The Application of Circulating Tumor DNA in the Screening, Surveillance, and Treatment Monitoring of Colorectal Cancer

Abstract

Precision medicine with genetic profiling of tumor tissue has become an essential part of routine clinical practice in colorectal cancer. However, tissue genetic profiling suffers from clonal evolution, tumor heterogeneity, and time needed to deliver critical information for prompt clinical decision making. In contrast, liquid biopsy with plasma circulating tumor DNA provides genetic and epigenetic information from both the primary and metastatic colorectal cancer, which can potentially capture tumor heterogeneity and evolution with time and treatment. In addition, liquid biopsy with circulating tumor DNA is minimally invasive, quicker, and easily repeatable with high patient compliance to provide both qualitative and quantitative molecular information in real-time. We provide an overview on the potential clinical applications of circulating tumor DNA in the screening, surveillance, and treatment monitoring of colorectal cancer.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3

References

  1. 1.

    Khan KH, Cunningham D, Werner B, et al. Longitudinal liquid biopsy and mathematical modeling of clonal evolution forecast time to treatment failure in the PROSPECT-C phase II colorectal cancer clinical trial. Cancer Discov. 2018;8(10):1270–1285. https://doi.org/10.1158/2159-8290.cd-17-0891.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  2. 2.

    Moorcraft SY, Gonzalez de Castro D, Cunningham D, et al. Investigating the feasibility of tumour molecular profiling in gastrointestinal malignancies in routine clinical practice. Ann Oncol Off J Eur Soc Med Oncol. 2018;29(1):230–236. https://doi.org/10.1093/annonc/mdx631.

    CAS  Article  Google Scholar 

  3. 3.

    Diehl F, Li M, Dressman D, et al. Detection and quantification of mutations in the plasma of patients with colorectal tumors. Proc Natl Acad Sci USA. 2005;102(45):16368–16373. https://doi.org/10.1073/pnas.0507904102.

    CAS  Article  Google Scholar 

  4. 4.

    Corcoran RB, Chabner BA. Application of cell-free DNA analysis to cancer treatment. New Engl J Med. 2018;379(18):1754–1765. https://doi.org/10.1056/nejmra1706174.

    CAS  Article  PubMed  Google Scholar 

  5. 5.

    Donaldson J, Park BH. Circulating tumor DNA: measurement and clinical utility. Annu Rev Med. 2018;69:223-234. https://doi.org/10.1146/annurev-med-041316-085721.

    CAS  Article  PubMed  Google Scholar 

  6. 6.

    Wan JCM, Massie C, Garcia-Corbacho J, et al. Liquid biopsies come of age: towards implementation of circulating tumour DNA. Nat Rev: Cancer. 2017;17(4):223–238. https://doi.org/10.1038/nrc.2017.7.

    CAS  Article  PubMed  Google Scholar 

  7. 7.

    Osumi H, Shinozaki E, Yamaguchi K, Zembutsu H. Clinical utility of circulating tumor DNA for colorectal cancer. Cancer Sci. 2019;110(4):1148–1155. https://doi.org/10.1111/cas.13972.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  8. 8.

    Hindson BJ, Ness KD, Masquelier DA, et al. High-throughput droplet digital PCR system for absolute quantitation of DNA copy number. Anal. Chem. 2011;83(22):8604–8610. https://doi.org/10.1021/ac202028g.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  9. 9.

    Diehl F, Li M, He Y, Kinzler KW, Vogelstein B, Dressman D. BEAMing: single-molecule PCR on microparticles in water-in-oil emulsions. Nat Methods 2006;3(7):551–559. https://doi.org/10.1038/nmeth898.

    CAS  Article  PubMed  Google Scholar 

  10. 10.

    Mouliere F, El Messaoudi S, Pang D, Dritschilo A, Thierry AR. Multi-marker analysis of circulating cell-free DNA toward personalized medicine for colorectal cancer. Mol Oncol. 2014;8(5):927–941. https://doi.org/10.1016/j.molonc.2014.02.005.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  11. 11.

