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The Role of Liquid Biopsies in Cancer Diagnosis and Prognostics

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Handbook of Cancer and Immunology

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Abstract

Accurate diagnosis of solid organ malignancies currently relies upon acquisition of a tissue sample directly from the tumor itself. While this method is the gold standard and typically provides enough tissue to perform histopathological, immunohistochemical, and molecular analysis, it does have several drawbacks. Depending on the disease location, tissue biopsies are relatively invasive. There may be technical challenges with biopsying anatomically remote locations as well as the potential for biopsy-related complications. Image-guided, endoscopic and surgical procedures are resource intensive and require substantial logistical input to arrange. In addition, a biopsy necessarily represents only a small fraction of the entire neoplastic process at a single timepoint. Spatial and temporal tumor heterogeneity not captured may nevertheless impact on the success of treatment protocols and targeted therapies.

Liquid biopsy, the process whereby tumor fragments are detected in bodily fluids (typically blood), represents an easily accessible, minimally invasive alternative to formal tissue diagnosis. It also has prognostic value, both with respect to the absolute concentration detected at diagnosis, dynamic stratification based on response to treatment, and monitoring of development of treatment resistance. It also has the facility to extensively capture tumor heterogeneity. Various methods exist, most commonly based on analysis of circulating tumor cells or DNA fragments. Liquid biopsy has been utilized as a diagnostic and prognostic adjunct in a wide range of solid tumor types, including breast, prostate, pancreas, colorectal, and lung.

Despite these advantages, liquid biopsy remains inferior to tissue biopsy for diagnostic sensitivity and specificity, especially for early-stage tumors. In clinical applications, it is unlikely that liquid biopsy will replace tissue biopsy for formal diagnosis, but is likely to have a significant role as a biomarker to assist with prognostication, development of treatment resistance, and early identification of disease recurrence.

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References

  • Abbosh C, Birkbak NJ, Wilson GA, Jamal-Hanjani M, Constantin T, Salari R et al (2017) Phylogenetic ctDNA analysis depicts early-stage lung cancer evolution. Nature 545(7655):446–451

    Article  CAS  Google Scholar 

  • Agostini M, Pucciarelli S, Enzo MV, Del Bianco P, Briarava M, Bedin C et al (2011) Circulating cell-free DNA: a promising marker of pathologic tumor response in rectal cancer patients receiving preoperative chemoradiotherapy. Ann Surg Oncol 18(9):2461–2468

    Article  Google Scholar 

  • Alimirzaie S, Bagherzadeh M, Akbari MR (2019) Liquid biopsy in breast cancer: a comprehensive review. Clin Genet 95(6):643–660

    Article  CAS  Google Scholar 

  • Anagnostou V, Forde PM, White JR, Niknafs N, Hruban C, Naidoo J et al (2019) Dynamics of tumor and immune responses during immune checkpoint blockade in non-small cell lung cancer. Cancer Res 79(6):1214–1225

    Article  CAS  Google Scholar 

  • Bettegowda C, Sausen M, Leary RJ, Kinde I, Wang Y, Agrawal N et al (2014) Detection of circulating tumor DNA in early- and late-stage human malignancies. Sci Transl Med 6(224):224ra24

    Article  Google Scholar 

  • Bianchi DW, Chiu RWK (2018) Sequencing of circulating cell-free DNA during pregnancy. N Engl J Med 379(5):464–473

    Article  CAS  Google Scholar 

  • Carpinetti P, Donnard E, Bettoni F, Asprino P, Koyama F, Rozanski A et al (2015) The use of personalized biomarkers and liquid biopsies to monitor treatment response and disease recurrence in locally advanced rectal cancer after neoadjuvant chemoradiation. Oncotarget 6(35):38360–38371

    Article  Google Scholar 

  • Chaudhuri AA, Chabon JJ, Lovejoy AF, Newman AM, Stehr H, Azad TD et al (2017) Early detection of molecular residual disease in localized lung cancer by circulating tumor DNA profiling. Cancer Discov 7(12):1394–1403

    Article  CAS  Google Scholar 

  • Chen M, Zhao H (2019) Next-generation sequencing in liquid biopsy: cancer screening and early detection. Hum Genomics 13(1):34

    Article  Google Scholar 

  • Das J, Ivanov I, Sargent EH, Kelley SO (2016) DNA clutch probes for circulating tumor DNA analysis. J Am Chem Soc 138(34):11009–11016

