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01-08-2017 | Invited Annual Review Issue

Liquid biopsy: unlocking the potentials of cell-free DNA

Authors: David Chu, Ben Ho Park

Published in: Virchows Archiv | Issue 2/2017

Abstract

Circulating tumor DNA (ctDNA) has garnered much excitement over the past few years for its potential clinical utility as a surrogate for tumor biopsies in early cancer detection and prognosis. Numerous studies have demonstrated that ctDNA is shed into the circulation and is elevated in disease states such as cancer. Despite the low levels of ctDNA in the “sea” of normal DNA, advances in next generation sequencing (NGS) and digital polymerase chain reaction (PCR) technologies have led to dramatic improvements in variant detection sensitivity and specificity. These technologies allow the quantification of ctDNA, providing both prognostic and predictive information. Here, we review the history of cell-free DNA and different technologies for the detection of ctDNA in cancer and describe the different modalities for using ctDNA in clinical oncology.

Wood LD, Parsons DW, Jones S et al (2007) The genomic landscapes of human breast and colorectal cancers. Science 318:1108–1113CrossRefPubMed

Gerlinger M, Rowan AJ, Horswell S et al (2012) Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med 366:883–892CrossRefPubMedPubMedCentral

Benesova L, Belsanova B, Suchanek S et al (2013) Mutation-based detection and monitoring of cell-free tumor DNA in peripheral blood of cancer patients. Anal Biochem 433:227–234CrossRefPubMed

Rothe F, Laes JF, Lambrechts D et al (2014) Plasma circulating tumor DNA as an alternative to metastatic biopsies for mutational analysis in breast cancer. Ann Oncol 25:1959–1965CrossRefPubMed

Lebofsky R, Decraene C, Bernard V et al (2015) Circulating tumor DNA as a non-invasive substitute to metastasis biopsy for tumor genotyping and personalized medicine in a prospective trial across all tumor types. Mol Oncol 9:783–790CrossRefPubMed

Mandel P, Metais P (1948) Nucleic acids of human blood plasma. CR Seances Soc Biol Paris 142:241–243

Leon SA, Shapiro B, Sklaroff DM, Yaros MJ (1977) Free DNA in the serum of cancer patients and the effect of therapy. Cancer Res 37:646–650PubMed

Shapiro B, Chakrabarty M, Cohn EM, Leon SA (1983) Determination of circulating DNA levels in patients with benign or malignant gastrointestinal disease. Cancer 51:2116–2120CrossRefPubMed

Stroun M, Anker P, Lyautey J, Lederrey C, Maurice PA (1987) Isolation and characterization of DNA from the plasma of cancer patients. Eur J Cancer Clin Oncol 23:707–712CrossRefPubMed

10.

Maebo A (1990) Plasma DNA level as a tumor marker in primary lung cancer. Nihon Kyobu Shikkan Gakkai Zasshi 28:1085–1091PubMed

11.

Fournie GJ, Courtin JP, Laval F et al (1995) Plasma DNA as a marker of cancerous cell death. Investigations in patients suffering from lung cancer and in nude mice bearing human tumours. Cancer Lett 91:221–227CrossRefPubMed

12.

Diehl F, Li M, Dressman D et al (2005) Detection and quantification of mutations in the plasma of patients with colorectal tumors. Proc Natl Acad Sci U S A 102:16368–16373CrossRefPubMedPubMedCentral

13.

Choi JJ, Reich CF 3rd, Pisetsky DS (2005) The role of macrophages in the in vitro generation of extracellular DNA from apoptotic and necrotic cells. Immunology 115:55–62CrossRefPubMedPubMedCentral

14.

Underhill HR, Kitzman JO, Hellwig S et al (2016) Fragment length of circulating tumor DNA. PLoS Genet 12:e1006162CrossRefPubMedPubMedCentral

15.

Stroun M, Anker P (1972) Nucleic acids spontaneously released by living frog auricles. Biochem J 128:100P–101PCrossRefPubMedPubMedCentral

16.

Anker P, Stroun M, Maurice PA (1975) Spontaneous release of DNA by human blood lymphocytes as shown in an in vitro system. Cancer Res 35:2375–2382PubMed

17.

Stroun M, Lyautey J, Lederrey C, Olson-Sand A, Anker P (2001) About the possible origin and mechanism of circulating DNA apoptosis and active DNA release. Clin Chim Acta 313:139–142CrossRefPubMed

18.

