Skip to main content
SpringerLink
Log in

Application of liquid biopsy in precision medicine: opportunities and challenges

  • Review
  • Published:
Frontiers of Medicine Aims and scope Submit manuscript

Abstract

Precision medicine for cancer patients aims to adopt the most suitable treatment options during diagnosis and treatment of individuals. Detecting circulating tumor cell (CTC) or circulating tumor DNA (ctDNA) in plasma or serum could serve as liquid biopsy, which would be useful for numerous diagnostic applications. Liquid biopsies can help clinicians screen and detect cancer early, stratify patients to the most suitable treatment and real-time monitoring of treatment response and resistance mechanisms in the tumor, evaluate the risk for metastatic relapse, and estimate prognosis.We summarized the advantages and disadvantages of tissue and liquid biopsies.We also further compared and analyzed the advantages and limitations of detecting CTCs, ctDNAs, and exosomes. Furthermore, we reviewed the literature related with the application of serum or plasma CTCs, ctDNAs, and exosomes for diagnosis and prognosis of cancer.We also analyzed their opportunities and challenges as future biomarkers. In the future, liquid biopsies could be used to guide cancer treatment. They could also provide the ideal scheme to personalize treatment in precision medicine.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Chan KCA, Jiang PY, Zheng YWL, Liao GJW, Sun H, Wong J, Siu SSN, Chan WC, Chan SL, Chan ATC, Lai PBS, Chiu RWK, Lo YMD. Cancer genome scanning in plasma: detection of tumorassociated copy number aberrations, single-nucleotide variants, and tumoral heterogeneity by massively parallel sequencing. Clin Chem 2013; 59(1): 211–224

    Article  CAS  PubMed  Google Scholar 

  2. Crowley E, Di Nicolantonio F, Loupakis F, Bardelli A. Liquid biopsy: monitoring cancer-genetics in the blood. Nat Rev Clin Oncol 2013; 10(8): 472–484

    Article  CAS  PubMed  Google Scholar 

  3. Brock G, Castellanos-Rizaldos E, Hu L, Coticchia C, Skog J. Liquid biopsy for cancer screening, patient stratification and monitoring. Transl Cancer Res 2015; 4(3): 280–290

    CAS  Google Scholar 

  4. Snyder MW, Kircher M, Hill AJ, Daza RM, Shendure J. Cell-free DNA comprises an in vivo nucleosome footprint that informs its tissues-of-origin. Cell 2016; 164(1–2): 57–68

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Alix-Panabieres C, Pantel K. Clinical applications of circulating tumor cells and circulating tumor DNA as liquid biopsy. Cancer Discov 2016; 6(5): 479–491

    Article  CAS  PubMed  Google Scholar 

  6. Diaz LA Jr, Bardelli A. Liquid biopsies: genotyping circulating tumor DNA. J Clin Oncol 2014; 32(6): 579–586

    Article  PubMed  PubMed Central  Google Scholar 

  7. Cristofanilli M, Budd GT, Ellis MJ, Stopeck A, Matera J, Miller MC, Reuben JM, Doyle GV, Allard WJ, Terstappen LW, Hayes DF. Circulating tumor cells, disease progression, and survival in metastatic breast cancer. N Engl J Med 2004; 351(8): 781–791

    Article  CAS  PubMed  Google Scholar 

  8. Cohen SJ, Punt CJA, Iannotti N, Saidman BH, Sabbath KD, Gabrail NY, Picus J, Morse M, Mitchell E, Miller MC, Doyle GV, Tissing H, Terstappen LWMM, Meropol NJ. Relationship of circulating tumor cells to tumor response, progression-free survival, and overall survival in patients with metastatic colorectal cancer. J Clin Oncol 2008; 26(19): 3213–3221

    Article  PubMed  Google Scholar 

  9. De Bono JS, Scher HI, Montgomery RB, Parker C, Miller MC, Tissing H, Doyle GV, Terstappen LW, Pienta KJ, Raghavan D. Circulating tumor cells predict survival benefit from treatment in metastatic castration-resistant prostate cancer. Clinic Cancer Res 2008; 14(19): 6302–6309

    Article  Google Scholar 

  10. Rhim AD, Mirek ET, Aiello NM, Maitra A, Bailey JM, McAllister F, Reichert M, Beatty GL, Rustgi AK, Vonderheide RH, Leach SD, Stanger BZ. EMT and dissemination precede pancreatic tumor formation. Cell 2012; 148(1–2): 349–361