    Forshew T, Murtaza M, Parkinson C, et al. Noninvasive identification and monitoring of cancer mutations by targeted deep sequencing of plasma DNA. Sci Transl Med. 2012;4(136):136ra68. https://doi.org/10.1126/scitranslmed.3003726.

    CAS  Article  PubMed  Google Scholar 

  12. 12.

    Kinde I, Wu J, Papadopoulos N, Kinzler KW, Vogelstein B. Detection and quantification of rare mutations with massively parallel sequencing. Proc Natl Acad Sci USA. 2011;108(23):9530–9535. https://doi.org/10.1073/pnas.1105422108.

    Article  PubMed  PubMed Central  Google Scholar 

  13. 13.

    Newman AM, Bratman SV, To J, et al. An ultrasensitive method for quantitating circulating tumor DNA with broad patient coverage. Nat Med. 2014;20(5):548–554. https://doi.org/10.1038/nm.3519.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  14. 14.

    Murtaza M, Dawson S-J, Tsui DWY, et al. Non-invasive analysis of acquired resistance to cancer therapy by sequencing of plasma DNA. Nature. 2013;497(7447):108–112. https://doi.org/10.1038/nature12065.

    CAS  Article  PubMed  Google Scholar 

  15. 15.

    Chan KCA, Jiang P, Zheng YWL, 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):211–224. https://doi.org/10.1373/clinchem.2012.196014.

    CAS  Article  PubMed  Google Scholar 

  16. 16.

    Zviran A, Schulman RC, Shah M, et al. Genome-wide cell-free DNA mutational integration enables ultra-sensitive cancer monitoring. Nat Med. 2020. https://doi.org/10.1038/s41591-020-0915-3.

    Article  PubMed  Google Scholar 

  17. 17.

    Strickler JH, Loree JM, Ahronian LG, et al. Genomic landscape of cell-free DNA in patients with colorectal cancer. Cancer Discov. 2018;8(2):164–173. https://doi.org/10.1158/2159-8290.cd-17-1009.

    CAS  Article  PubMed  Google Scholar 

  18. 18.

    Osumi H, Shinozaki E, Takeda Y, et al. Clinical relevance of circulating tumor DNA assessed through deep sequencing in patients with metastatic colorectal cancer. Cancer Med. 2019;8(1):408–417. https://doi.org/10.1002/cam4.1913.

    CAS  Article  PubMed  Google Scholar 

  19. 19.

    Bettegowda C, Sausen M, Leary RJ, et al. Detection of circulating tumor DNA in early- and late-stage human malignancies. Sci Transl Med. 2014;6(224):224ra24. https://doi.org/10.1126/scitranslmed.3007094.

    CAS  Article  Google Scholar 

  20. 20.

    Bachet JB, Bouché O, Taieb J, et al. RAS mutation analysis in circulating tumor DNA from patients with metastatic colorectal cancer: the AGEO RASANC prospective multicenter study. Ann Oncol Off J Eur Soc Med Oncol. 2018;29(5):1211–1219. https://doi.org/10.1093/annonc/mdy061.

    CAS  Article  Google Scholar 

  21. 21.

    El Messaoudi S, Mouliere F, Du Manoir S, et al. Circulating DNA as a strong multimarker prognostic tool for metastatic colorectal cancer patient management care. Clin Cancer Res Off J Am Assoc Cancer Res. 2016;22(12):3067–3077. https://doi.org/10.1158/1078-0432.ccr-15-0297.

    CAS  Article  Google Scholar 

  22. 22.

    Spindler K-LG, Pallisgaard N, Appelt AL, et al. Clinical utility of KRAS status in circulating plasma DNA compared to archival tumour tissue from patients with metastatic colorectal cancer treated with anti-epidermal growth factor receptor therapy. Eur J Cancer (Oxford, England: 1990). 2015;51(17):2678–2685. https://doi.org/10.1016/j.ejca.2015.06.118.

    CAS  Article  PubMed  Google Scholar 

  23. 23.

    Cohen JD, Li L, Wang Y, et al. Detection and localization of surgically resectable cancers with a multi-analyte blood test. Science (New York, N.Y.). 2018;359(6378):926–930. https://doi.org/10.1126/science.aar3247.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  24. 24.

