pathway activation. Cancer Res. 2006;66(16):8123–30. https://doi.org/10.1158/0008-5472.CAN-06-1215.CrossRefPubMed

70.

Henriet E, Sala M, Abou Hammoud A, Tuariihionoa A, Di Martino J, Ros M, et al. Multitasking discoidin domain receptors are involved in several and specific hallmarks of cancer. Cell Adhes Migr. 2018;12(4):363–77. https://doi.org/10.1080/19336918.2018.1465156.CrossRef

71.

Choi M, Kipps T, Kurzrock R. ATM mutations in Cancer: therapeutic implications. Mol Cancer Ther. 2016;15(8):1781–91. https://doi.org/10.1158/1535-7163.MCT-15-0945.CrossRefPubMed

72.

Beggs AD, Domingo E, McGregor M, Presz M, Johnstone E, Midgley R, et al. Loss of expression of the double strand break repair protein ATM is associated with worse prognosis in colorectal cancer and loss of Ku70 expression is associated with CIN. Oncotarget. 2012;3(11):1348–55. https://doi.org/10.18632/oncotarget.694.CrossRefPubMedPubMedCentral

73.

Lin K, Adamson J, Johnson GG, Carter A, Oates M, Wade R, et al. Functional analysis of the ATM-p53-p21 pathway in the LRF CLL4 trial: blockade at the level of p21 is associated with short response duration. Clin Cancer Res. 2012;18(15):4191–200. https://doi.org/10.1158/1078-0432.CCR-11-2936.CrossRefPubMed

74.

Fujimaki S, Matsuda Y, Wakai T, Sanpei A, Kubota M, Takamura M, et al. Blockade of ataxia telangiectasia mutated sensitizes hepatoma cell lines to sorafenib by interfering with Akt signaling. Cancer Lett. 2012;319(1):98–108. https://doi.org/10.1016/j.canlet.2011.12.043.CrossRefPubMed

75.

Liu J, Liu Y, Meng L, Ji B, Yang D. Synergistic antitumor effect of Sorafenib in combination with ATM inhibitor in hepatocellular carcinoma cells. Int J Med Sci. 2017;14(6):523–9. https://doi.org/10.7150/ijms.19033.CrossRefPubMedPubMedCentral

76.

Jeric I, Maurer G, Cavallo AL, Raguz J, Desideri E, Tarkowski B, et al. A cell-autonomous tumour suppressor role of RAF1 in hepatocarcinogenesis. Nat Commun. 2016;7(1):13781. https://doi.org/10.1038/ncomms13781.CrossRefPubMedPubMedCentral

77.

Ghousein A, Mosca N, Cartier F, Charpentier J, Dupuy JW, Raymond AA. miR-4510 blocks hepatocellular carcinoma development through RAF1 targeting and RAS/RAF/MEK/ERK signalling inactivation. Liver Int. 2020;40(1):240–51. https://doi.org/10.1111/liv.14276.CrossRefPubMed

78.

Tian N, Wu D, Tang M, Sun H, Ji Y, Huang C, et al. RAF1 expression is correlated with HAF, a parameter of liver computed tomographic perfusion, and may predict the early therapeutic response to Sorafenib in advanced hepatocellular carcinoma patients. Open Med. 2020;15(1):167–74. https://doi.org/10.1515/med-2020-0024.CrossRef

79.

Jeong WJ, Yoon J, Park JC, Lee SH, Lee SH, Kaduwal S, et al. Ras stabilization through aberrant activation of Wnt/β-catenin signaling promotes intestinal tumorigenesis. Sci Signal. 2012;5(219):ra30.CrossRefPubMed

80.

Biechele TL, Kulikauskas RM, Toroni RA, Lucero OM, Swift RD, James RG, et al. Wnt/β-catenin signaling and AXIN1 regulate apoptosis triggered by inhibition of the mutant kinase BRAFV600E in human melanoma. Sci Signal. 2012;5(206):ra3.PubMedPubMedCentral

81.

Hu ZQ, Xin HY, Luo CB, Li J, Zhou ZJ, Zou JX, et al. Associations among the mutational landscape, immune microenvironment, and prognosis in Chinese patients with hepatocellular carcinoma. Cancer Immunol Immunother. 2021;70(2):377–89. https://doi.org/10.1007/s00262-020-02685-7.CrossRefPubMed

82.

Sia D, Jiao Y, Martinez-Quetglas I, Kuchuk O, Villacorta-Martin C. Castro de Moura M, et al. identification of an immune-specific class of hepatocellular carcinoma, based on molecular features. Gastroenterology. 2017;153(3):812–26. https://doi.org/10.1053/j.gastro.2017.06.007.CrossRefPubMed

Title: Identification and monitoring of mutations in circulating cell-free tumor DNA in hepatocellular carcinoma treated with lenvatinib
Authors: Yasutoshi Fujii
Atsushi Ono
C. Nelson Hayes
Hiroshi Aikata
Masami Yamauchi
Shinsuke Uchikawa
Kenichiro Kodama
Yuji Teraoka
Hatsue Fujino
Takashi Nakahara
Eisuke Murakami
Daiki Miki
Wataru Okamoto
Tomokazu Kawaoka
Masataka Tsuge
Michio Imamura
Kazuaki Chayama
Publication date: 01-12-2021
Publisher: BioMed Central
Keywords: Hepatocellular Carcinoma
Hepatocellular Carcinoma
Lenvatinib
Published in: Journal of Experimental & Clinical Cancer Research / Issue 1/2021
Electronic ISSN: 1756-9966
DOI: https://doi.org/10.1186/s13046-021-02016-3

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Correction to: Short hairpin RNA- mediated gene knockdown of FOXM1 inhibits the proliferation and metastasis of human colon cancer cells through reversal of epithelial-to-mesenchymal transformation

Noncoding RNAs regulate alternative splicing in Cancer

PARP inhibitors in gastric cancer: beacon of hope

Cellular based immunotherapy for primary liver cancer

Keynote webinar | Spotlight on antibody–drug conjugates in cancer