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Chaffer CL, Weinberg RA. A perspective on cancer cell metastasis. Science 2011; 331(6024): 1559–1564

    Article  CAS  PubMed  Google Scholar 

  12. Gold B, Cankovic M, Furtado LV, Meier F, Gocke CD. Do circulating tumor cells, exosomes, and circulating tumor nucleic acids have clinical utility? A report of the association for molecular pathology. J Mol Diagn 2015; 17(3): 209–224

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Bidard FC, Fehm T, Ignatiadis M, Smerage JB, Alix-Panabieres C, Janni W, Messina C, Paoletti C, Muller V, Hayes DF, Piccart M, Pierga JY. Clinical application of circulating tumor cells in breast cancer: overview of the current interventional trials. Cancer Metastasis Rev 2013; 32(1–2): 179–188

    Article  PubMed  Google Scholar 

  14. Plaks V, Koopman CD, Werb Z. Cancer. Circulating tumor cells. Science 2013; 341(6151): 1186–1188

    CAS  PubMed  Google Scholar 

  15. Alix-Panabieres C, Pantel K. Challenges in circulating tumour cell research. Nat Rev Cancer 2014; 14(9): 623–631

    Article  CAS  PubMed  Google Scholar 

  16. Schlange T, Pantel K. Potential of circulating tumor cells as bloodbased biomarkers in cancer liquid biopsy. Pharmacogenomics 2016; 17(3): 183–186

    Article  CAS  PubMed  Google Scholar 

  17. Leon SA, Shapiro B, Sklaroff DM, Yaros MJ. Free DNA in the serum of cancer patients and the effect of therapy. Cancer Res 1977; 37(3): 646–650

    CAS  PubMed  Google Scholar 

  18. Stroun M, Anker P, Lyautey J, Lederrey C, Maurice PA. Isolation and characterization of DNA from the plasma of cancer patients. Eur J Cancer Clin Oncol 1987; 23(6): 707–712

    Article  CAS  PubMed  Google Scholar 

  19. Scher HI, Heller G, Molina A, Attard G, Danila DC, Jia XY, Peng WM, Sandhu SK, Olmos D, Riisnaes R, McCormack R, Burzykowski T, Kheoh T, Fleisher M, Buyse M, de Bono JS. Circulating tumor cell biomarker panel as an individual-level surrogate for survival in metastatic castration-resistant prostate cancer. J Clin Oncol 2015; 33(12): 1348–1355

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Cheng F, Su L, Qian C. Circulating tumor DNA: a promising biomarker in the liquid biopsy of cancer. Oncotarget 2016; 7(30): 48832–48841

    PubMed  PubMed Central  Google Scholar 

  21. Moran S, Martínez-Cardús A, Sayols S, Musulén E, Balañá C, Estival-Gonzalez A, Moutinho C, Heyn H, Diaz-Lagares A, de Moura MC, Stella GM, Comoglio PM, Ruiz-Miró M, Matias-Guiu X, Pazo-Cid R, Antón A, Lopez-Lopez R, Soler G, Longo F, Guerra I, Fernandez S, Assenov Y, Plass C, Morales R, Carles J, Bowtell D, Mileshkin L, Sia D, Tothill R, Tabernero J, Llovet JM, Esteller M. Epigenetic profiling to classify cancer of unknown primary: a multicentre, retrospective analysis. Lancet Oncol 2016; 17(10): 1386–1395

    Article  PubMed  Google Scholar 

  22. Heyn H, Esteller M. DNA methylation profiling in the clinic: applications and challenges. Nat Rev Genet 2012; 13(10): 679–692

    Article  CAS  PubMed  Google Scholar 

  23. Van Neste L, Herman JG, Otto G, Bigley JW, Epstein JI, Van Criekinge W. The epigenetic promise for prostate cancer diagnosis. Prostate 2012; 72(11): 1248–1261

    Article  PubMed  Google Scholar 

  24. Dawson SJ, Tsui DW, Murtaza M, Biggs H, Rueda OM, Chin SF, Dunning MJ, Gale D, Forshew T, Mahler-Araujo B, Rajan S, Humphray S, Becq J, Halsall D, Wallis M, Bentley D, Caldas C, Rosenfeld N. Analysis of circulating tumor DNA to monitor metastatic breast cancer. N Engl J Med 2013; 368(13): 1199–1209