    Dasari A, Grothey A, Kopetz S. Circulating tumor DNA-defined minimal residual disease in solid tumors: opportunities to accelerate the development of adjuvant therapies. J Clin Oncol Off J Am Soc Clin Oncol. 2018:JCO2018789032. https://doi.org/10.1200/jco.2018.78.9032.

  25. 25.

    Ryan BM, Lefort F, McManus R, et al. A prospective study of circulating mutant KRAS2 in the serum of patients with colorectal neoplasia: strong prognostic indicator in postoperative follow up. Gut. 2003;52(1):101–108. https://doi.org/10.1136/gut.52.1.101.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  26. 26.

    Diehn M, Alizadeh AA, Adams H-P, et al. Early prediction of clinical outcomes in resected stage II and III colorectal cancer (CRC) through deep sequencing of circulating tumor DNA (ctDNA). JCO. 2017;35(15_suppl):3591. https://doi.org/10.1200/jco.2017.35.15_suppl.3591.

    Article  Google Scholar 

  27. 27.

    Tie J, Wang Y, Tomasetti C, et al. Circulating tumor DNA analysis detects minimal residual disease and predicts recurrence in patients with stage II colon cancer. Sci Transl Med. 2016;8(346):346ra92. https://doi.org/10.1126/scitranslmed.aaf6219.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  28. 28.

    Tie J, Cohen JD, Wang Y, et al. Circulating tumor DNA analyses as markers of recurrence risk and benefit of adjuvant therapy for stage III colon cancer. JAMA Oncol. 2019. https://doi.org/10.1001/jamaoncol.2019.3616.

    Article  PubMed  PubMed Central  Google Scholar 

  29. 29.

    Tie J, Cohen JD, Wang Y, et al. Serial circulating tumour DNA analysis during multimodality treatment of locally advanced rectal cancer: a prospective biomarker study. Gut. 2019;68(4):663–671. https://doi.org/10.1136/gutjnl-2017-315852.

    CAS  Article  PubMed  Google Scholar 

  30. 30.

    Khakoo S, Carter PD, Brown G, et al. MRI tumor regression grade and circulating tumor dna as complementary tools to assess response and guide therapy adaptation in rectal cancer. Clin Cancer Res Off J Am Assoc Cancer Res 2020;26(1):183–192. https://doi.org/10.1158/1078-0432.ccr-19-1996.

    CAS  Article  Google Scholar 

  31. 31.

    Wang Y, Li L, Cohen JD, et al. Prognostic potential of circulating tumor dna measurement in postoperative surveillance of nonmetastatic colorectal cancer. JAMA Oncol. 2019. https://doi.org/10.1001/jamaoncol.2019.0512.

    Article  PubMed  PubMed Central  Google Scholar 

  32. 32.

    Schøler LV, Reinert T, Ørntoft M-BW, et al. Clinical implications of monitoring circulating tumor dna in patients with colorectal cancer. Clin Cancer Res Off J Am Assoc Cancer Res. 2017;23(18):5437–5445. https://doi.org/10.1158/1078-0432.ccr-17-0510.

    Article  PubMed  Google Scholar 

  33. 33.

    Tarazona N, Gimeno-Valiente F, Gambardella V, et al. Targeted next-generation sequencing of circulating-tumor DNA for tracking minimal residual disease in localized colon cancer. Ann Oncol Off J Eur Soc Med Oncol. 2019;30(11):1804–1812. https://doi.org/10.1093/annonc/mdz390.

    CAS  Article  Google Scholar 

  34. 34.

    Reinert T, Schøler LV, Thomsen R, et al. Analysis of circulating tumour DNA to monitor disease burden following colorectal cancer surgery. Gut. 2016;65(4):625–634. https://doi.org/10.1136/gutjnl-2014-308859.

    CAS  Article  PubMed  Google Scholar 

  35. 35.

    Reinert T, Henriksen TV, Christensen E, et al. Analysis of plasma cell-free DNA by ultradeep sequencing in patients with stages I to III colorectal cancer. JAMA Oncol. 2019. https://doi.org/10.1001/jamaoncol.2019.0528.

    Article  PubMed  PubMed Central  Google Scholar 

  36. 36.