    Article  CAS  Google Scholar 

  • De Mattos-Arruda L, Mayor R, Ng CKY, Weigelt B, Martínez-Ricarte F, Torrejon D et al (2015) Cerebrospinal fluid-derived circulating tumour DNA better represents the genomic alterations of brain tumours than plasma. Nat Commun 6:8839

    Article  Google Scholar 

  • Diehl F, Li M, He Y, Kinzler KW, Vogelstein B, Dressman D (2006) BEAMing: single-molecule PCR on microparticles in water-in-oil emulsions. Nat Methods 3(7):551–559

    Article  CAS  Google Scholar 

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

    Article  Google Scholar 

  • Ferreira MM, Ramani VC, Jeffrey SS (2016) Circulating tumor cell technologies. Mol Oncol 10(3):374–394

    Article  CAS  Google Scholar 

  • Forshew T, Murtaza M, Parkinson C, Gale D, Tsui DWY, Kaper F et al (2012) Noninvasive identification and monitoring of cancer mutations by targeted deep sequencing of plasma DNA. Sci Transl Med 4(136):136ra68

    Article  Google Scholar 

  • Garcia-Murillas I, Schiavon G, Weigelt B, Ng C, Hrebien S, Cutts RJ et al (2015) Mutation tracking in circulating tumor DNA predicts relapse in early breast cancer. Sci Transl Med 7(302):302ra133

    Article  Google Scholar 

  • Garcia-Olmo DC, Dominguez C, Garcia-Arranz M, Anker P, Stroun M, Garcia-Verdugo JM et al (2010) Cell-free nucleic acids circulating in the plasma of colorectal cancer patients induce the oncogenic transformation of susceptible cultured cells [Internet]. Cancer Res 70:560–567. Available from: https://doi.org/10.1158/0008-5472.can-09-3513

  • Georgiou A, Stewart A, Cunningham D, Banerji U, Whittaker SR (2020) Inactivation of NF1 promotes resistance to EGFR inhibition in KRAS/NRAS/BRAFV600-Wild-Type colorectal cancer. Mol Cancer Res [Internet]; Available from: https://doi.org/10.1158/1541-7786.MCR-19-1201

  • Giacona MB, Ruben GC, Iczkowski KA, Roos TB, Porter DM, Sorenson GD (1998) Cell-free DNA in human blood plasma [Internet]. Pancreas 17:89–97. Available from: https://doi.org/10.1097/00006676-199807000-00012

  • Gögenur M, Burcharth J, Gögenur I (2017) The role of total cell-free DNA in predicting outcomes among trauma patients in the intensive care unit: a systematic review. Crit Care 21(1):14

    Article  Google Scholar 

  • Greytak SR, Engel KB, Parpart-Li S, Murtaza M, Bronkhorst AJ, Pertile MD et al (2020) Harmonizing cell-free DNA collection and processing practices through evidence-based guidance. Clin Cancer Res 26(13):3104–3109

    Article  CAS  Google Scholar 

  • Guibert N, Pradines A, Favre G, Mazieres J (2020) Current and future applications of liquid biopsy in nonsmall cell lung cancer from early to advanced stages. Eur Respir Rev [Internet] 29(155). Available from: https://doi.org/10.1183/16000617.0052-2019

  • Hawkins RB, Stortz JA, Holden DC, Wang Z, Raymond SL, Cox MC et al (2020) Persistently increased cell-free DNA concentrations only modestly contribute to outcome and host response in sepsis survivors with chronic critical illness. Surgery 167(3):646–652

    Article  Google Scholar 

  • Heredia-Soto V, Rodríguez-Salas N, Feliu J (2021) Liquid biopsy in pancreatic cancer: are we ready to apply it in the clinical practice? Cancers [Internet] 13(8). Available from: https://doi.org/10.3390/cancers13081986

  • Hindson BJ, Ness KD, Masquelier DA, Belgrader P, Heredia NJ, Makarewicz AJ et al (2011) High-throughput droplet digital PCR system for absolute quantitation of DNA copy number. Anal Chem 83(22):8604–8610

    Article  CAS  Google Scholar 

  • Hrebien S, O’Leary B, Beaney M, Schiavon G, Fribbens C, Bhambra A et al (2016) Reproducibility of digital PCR assays for circulating tumor DNA analysis in advanced breast cancer. PLoS One 11(10):e0165023

    Article  Google Scholar 

  • Husain H, Nykin D, Bui N, Quan D, Gomez G, Woodward B et al (2017) Cell-free DNA from ascites and pleural effusions: molecular insights into genomic aberrations and disease biology. Mol Cancer Ther 16(5):948–955