    Article  CAS  PubMed  Google Scholar 

  25. Kidess E, Jeffrey SS. Circulating tumor cells versus tumor-derived cell-free DNA: rivals or partners in cancer care in the era of single-cell analysis? Genome Med 2013; 5(8): 70

    Article  PubMed  PubMed Central  Google Scholar 

  26. Tan CR, Zhou L, El-Deiry WS. Circulating tumor cells versus circulating tumor DNA in colorectal cancer: pros and cons. Curr Colorectal Cancer Rep 2016; 12(3): 151–161

    Article  PubMed  PubMed Central  Google Scholar 

  27. Bettegowda C, Sausen M, Leary RJ, Kinde I, Wang YX, Agrawal N, Bartlett BR, Wang H, Luber B, Alani RM, Antonarakis ES, Azad NS, Bardelli A, Brem H, Cameron JL, Lee CC, Fecher LA, Gallia GL, Gibbs P, Le D, Giuntoli RL, Goggins M, Hogarty MD, Holdhoff M, Hong SM, Jiao YC, Juhl HH, Kim JJ, Siravegna G, Laheru DA, Lauricella C, Lim M, Lipson EJ, Marie SKN, Netto GJ, Oliner KS, Olivi A, Olsson L, Riggins GJ, Sartore-Bianchi A, Schmidt K, Shih IM, Oba-Shinjo SM, Siena S, Theodorescu D, Tie JN, Harkins TT, Veronese S, Wang TL, Weingart JD, Wolfgang CL, Wood LD, Xing DM, Hruban RH, Wu J, Allen PJ, Schmidt CM, Choti MA, Velculescu VE, Kinzler KW, Vogelstein B, Papadopoulos N, Luis AJ. Detection of circulating tumor DNA in early- and late-stage human malignancies. Sci Transl Med 2014; 6(224): 224ra24

    Article  Google Scholar 

  28. Laird PW. Principles and challenges of genomewide DNA methylation analysis. Nat Rev Genet 2010; 11(3): 191–203

    Article  CAS  PubMed  Google Scholar 

  29. Yong E. Cancer biomarkers: written in blood. Nature 2014; 511(7511): 524–526

    Article  CAS  PubMed  Google Scholar 

  30. Al-Nedawi K, Meehan B, Micallef J, Lhotak V, May L, Guha A, Rak J. Intercellular transfer of the oncogenic receptor EGFrvIII by microvesicles derived from tumour cells. Nat Cell Biol 2008; 10(5): 619–624

    Article  CAS  PubMed  Google Scholar 

  31. Baj-Krzyworzeka M, Szatanek R, Weglarczyk K, Baran J, Urbanowicz B, Branski P, Ratajczak MZ, Zembala M. Tumourderived microvesicles carry several surface determinants and mRNA of tumour cells and transfer some of these determinants to monocytes. Cancer Immunol Immunother 2006; 55(7): 808–818

    Article  CAS  PubMed  Google Scholar 

  32. Miranda KC, Bond DT, McKee M, Skog J, Paunescu TG, Da Silva N, Brown D, Russo LM. Nucleic acids within urinary exosomes/ microvesicles are potential biomarkers for renal disease. Kidney Int 2010; 78(2): 191–199

    Article  PubMed  PubMed Central  Google Scholar 

  33. Noerholm M, Balaj L, Limperg T, Salehi A, Zhu LD, Hochberg FH, Breakefield XO, Carter BS, Skog J. RNA expression patterns in serum microvesicles from patients with glioblastoma multiforme and controls. BMC Cancer 2012; 12(1): 22

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Valadi H, Ekstrom K, Bossios A, Sjostrand M, Lee JJ, Lotvall JO. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat Cell Biol 2007; 9(6): 654–659

    Article  CAS  PubMed  Google Scholar 

  35. van der Vos KE, Balaj L, Skog J, Breakefield XO. Brain tumor microvesicles: insights into intercellular communication in the nervous system. Cell Mol Neurobiol 2011; 31(6): 949–959