    Parikh AR, van Seventer EE, Boland GM, et al. A plasma-only integrated genomic and epigenomic circulating tumor DNA (ctDNA) assay to inform recurrence risk in colorectal cancer (CRC). JCO. 2019;37(15_suppl):3602. https://doi.org/10.1200/jco.2019.37.15_suppl.3602.

    Article  Google Scholar 

  37. 37.

    Tie J, Wang Y, Springer S, et al. Serial circulating tumor DNA (ctDNA) and recurrence risk in patients (pts) with resectable colorectal liver metastasis (CLM). JCO. 2016;34(15_suppl):e15131–e15131. https://doi.org/10.1200/jco.2016.34.15_suppl.e15131.

    Article  Google Scholar 

  38. 38.

    Overman MJ, Vauthey J-N, Aloia TA, et al. Circulating tumor DNA (ctDNA) utilizing a high-sensitivity panel to detect minimal residual disease post liver hepatectomy and predict disease recurrence. JCO. 2017;35(15_suppl):3522. https://doi.org/10.1200/jco.2017.35.15_suppl.3522.

    Article  Google Scholar 

  39. 39.

    NRG Oncology. Phase II/III study of circulating tumor DNA as a predictive biomarker in adjuvant chemotherapy in patients with stage IIA Colon Cancer (COBRA): Identifier: NRG-GI005, NCT04068103. Available: https://www.nrgoncology.org/Clinical-Trials/Protocol/nrg-gi005-1?filter=nrg-gi005-1. Accessed January 19, 2020.

  40. 40.

    australianclinicaltrials.gov.au. Circulating tumour DNA (ctDNA) analysis informing adjuvant chemotherapy in Stage II Colon Cancer: Identifier: ACTRN12615000381583. Available: https://www.australianclinicaltrials.gov.au/anzctr/trial/ACTRN12615000381583. Accessed January 18, 2020.

  41. 41.

    Clinicaltrials.gov. Circulating tumor DNA based decision for adjuvant treatment in colon cancer stage II (CIRCULATE): Identifier: NCT04120701. Available: https://clinicaltrials.gov/ct2/show/NCT04120701. Accessed January 19, 2020.

  42. 42.

    Clinicaltrials.gov. Circulating tumour DNA based decision for adjuvant treatment in colon cancer stage II evaluation (CIRCULATE): Identifier: NCT04089631. Available: https://clinicaltrials.gov/ct2/show/NCT04089631. accessed January 19, 2020.

  43. 43.

    Clinicaltrials.gov. IMPROVE intervention trial implementing non-invasive circulating tumor DNA analysis to optimize the operative and postoperative treatment for patients with colorectal cancer (IMPROVE-IT): ClinicalTrials.gov Identifier: NCT03748680. Available: https://clinicaltrials.gov/ct2/show/NCT03748680. Accessed January 18, 2020.

  44. 44.

    australianclinicaltrials.gov.au. Circulating tumour DNA analysis informing adjuvant chemotherapy in stage III colon cancer: a multicentre phase II/III randomised controlled study (DYNAMIC-III): Identifier: ACTRN12617001566325. Available: https://www.australianclinicaltrials.gov.au/anzctr/trial/ACTRN12617001566325. Accessed January 18, 2020.

  45. 45.

    Clinicaltrials.gov. Identification and treatment of micrometastatic disease in stage III colon cancer: Identifier: NCT03803553. Available: https://clinicaltrials.gov/ct2/show/NCT03803553. Accessed January 19, 2020.

  46. 46.

    Clinicaltrials.gov. Circulating tumor DNA analysis to optimize the operative and postoperative treatment for patients with colorectal cancer - intervention Trial 2 (IMPROVE-IT2): Identifier: NCT04084249. Available: https://clinicaltrials.gov/ct2/show/NCT04084249. Accessed January 19, 2020.

  47. 47.

    australianclinicaltrials.gov.au. Use of circulating tumour DNA (ctDNA) results to inform the decision for adjuvant chemotherapy in patients with locally advanced rectal cancer who have been treated with pre-operative chemo-radiation and surgery. Identifier: ACTRN12617001560381. Available: https://www.australianclinicaltrials.gov.au/anzctr/trial/ACTRN12617001560381. Accessed January 18, 2020.