    Article  CAS  Google Scholar 

  • Ignatiadis M, Sledge GW, Jeffrey SS (2021) Liquid biopsy enters the clinic – implementation issues and future challenges. Nat Rev Clin Oncol 18(5):297–312

    Article  Google Scholar 

  • Ilie M, Hofman V, Long-Mira E, Selva E, Vignaud J-M, Padovani B et al (2014) “Sentinel” circulating tumor cells allow early diagnosis of lung cancer in patients with chronic obstructive pulmonary disease. PLoS One 9(10):e111597

    Article  Google Scholar 

  • Jain S, Lin SY, Song W, Su Y-H (2019) Urine-based liquid biopsy for nonurological cancers. Genet Test Mol Biomarkers 23(4):277–283

    Article  CAS  Google Scholar 

  • Jamal-Hanjani M, Wilson GA, McGranahan N, Birkbak NJ, Watkins TBK, Veeriah S et al (2017) Tracking the evolution of non-small-cell lung cancer. N Engl J Med 376(22):2109–2121

    Article  CAS  Google Scholar 

  • Jing R, Cui M, Wang H, Ju S (2013) Cell-free DNA: characteristics, detection and its applications in myocardial infarction. Curr Pharm Des 19(28):5135–5145

    Article  CAS  Google Scholar 

  • Kalluri R, LeBleu VS (2020) The biology, function, and biomedical applications of exosomes. Science [Internet] 367(6478). Available from: https://doi.org/10.1126/science.aau6977

  • Kamerkar S, LeBleu VS, Sugimoto H, Yang S, Ruivo CF, Melo SA et al (2017) Exosomes facilitate therapeutic targeting of oncogenic KRAS in pancreatic cancer. Nature 546(7659):498–503

    Article  CAS  Google Scholar 

  • Kamyabi N, Bernard V, Maitra A (2019) Liquid biopsies in pancreatic cancer. Expert Rev Anticancer Ther 19(10):869–878

    Article  CAS  Google Scholar 

  • Keller L, Pantel K (2019) Unravelling tumour heterogeneity by single-cell profiling of circulating tumour cells. Nat Rev Cancer 19(10):553–567

    Article  CAS  Google Scholar 

  • Kinde I, Wu J, Papadopoulos N, Kinzler KW, Vogelstein B (2011) Detection and quantification of rare mutations with massively parallel sequencing. Proc Natl Acad Sci U S A 108(23):9530–9535

    Article  Google Scholar 

  • Lee J-H, Jeong H, Choi J-W, Oh HE, Kim Y-S (2018) Liquid biopsy prediction of axillary lymph node metastasis, cancer recurrence, and patient survival in breast cancer: a meta-analysis. Medicine 97(42):e12862

    Article  Google Scholar 

  • Lehmann-Werman R, Neiman D, Zemmour H, Moss J, Magenheim J, Vaknin-Dembinsky A et al (2016) Identification of tissue-specific cell death using methylation patterns of circulating DNA. Proc Natl Acad Sci U S A 113(13):E1826–E1834

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  • 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(3):646–650

    CAS  Google Scholar 

  • Leszinski G, Lehner J, Gezer U, Holdenrieder S (2014) Increased DNA integrity in colorectal cancer. In Vivo 28(3):299–303

    CAS  Google Scholar 

  • Lousada-Fernandez F, Rapado-Gonzalez O, Lopez-Cedrun J-L, Lopez-Lopez R, Muinelo-Romay L, Suarez-Cunqueiro MM (2018) Liquid biopsy in oral cancer. Int J Mol Sci [Internet] 19(6). Available from: https://doi.org/10.3390/ijms19061704

  • Mandel P, Metais P (1948) Nuclear acids in human blood plasma. C R Seances Soc Biol Fil 142(3-4):241–3. Available from: https://pubmed.ncbi.nlm.nih.gov/18875018/

  • Manier S, Park J, Capelletti M, Bustoros M, Freeman SS, Ha G et al (2018) Whole-exome sequencing of cell-free DNA and circulating tumor cells in multiple myeloma. Nat Commun 9(1):1691

    Article  CAS  Google Scholar 

  • Marquette C-H, Boutros J, Benzaquen J, Ferreira M, Pastre J, Pison C et al (2020) Circulating tumour cells as a potential biomarker for lung cancer screening: a prospective cohort study. Lancet Respir Med 8(7):709–716