Rogers JC, Boldt D, Kornfeld S, Skinner A, Valeri CR (1972) Excretion of deoxyribonucleic acid by lymphocytes stimulated with phytohemagglutinin or antigen. Proc Natl Acad Sci U S A 69:1685–1689CrossRefPubMedPubMedCentral

19.

Ke WL, Zhao WH, Wang XY (2015) Detection of fetal cell-free DNA in maternal plasma for Down syndrome, Edward syndrome and Patau syndrome of high risk fetus. Int J Clin Exp Med 8:9525–9530PubMedPubMedCentral

20.

Benachi A, Letourneau A, Kleinfinger P et al (2015) Cell-free DNA analysis in maternal plasma in cases of fetal abnormalities detected on ultrasound examination. Obstet Gynecol 125:1330–1337CrossRefPubMed

21.

Wagner AJ, Mitchell ME, Tomita-Mitchell A (2014) Use of cell-free fetal DNA in maternal plasma for noninvasive prenatal screening. Clin Perinatol 41:957–966CrossRefPubMed

22.

El Messaoudi S, Rolet F, Mouliere F, Thierry AR (2013) Circulating cell free DNA: preanalytical considerations. Clin Chim Acta 424:222–230CrossRefPubMed

23.

Vogelstein B, Kinzler KW (1999) Digital PCR. Proc Natl Acad Sci U S A 96:9236–9241CrossRefPubMedPubMedCentral

24.

Diehl F, Schmidt K, Choti MA et al (2008) Circulating mutant DNA to assess tumor dynamics. Nat Med 14:985–990CrossRefPubMed

25.

Forshew T, Murtaza M, Parkinson C et al (2012) Noninvasive identification and monitoring of cancer mutations by targeted deep sequencing of plasma DNA. Sci Transl Med 4:136ra68CrossRefPubMed

26.

Newman AM, Bratman SV, To J et al (2014) An ultrasensitive method for quantitating circulating tumor DNA with broad patient coverage. Nat Med 20:548–554CrossRefPubMedPubMedCentral

27.

Beaver JA, Jelovac D, Balukrishna S et al (2014) Detection of cancer DNA in plasma of patients with early-stage breast cancer. Clin Cancer Res 20:2643–2650CrossRefPubMedPubMedCentral

28.

Bettegowda C, Sausen M, Leary RJ et al (2014) Detection of circulating tumor DNA in early- and late-stage human malignancies. Sci Transl Med 6:224ra24CrossRefPubMedPubMedCentral

29.

Hayes DF, Zurawski VR Jr, Kufe DW (1986) Comparison of circulating CA15-3 and carcinoembryonic antigen levels in patients with breast cancer. J Clin Oncol 4:1542–1550CrossRefPubMed

30.

Yoshimasu T, Maebeya S, Suzuma T et al (1999) Disappearance curves for tumor markers after resection of intrathoracic malignancies. Int J Biol Markers 14:99–105PubMed

31.

Ito K, Hibi K, Ando H et al (2002) Usefulness of analytical CEA doubling time and half-life time for overlooked synchronous metastases in colorectal carcinoma. Jpn J Clin Oncol 32:54–58CrossRefPubMed

32.

Riedinger JM, Wafflart J, Ricolleau G et al (2006) CA 125 half-life and CA 125 nadir during induction chemotherapy are independent predictors of epithelial ovarian cancer outcome: results of a French multicentric study. Ann Oncol 17:1234–1238CrossRefPubMed

33.

Lehner J, Stotzer OJ, Fersching D, Nagel D, Holdenrieder S (2013) Circulating plasma DNA and DNA integrity in breast cancer patients undergoing neoadjuvant chemotherapy. Clin Chim Acta 425:206–211CrossRefPubMed

34.

Lo YM, Zhang J, Leung TN, Lau TK, Chang AM, Hjelm NM (1999) Rapid clearance of fetal DNA from maternal plasma. Am J Hum Genet 64:218–224CrossRefPubMedPubMedCentral

35.

Fleischhacker M, Schmidt B (2007, 1775) Circulating nucleic acids (CNAs) and cancer—a survey. Biochim Biophys Acta:181–232

36.

Dawson SJ, Tsui DW, Murtaza M et al (2013) Analysis of circulating tumor DNA to monitor metastatic breast cancer. N Engl J Med 368:1199–1209CrossRefPubMed

37.