  48. 48.

    Clinicaltrials.gov. Study of Pembrolizumab or Placebo following surgery in patients with microsatellite instability high (MSI-H) Solid Tumors: Identifier: NCT03832569. Available: https://clinicaltrials.gov/ct2/show/NCT03832569. Accessed January 31, 2020.

  49. 49.

    Schmiegel W, Scott RJ, Dooley S, et al. Blood-based detection of RAS mutations to guide anti-EGFR therapy in colorectal cancer patients: concordance of results from circulating tumor DNA and tissue-based RAS testing. Mol Oncol. 2017;11(2):208–219. https://doi.org/10.1002/1878-0261.12023.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  50. 50.

    Spindler KG, Appelt AL, Pallisgaard N, Andersen RF, Jakobsen A. KRAS-mutated plasma DNA as predictor of outcome from irinotecan monotherapy in metastatic colorectal cancer. Br J Cancer. 2013;109(12):3067–3072. https://doi.org/10.1038/bjc.2013.633.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  51. 51.

    Hsu H-C, Lapke N, Wang C-W, et al. Targeted sequencing of circulating tumor DNA to monitor genetic variants and therapeutic response in metastatic colorectal cancer. Mol Cancer Therap. 2018;17(10):2238–2247. https://doi.org/10.1158/1535-7163.mct-17-1306.

    CAS  Article  PubMed  Google Scholar 

  52. 52.

    Diehl F, Schmidt K, Choti MA, et al. Circulating mutant DNA to assess tumor dynamics. Nat Med. 2008;14(9):985–990. https://doi.org/10.1038/nm.1789.

    CAS  Article  PubMed  Google Scholar 

  53. 53.

    Sato KA, Hachiya T, Iwaya T, et al. Individualized mutation detection in circulating tumor DNA for monitoring colorectal tumor burden using a cancer-associated gene sequencing panel. PloS One. 2016;11(1):e0146275. https://doi.org/10.1371/journal.pone.0146275.

    Article  PubMed  PubMed Central  Google Scholar 

  54. 54.

    Diaz LA, Williams RT, Wu J, et al. The molecular evolution of acquired resistance to targeted EGFR blockade in colorectal cancers. Nature. 2012;486(7404):537–540. https://doi.org/10.1038/nature11219.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  55. 55.

    Misale S, Yaeger R, Hobor S, et al. Emergence of KRAS mutations and acquired resistance to anti-EGFR therapy in colorectal cancer. Nature. 2012;486(7404):532–536. https://doi.org/10.1038/nature11156.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  56. 56.

    Siravegna G, Mussolin B, Buscarino M, et al. Clonal evolution and resistance to EGFR blockade in the blood of colorectal cancer patients. Nat Med. 2015;21(7):795–801. https://doi.org/10.1038/nm.3870.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  57. 57.

    Vidal J, Muinelo L, Dalmases A, et al. Plasma ctDNA RAS mutation analysis for the diagnosis and treatment monitoring of metastatic colorectal cancer patients. Ann Oncol Off J Eur Soc Med Oncol. 2017;28(6):1325–1332. https://doi.org/10.1093/annonc/mdx125.

    CAS  Article  Google Scholar 

  58. 58.

    Woolston A, Khan K, Spain G, et al. Genomic and transcriptomic determinants of therapy resistance and immune landscape evolution during anti-EGFR treatment in colorectal cancer. Cancer Cell. 2019;36(1):35–50.e9. https://doi.org/10.1016/j.ccell.2019.05.013.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  59. 59.

    Parseghian CM, Loree JM, Morris VK, et al. Anti-EGFR-resistant clones decay exponentially after progression: implications for anti-EGFR re-challenge. Ann Oncol Off J Eur Soc Med Oncol. 2019;30(2):243–249. https://doi.org/10.1093/annonc/mdy509.

    CAS  Article  Google Scholar 

  60. 60.