    Article  Google Scholar 

  • Medina Diaz I, Nocon A, Mehnert DH, Fredebohm J, Diehl F, Holtrup F (2016) Performance of Streck cfDNA blood collection tubes for liquid biopsy testing. PLoS One 11(11):e0166354

    Article  Google Scholar 

  • Misale S, Yaeger R, Hobor S, Scala E, Janakiraman M, Liska D et al (2012) Emergence of KRAS mutations and acquired resistance to anti-EGFR therapy in colorectal cancer. Nature 486(7404):532–536

    Article  CAS  Google Scholar 

  • Mouliere F, El Messaoudi S, Pang D, Dritschilo A, Thierry AR (2014) Multi-marker analysis of circulating cell-free DNA toward personalized medicine for colorectal cancer. Mol Oncol 8(5):927–941

    Article  CAS  Google Scholar 

  • Newman AM, Lovejoy AF, Klass DM, Kurtz DM, Chabon JJ, Scherer F et al (2016) Integrated digital error suppression for improved detection of circulating tumor DNA [Internet]. Nat Biotechnol 34:547–555. Available from: https://doi.org/10.1038/nbt.3520

  • Nguyen HH, Park J, Kang S, Kim M (2015) Surface plasmon resonance: a versatile technique for biosensor applications. Sensors 15(5):10481–10510

    Article  CAS  Google Scholar 

  • Osumi H, Shinozaki E, Yamaguchi K, Zembutsu H (2019) Clinical utility of circulating tumor DNA for colorectal cancer. Cancer Sci 110(4):1148–1155

    Article  CAS  Google Scholar 

  • Parseghian CM, Loree JM, Morris VK, Liu X, Clifton KK, Napolitano S et al (2019) Anti-EGFR-resistant clones decay exponentially after progression: implications for anti-EGFR re-challenge. Ann Oncol 30(2):243–249

    Article  CAS  Google Scholar 

  • Petit J, Carroll G, Gould T, Pockney P, Dun M, Scott RJ (2019) Cell-free DNA as a diagnostic blood-based biomarker for colorectal cancer: a systematic review. J Surg Res 236:184–197

    Article  CAS  Google Scholar 

  • Ponti G, Manfredini M, Tomasi A (2019) Non-blood sources of cell-free DNA for cancer molecular profiling in clinical pathology and oncology. Crit Rev Oncol Hematol 141:36–42

    Article  Google Scholar 

  • Rafaeli-Yehudai T, Imterat M, Douvdevani A, Tirosh D, Benshalom-Tirosh N, Mastrolia SA et al (2018) Maternal total cell-free DNA in preeclampsia and fetal growth restriction: evidence of differences in maternal response to abnormal implantation. PLoS One 13(7):e0200360

    Article  Google Scholar 

  • Restivo A, Zorcolo L, Cocco IMF, Manunza R, Margiani C, Marongiu L et al (2013) Elevated CEA levels and low distance of the tumor from the anal verge are predictors of incomplete response to chemoradiation in patients with rectal cancer. Ann Surg Oncol 20(3):864–871

    Article  Google Scholar 

  • Roweth HG, Battinelli EM (2021) Lessons to learn from tumor-educated platelets. Blood 137(23):3174–3180

    Article  CAS  Google Scholar 

  • Sanmamed MF, Fernández-Landázuri S, Rodríguez C, Zárate R, Lozano MD, Zubiri L et al (2015) Quantitative cell-free circulating BRAFV600E mutation analysis by use of droplet digital PCR in the follow-up of patients with melanoma being treated with BRAF inhibitors. Clin Chem 61(1):297–304

    Article  CAS  Google Scholar 

  • Schou JV, Larsen FO, Sørensen BS, Abrantes R, Boysen AK, Johansen JS et al (2018) Circulating cell-free DNA as predictor of treatment failure after neoadjuvant chemo-radiotherapy before surgery in patients with locally advanced rectal cancer. Ann Oncol 29(3):610–615

    Article  CAS  Google Scholar 

  • Siravegna G, Mussolin B, Buscarino M, Corti G, Cassingena A, Crisafulli G et al (2015) Clonal evolution and resistance to EGFR blockade in the blood of colorectal cancer patients. Nat Med 21(7):827

    Article  CAS  Google Scholar 

  • Song T, Mao F, Shi L, Xu X, Wu Z, Zhou J et al (2018) Urinary measurement of circulating tumor DNA for treatment monitoring and prognosis of metastatic colorectal cancer patients. Clin Chem Lab Med 57(2):268–275