Huang ZH, Li LH, Hua D (2006) Quantitative analysis of plasma circulating DNA at diagnosis and during follow-up of breast cancer patients. Cancer Lett 243:64–70CrossRefPubMed

38.

Garcia JM, Garcia V, Silva J et al (2006) Extracellular tumor DNA in plasma and overall survival in breast cancer patients. Genes Chromosomes Cancer 45:692–701CrossRefPubMed

39.

Madic J, Kiialainen A, Bidard FC et al (2015) Circulating tumor DNA and circulating tumor cells in metastatic triple negative breast cancer patients. Int J Cancer 136:2158–2165CrossRefPubMed

40.

Higgins MJ, Jelovac D, Barnathan E et al (2012) Detection of tumor PIK3CA status in metastatic breast cancer using peripheral blood. Clin Cancer Res 18:3462–3469CrossRefPubMedPubMedCentral

41.

Board RE, Wardley AM, Dixon JM et al (2010) Detection of PIK3CA mutations in circulating free DNA in patients with breast cancer. Breast Cancer Res Treat 120:461–467CrossRefPubMed

42.

Parsons HA, Beaver JA, Cimino-Mathews A, et al 2017 Individualized Molecular Analyses Guide Efforts (IMAGE): a prospective study of molecular profiling of tissue and blood in metastatic triple negative breast cancer. Clin Cancer Res 23(2):379–386

43.

Murtaza M, Dawson SJ, Tsui DW et al (2013) Non-invasive analysis of acquired resistance to cancer therapy by sequencing of plasma DNA. Nature 497:108–112CrossRefPubMed

44.

Leary RJ, Kinde I, Diehl F et al (2010) Development of personalized tumor biomarkers using massively parallel sequencing. Sci Transl Med 2:20ra14CrossRefPubMedPubMedCentral

45.

Olsson E, Winter C, George A et al (2015) Serial monitoring of circulating tumor DNA in patients with primary breast cancer for detection of occult metastatic disease. EMBO Mol Med 7:1034–1047CrossRefPubMedPubMedCentral

46.

Oshiro C, Kagara N, Naoi Y et al (2015) PIK3CA mutations in serum DNA are predictive of recurrence in primary breast cancer patients. Breast Cancer Res Treat 150:299–307CrossRefPubMed

47.

Garcia-Murillas I, Schiavon G, Weigelt B et al (2015) Mutation tracking in circulating tumor DNA predicts relapse in early breast cancer. Sci Transl Med 7:302ra133CrossRefPubMed

48.

Lynch TJ, Bell DW, Sordella R et al (2004) Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 350:2129–2139CrossRefPubMed

49.

Paez JG, Janne PA, Lee JC et al (2004) EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 304:1497–1500CrossRefPubMed

50.

Rosell R, Moran T, Queralt C et al (2009) Screening for epidermal growth factor receptor mutations in lung cancer. N Engl J Med 361:958–967CrossRefPubMed

51.

Taniguchi K, Uchida J, Nishino K et al (2011) Quantitative detection of EGFR mutations in circulating tumor DNA derived from lung adenocarcinomas. Clin Cancer Res 17:7808–7815CrossRefPubMed

52.

Pao W, Miller VA, Politi KA et al (2005) Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain. PLoS Med 2:e73CrossRefPubMedPubMedCentral

53.

Oxnard GR, Paweletz CP, Kuang Y et al (2014) Noninvasive detection of response and resistance in EGFR-mutant lung cancer using quantitative next-generation genotyping of cell-free plasma DNA. Clin Cancer Res 20:1698–1705CrossRefPubMedPubMedCentral

54.

Piotrowska Z, Niederst MJ, Karlovich CA et al (2015) Heterogeneity underlies the emergence of EGFRT790 wild-type clones following treatment of T790M-positive cancers with a third-generation EGFR inhibitor. Cancer Discov 5:713–722CrossRefPubMedPubMedCentral

55.

Chabon JJ, Simmons AD, Lovejoy AF et al (2016) Circulating tumour DNA profiling reveals heterogeneity of EGFR inhibitor resistance mechanisms in lung cancer patients. Nat Commun 7:11815CrossRefPubMedPubMedCentral

56.

Wong NA, Gonzalez D, Salto-Tellez M et al (2014) RAS testing of colorectal carcinoma—a guidance document from the Association of Clinical Pathologists Molecular Pathology and Diagnostics Group. J Clin Pathol 67:751–757CrossRefPubMed

57.