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Melo SA, Luecke LB, Kahlert C, Fernandez AF, Gammon ST, Kaye J, LeBleu VS, Mittendorf EA, Weitz J, Rahbari N, Reissfelder C, Pilarsky C, Fraga MF, Piwnica-Worms D, Kalluri R. Glypican-1 identifies cancer exosomes and detects early pancreatic cancer. Nature 2015; 523(7559): 177–182

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Williams C, Rodriguez-Barrueco R, Silva JM, Zhang WJ, Hearn S, Elemento O, Paknejad N, Manova-Todorova K, Welte K, Bromberg J, Peinado H, Lyden D. Double-stranded DNA in exosomes: a novel biomarker in cancer detection. Cell Res 2014; 24(6): 766–769

    Article  PubMed  PubMed Central  Google Scholar 

  38. Syn N, Wang LZ, Sethi G, Thiery JP, Goh BC. Exosome-mediated metastasis: from epithelial-mesenchymal transition to escape from immunosurveillance. Trends Pharmacol Sci 2016; 37(7): 606–617

    Article  CAS  PubMed  Google Scholar 

  39. Peinado H, Aleckovic M, Lavotshkin S, Matei I, Costa-Silva B, Moreno-Bueno G, Hergueta-Redondo M, Williams C, Garcia-Santos G, Ghajar CM, Nitadori-Hoshino A, Hoffman C, Badal K, Garcia BA, Callahan MK, Yuan JD, Martins VR, Skog J, Kaplan RN, Brady MS, Wolchok JD, Chapman PB, Kang YB, Bromberg J, Lyden D. Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through MET. Nat Med 2012; 18(6): 883–891

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Ilie M, Hofman V, Long E, Bordone O, Selva E, Washetine K, Marquette CH, Hofman P. Current challenges for detection of circulating tumor cells and cell-free circulating nucleic acids, and their characterization in non-small cell lung carcinoma patients. What is the best blood substrate for personalized medicine? Ann Transl Med 2014; 2(11): 107

    PubMed  PubMed Central  Google Scholar 

  41. Pantel K, Alix-Panabieres C. Liquid biopsy: potential and challenges. Mol Oncol 2016; 10(3): 371–373

    Article  PubMed  PubMed Central  Google Scholar 

  42. Hoshino A, Costa-Silva B, Shen TL, Rodrigues G, Hashimoto A, Tesic Mark M, Molina H, Kohsaka S, Di Giannatale A, Ceder S, Singh S, Williams C, Soplop N, Uryu K, Pharmer L, King T, Bojmar L, Davies AE, Ararso Y, Zhang T, Zhang H, Hernandez J, Weiss JM, Dumont-Cole VD, Kramer K, Wexler LH, Narendran A, Schwartz GK, Healey JH, Sandstrom P, Jørgen Labori K, Kure EH, Grandgenett PM, Hollingsworth MA, de Sousa M, Kaur S, Jain M, Mallya K, Batra SK, Jarnagin WR, Brady MS, Fodstad O, Muller V, Pantel K, Minn AJ, Bissell MJ, Garcia BA, Kang Y, Rajasekhar VK, Ghajar CM, Matei I, Peinado H, Bromberg J, Lyden D. Tumour exosome integrins determine organotropic metastasis. Nature 2015; 527(7578): 329–335

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was supported by the Precision Medicine Research Program of the Chinese Academy of Sciences (No. KJZD-EW-L14), the Strategic Priority Research Program of the Chinese Academy of Sciences (No. XDA12020343), the National Basic Research Program (973 Program, Nos. 2013CB911001 and 2012CB518 302), and the National Natural Science Foundation of China (No. 31540033).

Author information

Authors and Affiliations

  1. Key Laboratory of Genomic and Precision Medicine, China Gastrointestinal Cancer Research Center, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, 100101, China

    Junyun Wang, Shuang Chang, Guochao Li & Yingli Sun

  2. University of Chinese Academy of Sciences, Beijing, 100049, China

    Junyun Wang, Shuang Chang, Guochao Li & Yingli Sun

Authors
  1. Junyun Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Shuang Chang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Guochao Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yingli Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yingli Sun.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wang, J., Chang, S., Li, G. et al. Application of liquid biopsy in precision medicine: opportunities and challenges. Front. Med. 11, 522–527 (2017). https://doi.org/10.1007/s11684-017-0526-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11684-017-0526-7

Keywords

Search

Navigation