    Cremolini C, Antoniotti C, Lonardi S, et al. Activity and safety of Cetuximab Plus modified FOLFOXIRI followed by maintenance with Cetuximab or Bevacizumab for RAS and BRAF wild-type metastatic colorectal cancer: a randomized phase 2 clinical trial. JAMA Oncol. 2018;4(4):529–536. https://doi.org/10.1001/jamaoncol.2017.5314.

    Article  PubMed  PubMed Central  Google Scholar 

  61. 61.

    Tie J, Kinde I, Wang Y, et al. Circulating tumor DNA as an early marker of therapeutic response in patients with metastatic colorectal cancer. Ann Oncol Off J Eur Soc Med Oncol. 2015;26(8):1715–1722. https://doi.org/10.1093/annonc/mdv177.

    CAS  Article  Google Scholar 

  62. 62.

    Garlan F, Laurent-Puig P, Sefrioui D, et al. Early evaluation of circulating tumor DNA as marker of therapeutic efficacy in metastatic colorectal cancer patients (PLACOL study). Clin Cancer Res Off J Am Assoc Cancer Res. 2017;23(18):5416–5425. https://doi.org/10.1158/1078-0432.ccr-16-3155.

    CAS  Article  Google Scholar 

  63. 63.

    Parikh AR, Mojtahed A, Schneider JL, et al. Serial ctDNA monitoring to predict response to systemic therapy in metastatic gastrointestinal cancers. Clin Cancer Res Off J Am Assoc Cancer Res. 2020. https://doi.org/10.1158/1078-0432.ccr-19-3467.

    Article  Google Scholar 

  64. 64.

    Khan K, Rata M, Cunningham D, et al. Functional imaging and circulating biomarkers of response to regorafenib in treatment-refractory metastatic colorectal cancer patients in a prospective phase II study. Gut. 2018;67(8):1484–1492. https://doi.org/10.1136/gutjnl-2017-314178.

    CAS  Article  PubMed  Google Scholar 

  65. 65.

    Clinicaltrials.gov. Circulating cell-free tumor DNA testing in guiding treatment for patients with advanced or metastatic colorectal cancer: Identifier: NCT03844620. Available: https://clinicaltrials.gov/ct2/show/NCT03844620. Accessed January 19, 2020.

  66. 66.

    Krawczyk N, Fehm T, Banys-Paluchowski M, Janni W, Schramm A. Liquid biopsy in metastasized breast cancer as basis for treatment decisions. Oncol Res Treat. 2016;39(3):112–116. https://doi.org/10.1159/000444605.

    CAS  Article  PubMed  Google Scholar 

  67. 67.

    García-Saenz JA, Ayllón P, Laig M, et al. Tumor burden monitoring using cell-free tumor DNA could be limited by tumor heterogeneity in advanced breast cancer and should be evaluated together with radiographic imaging. BMC Cancer. 2017;17(1):210. https://doi.org/10.1186/s12885-017-3185-9.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  68. 68.

    Chan KCA, Jiang P, Chan CWM, et al. Noninvasive detection of cancer-associated genome-wide hypomethylation and copy number aberrations by plasma DNA bisulfite sequencing. Proc Natl Acad Sci USA. 2013;110(47):18761–18768. https://doi.org/10.1073/pnas.1313995110.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  69. 69.

    Lofton-Day C, Model F, Devos T, et al. DNA methylation biomarkers for blood-based colorectal cancer screening. Clin Chem. 2008;54(2):414–423. https://doi.org/10.1373/clinchem.2007.095992.

    CAS  Article  PubMed  Google Scholar 

  70. 70.

    Shen SY, Singhania R, Fehringer G, et al. Sensitive tumour detection and classification using plasma cell-free DNA methylomes. Nature. 2018;563(7732):579–583. https://doi.org/10.1038/s41586-018-0703-0.

    CAS  Article  PubMed  Google Scholar 

  71. 71.

    Aravanis AM, Lee M, Klausner RD. Next-generation sequencing of circulating tumor DNA for early cancer detection. Cell. 2017;168(4):571–574. https://doi.org/10.1016/j.cell.2017.01.030.

    CAS  Article  PubMed  Google Scholar 

  72. 72.