De Roock W, Claes B, Bernasconi D et al (2010) Effects of KRAS, BRAF, NRAS, and PIK3CA mutations on the efficacy of cetuximab plus chemotherapy in chemotherapy-refractory metastatic colorectal cancer: a retrospective consortium analysis. Lancet Oncol 11:753–762CrossRefPubMed

58.

Diaz LA Jr, Williams RT, Wu J et al (2012) The molecular evolution of acquired resistance to targeted EGFR blockade in colorectal cancers. Nature 486:537–540PubMedPubMedCentral

59.

Misale S, Yaeger R, Hobor S et al (2012) Emergence of KRAS mutations and acquired resistance to anti-EGFR therapy in colorectal cancer. Nature 486:532–536PubMedPubMedCentral

60.

Siravegna G, Mussolin B, Buscarino M et al (2015) Clonal evolution and resistance to EGFR blockade in the blood of colorectal cancer patients. Nat Med 21:827CrossRefPubMed

61.

Tie J, Kinde I, Wang Y et al (2015) Circulating tumor DNA as an early marker of therapeutic response in patients with metastatic colorectal cancer. Ann Oncol 26:1715–1722CrossRefPubMedPubMedCentral

62.

Li S, Shen D, Shao J et al (2013) Endocrine-therapy-resistant ESR1 variants revealed by genomic characterization of breast-cancer-derived xenografts. Cell Rep 4:1116–1130CrossRefPubMed

63.

Merenbakh-Lamin K, Ben-Baruch N, Yeheskel A et al (2013) D538G mutation in estrogen receptor-alpha: a novel mechanism for acquired endocrine resistance in breast cancer. Cancer Res 73:6856–6864CrossRefPubMed

64.

Jeselsohn R, Yelensky R, Buchwalter G et al (2014) Emergence of constitutively active estrogen receptor-alpha mutations in pretreated advanced estrogen receptor-positive breast cancer. Clin Cancer Res 20:1757–1767CrossRefPubMedPubMedCentral

65.

Toy W, Shen Y, Won H et al (2013) ESR1 ligand-binding domain mutations in hormone-resistant breast cancer. Nat Genet 45:1439–1445CrossRefPubMedPubMedCentral

66.

Robinson DR, Wu YM, Vats P et al (2013) Activating ESR1 mutations in hormone-resistant metastatic breast cancer. Nat Genet 45:1446–1451CrossRefPubMedPubMedCentral

67.

Chu D, Paoletti C, Gersch C et al (2016) ESR1 mutations in circulating plasma tumor DNA from metastatic breast cancer patients. Clin Cancer Res 22:993–999CrossRefPubMed

68.

Sefrioui D, Perdrix A, Sarafan-Vasseur N et al (2015) Short report: monitoring ESR1 mutations by circulating tumor DNA in aromatase inhibitor resistant metastatic breast cancer. Int J Cancer 137:2513–2519CrossRefPubMed

69.

Guttery DS, Page K, Hills A et al (2015) Noninvasive detection of activating estrogen receptor 1 (ESR1) mutations in estrogen receptor-positive metastatic breast cancer. Clin Chem 61:974–982CrossRefPubMed

70.

Wang P, Bahreini A, Gyanchandani R et al (2016) Sensitive detection of mono- and polyclonal ESR1 mutations in primary tumors, metastatic lesions, and cell-free DNA of breast cancer patients. Clin Cancer Res 22:1130–1137CrossRefPubMed

71.

Schiavon G, Hrebien S, Garcia-Murillas I et al (2015) Analysis of ESR1 mutation in circulating tumor DNA demonstrates evolution during therapy for metastatic breast cancer. Sci Transl Med 7:313ra182CrossRefPubMedPubMedCentral

72.

Fribbens C, O’Leary B, Kilburn L et al (2016) Plasma ESR1 mutations and the treatment of estrogen receptor-positive advanced breast cancer. J Clin Oncol 34:2961–2968CrossRefPubMed

Title: Liquid biopsy: unlocking the potentials of cell-free DNA
Authors: David Chu
Ben Ho Park
Publication date: 01-08-2017
Publisher: Springer Berlin Heidelberg
Published in: Virchows Archiv / Issue 2/2017
Print ISSN: 0945-6317
Electronic ISSN: 1432-2307
DOI: https://doi.org/10.1007/s00428-017-2137-8

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Liquid biopsy: unlocking the potentials of cell-free DNA

Abstract

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