    Article  Google Scholar 

  • Sorenson GD (2006) A review of studies on the detection of mutated KRAS2 sequences as tumor markers in plasma/serum of patients with gastrointestinal cancer [Internet]. Ann N Y Acad Sci 906:13–16. Available from: https://doi.org/10.1111/j.1749-6632.2000.tb06582.x

  • Tahir MA, Dina NE, Cheng H, Valev VK, Zhang L (2021) Surface-enhanced Raman spectroscopy for bioanalysis and diagnosis. Nanoscale 13(27):11593–11634

    Article  CAS  Google Scholar 

  • Taly V, Pekin D, Benhaim L, Kotsopoulos SK, Le Corre D, Li X et al (2013) Multiplex picodroplet digital PCR to detect KRAS mutations in circulating DNA from the plasma of colorectal cancer patients. Clin Chem 59(12):1722–1731

    Article  CAS  Google Scholar 

  • Thierry AR, Mouliere F, El Messaoudi S, Mollevi C, Lopez-Crapez E, Rolet F et al (2014) Clinical validation of the detection of KRAS and BRAF mutations from circulating tumor DNA. Nat Med 20(4):430–435

    Article  CAS  Google Scholar 

  • Tie J, Kinde I, Wang Y, Wong HL, Roebert J, Christie M et al (2015) Circulating tumor DNA as an early marker of therapeutic response in patients with metastatic colorectal cancer. Ann Oncol 26(8):1715–1722

    Article  CAS  Google Scholar 

  • Tie J, Cohen JD, Wang Y, Li L, Christie M, Simons K et al (2019) Serial circulating tumour DNA analysis during multimodality treatment of locally advanced rectal cancer: a prospective biomarker study. Gut 68(4):663–671

    Article  CAS  Google Scholar 

  • Umetani N, Kim J, Hiramatsu S, Reber HA, Hines OJ, Bilchik AJ et al (2006) Increased integrity of free circulating DNA in sera of patients with colorectal or periampullary cancer: direct quantitative PCR for ALU repeats. Clin Chem 52(6):1062–1069

    Article  CAS  Google Scholar 

  • Vittori LN, Tarozzi A, Latessa PM (2019) Circulating cell-free DNA in physical activities. Methods Mol Biol 1909:183–197

    Article  CAS  Google Scholar 

  • Wallin U, Rothenberger D, Lowry A, Luepker R, Mellgren A (2013) CEA – a predictor for pathologic complete response after neoadjuvant therapy for rectal cancer. Dis Colon Rectum 56(7):859–868

    Article  Google Scholar 

  • Yoo RN, Kim HJ (2019) Total neoadjuvant therapy in locally advanced rectal cancer: role of systemic chemotherapy. Ann Gastroenterol Surg 3(4):356–367

    Article  Google Scholar 

  • Yu H, Han L, Yuan J, Sun Y (2020) Circulating tumor cell free DNA from plasma and urine in the clinical management of colorectal cancer. Cancer Biomark 27(1):29–37

    Article  CAS  Google Scholar 

  • Zhou J, Lin G, Gong Y, Zhang Y, Guan Y-F, Xia X et al (2019) Serial ctDNA analysis as a real-time indicator of neoadjuvant chemoradiotherapy in rectal cancer. J Clin Orthod 37(15_suppl):3569

    Google Scholar 

  • Zitt M, Müller HM, Rochel M, Schwendinger V, Zitt M, Goebel G et al (2008) Circulating cell-free DNA in plasma of locally advanced rectal cancer patients undergoing preoperative Chemoradiation: a potential diagnostic tool for therapy monitoring [Internet]. Dis Markers 25:159–165. Available from: https://doi.org/10.1155/2008/598071

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Authors and Affiliations

  1. Conway Institute for Biomolecular and Biomedical Science, University College Dublin, Dublin, Ireland

    Lauren V. O’Connell

  2. St Vincent’s University Hospital, Dublin, Ireland

    Des C. Winter

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  1. Lauren V. O’Connell
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  2. Des C. Winter
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Correspondence to Lauren V. O’Connell .

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  1. Division of Clinical Immunology, Karolinska University Hospital, Huddinge, Sweden

    Nima Rezaei

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O’Connell, L.V., Winter, D.C. (2022). The Role of Liquid Biopsies in Cancer Diagnosis and Prognostics. In: Rezaei, N. (eds) Handbook of Cancer and Immunology. Springer, Cham. https://doi.org/10.1007/978-3-030-80962-1_139-1

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  • DOI: https://doi.org/10.1007/978-3-030-80962-1_139-1

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