    Church TR, Wandell M, Lofton-Day C, et al. Prospective evaluation of methylated SEPT9 in plasma for detection of asymptomatic colorectal cancer. Gut. 2014;63(2):317–325. https://doi.org/10.1136/gutjnl-2012-304149.

    CAS  Article  PubMed  Google Scholar 

  73. 73.

    Pedersen SK, Symonds EL, Baker RT, et al. Evaluation of an assay for methylated BCAT1 and IKZF1 in plasma for detection of colorectal neoplasia. BMC Cancer. 2015;15:654. https://doi.org/10.1186/s12885-015-1674-2.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  74. 74.

    Luo H, Zhao Q, Wei W, et al. Circulating tumor DNA methylation profiles enable early diagnosis, prognosis prediction, and screening for colorectal cancer. Sci Transl Med. 2020;12(524). https://doi.org/10.1126/scitranslmed.aax7533.

  75. 75.

    Jensen SØ, Øgaard N, Ørntoft M-BW, et al. Novel DNA methylation biomarkers show high sensitivity and specificity for blood-based detection of colorectal cancer-a clinical biomarker discovery and validation study. Clin Epigenet. 2019;11(1):158. https://doi.org/10.1186/s13148-019-0757-3.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  76. 76.

    Roperch J-P, Incitti R, Forbin S, et al. Aberrant methylation of NPY, PENK, and WIF1 as a promising marker for blood-based diagnosis of colorectal cancer. BMC Cancer. 2013;13:566. https://doi.org/10.1186/1471-2407-13-566.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  77. 77.

    Clinicaltrials.gov. The circulating cell-free genome atlas study (CCGA): Identifier: NCT02889978. Available: https://clinicaltrials.gov/ct2/show/NCT02889978. Accessed May 4, 2020.

  78. 78.

    Klein EA, Hubbell E, Maddala T, et al. Development of a comprehensive cell-free DNA (cfDNA) assay for early detection of multiple tumor types: The Circulating Cell-free Genome Atlas (CCGA) study. JCO. 2018;36(15_suppl):12021. https://doi.org/10.1200/jco.2018.36.15_suppl.12021.

    Article  Google Scholar 

  79. 79.

    Clinicaltrials.gov. The implication of plasma ctDNA Methylation haplotypes in detecting colorectal cancer and adenomas: Identifier: NCT03737591. Available: https://clinicaltrials.gov/ct2/show/NCT03737591. Accessed January 19, 2020.

  80. 80.

    Garrigou S, Perkins G, Garlan F, et al. A study of hypermethylated circulating tumor DNA as a universal colorectal cancer biomarker. Clin Chem. 2016;62(8):1129–1139. https://doi.org/10.1373/clinchem.2015.253609.

    CAS  Article  PubMed  Google Scholar 

  81. 81.

    André T, Vernerey D, Mineur L, et al. Three versus 6 months of oxaliplatin-based adjuvant chemotherapy for patients with stage III colon cancer: disease-free survival results from a randomized, open-label, international duration evaluation of adjuvant (IDEA) France, Phase III Trial. J Clin Oncol Off J Am Soc Clin Oncol. 2018;36(15):1469–1477. https://doi.org/10.1200/jco.2017.76.0355.

    Article  Google Scholar 

  82. 82.

    Taieb J, Taly V, Vernerey D, et al. Analysis of circulating tumour DNA (ctDNA) from patients enrolled in the IDEA-FRANCE phase III trial: Prognostic and predictive value for adjuvant treatment duration. Ann Oncol. 2019;30:v867. https://doi.org/10.1093/annonc/mdz394.019.

    Article  Google Scholar 

  83. 83.

    Murray DH, Symonds EL, Young GP, et al. Relationship between post-surgery detection of methylated circulating tumor DNA with risk of residual disease and recurrence-free survival. J Cancer Res Clin Oncol. 2018;144(9):1741–1750. https://doi.org/10.1007/s00432-018-2701-x.

    CAS  Article  PubMed  Google Scholar 

  84. 84.

    Young GP, Pedersen SK, Mansfield S, et al. A cross-sectional study comparing a blood test for methylated BCAT1 and IKZF1 tumor-derived DNA with CEA for detection of recurrent colorectal cancer. Cancer Med. 2016;5(10):2763–2772. https://doi.org/10.1002/cam4.868.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  85. 85.

    Clinicaltrials.gov. Dynamic monitoring of ctDNA methylation to predict relapse in stage II-III colorectal cancer After Radical Resection: Identifier: NCT03737539. Available: https://clinicaltrials.gov/ct2/show/NCT03737539. Accessed January 19, 2020.

  86. 86.

    Barault L, Amatu A, Siravegna G, et al. Discovery of methylated circulating DNA biomarkers for comprehensive non-invasive monitoring of treatment response in metastatic colorectal cancer. Gut. 2018;67(11):1995–2005. https://doi.org/10.1136/gutjnl-2016-313372.

    CAS  Article  PubMed  Google Scholar 

  87. 87.

    Bhangu JS, Beer A, Mittlböck M, et al. Circulating free methylated tumor dna markers for sensitive assessment of tumor burden and early response monitoring in patients receiving systemic chemotherapy for colorectal cancer liver metastasis. Ann Surg. 2018;268(5):894–902. https://doi.org/10.1097/sla.0000000000002901.

    Article  PubMed  Google Scholar 

  88. 88.

    Phallen J, Sausen M, Adleff V, et al. Direct detection of early-stage cancers using circulating tumor DNA. Sci Transl Med. 2017;9(403). https://doi.org/10.1126/scitranslmed.aan2415.

  89. 89.

    Abbosh C, Birkbak NJ, Swanton C. Early stage NSCLC—challenges to implementing ctDNA-based screening and MRD detection. Nat Rev Clin Oncol. 2018;15(9):577–586. https://doi.org/10.1038/s41571-018-0058-3.

    CAS  Article  PubMed  Google Scholar 

  90. 90.

    Xie H, Mahoney DW, Foote PH, et al. Novel methylated DNA markers in plasma detect distant recurrence of colorectal cancer. JCO. 2020;38(15_suppl):4088. https://doi.org/10.1200/jco.2020.38.15_suppl.4088.

  91. 91.

    Jaiswal S, Fontanillas P, Flannick J, et al. Age-related clonal hematopoiesis associated with adverse outcomes. New Engl J Med. 2014;371(26):2488–2498.

    Article  Google Scholar 

  92. 92.

    Swanton C, Venn O, Aravanis A, et al. Prevalence of clonal hematopoiesis of indeterminate potential (CHIP) measured by an ultra-sensitive sequencing assay: Exploratory analysis of the Circulating Cancer Genome Atlas (CCGA) study. JCO. 2018;36(15_suppl):12003. https://doi.org/10.1200/jco.2018.36.15_suppl.12003.

  93. 93.

    Chin R-I, Chen K, Usmani A, et al. Detection of solid tumor molecular residual disease (MRD) using circulating tumor DNA (ctDNA). Mol Diagn Therap. 2019;23(3):311–331. https://doi.org/10.1007/s40291-019-00390-5.

    CAS  Article  Google Scholar 

  94. 94.

    Hu Y, Ulrich BC, Supplee J, et al. False-positive plasma genotyping due to clonal hematopoiesis. Clin Cancer Res Off J Am Assoc Cancer Res 2018;24(18):4437–4443.

    CAS  Article  Google Scholar 

  95. 95.

    Merker JD, Oxnard GR, Compton C, 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 Off J Am Soc Clin Oncol. 2018;36(16):1631–1641. https://doi.org/10.1200/jco.2017.76.8671.

    CAS  Article  Google Scholar 

Download references

Author information

Affiliations

Authors

Corresponding author

Correspondence to Richard D. Kim MD.

Ethics declarations

Disclosure

Richard Kim - consultant: Bayer, BMS, Lilly. Speaker Bureau: Lilly. Research funding: BMS, Lilly Eisai.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Xie, H., Kim, R.D. The Application of Circulating Tumor DNA in the Screening, Surveillance, and Treatment Monitoring of Colorectal Cancer. Ann Surg Oncol 28, 1845–1858 (2021). https://doi.org/10.1245/s10434-020-09002-7

Download citation