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Circulating tumor cells and circulating tumor DNA in colon cancer

Prospects and difficulties in implementation

Zirkulierende Tumorzellen und zirkulierende Tumor-DNA bei Kolonkarzinom

Aussichten und Schwierigkeiten bei der Anwendung

  • short review
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memo - Magazine of European Medical Oncology Aims and scope Submit manuscript

Abstract

It is known that tumor cells have the ability to penetrate into the bloodstream. The identification of such circulating tumor cells (CTC) determines the prognosis in several tumors, including colon cancer. Tumor DNA (ctDNA), which is only a part of the total circulating DNA obtained from the blood of cancer patients, is also further separated from plasma. This separation of the neoplastic derivatives of the primary tumor and metastases (CTC, ctDNA, RNA, proteome) in plasma is called “liquid biopsy.” CTC increasingly represents the pool of tumor cells that can initiate the growth of metastatic lesions, while the ctDNA provides the information about the whole tumor mass. Traditional tissue biopsy gives information based only on one small section of the primary tumor or metastasis, often retrieved before the start of treatment; however, liquid biopsy provides real-time information about the molecular disorders for the whole tumor mass and allows us to estimate the dynamics of the evolutionary tumor changes, the heterogeneity of the disease, and the effect of chemotherapy. With the possibility of obtaining multiple blood samples for analysis during the therapy, in contrast to traditional biopsy, it also allows us to evaluate the mechanisms of resistance to treatment, which in the future will perhaps lead to modification of the treatment in accordance with the detected molecular defects in tumors. Thus, this would facilitate implementing the principles of personalized therapy. In this literature review, we concentrate on liquid biopsy in patients with colon cancer.

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References

  1. Ashworth T. A case of cancer in which cells similar to those in the tumours were seen in the blood after death. Aust Med J. 1869;14:146–149.

    Google Scholar 

  2. Thiery JP. Epithelial-mesenchymal transitions in tumour progression. Nat Rev Cancer. 2002;2:442–454.

    Article  CAS  PubMed  Google Scholar 

  3. Miller MC, Doyle GV, Terstappen LW. Significance of circulating tumor cells detected by the CellSearch system in patients with metastatic breast colorectal and prostate cancer. J Oncol. 2010;2010:1–8.

    Article  Google Scholar 

  4. Hiraiwa K, Takeuchi H, Hasegawa H, et al. Clinical significance of circulating tumor cells in blood from patients with gastrointestinal cancers. Ann Surg Oncol. 2008;15(11):3092–3100.

    Article  PubMed  Google Scholar 

  5. Molnar B, Ladanyi A, Tanko L, et al. Circulating tumor cell clusters in the peripheral blood of colorectal cancer patients. Clin Cancer Res. 2001;7(12):4080–4085.

    CAS  PubMed  Google Scholar 

  6. Rahbari NN, Aigner M, Thorlund K, et al. Meta-analysis shows that detection of circulating tumor cells indicates poor prognosis in patients with colorectal cancer. Gastroenterology. 2010;138(5):1714–1726.

    Article  PubMed  Google Scholar 

  7. Thorsteinsson M, Soletormos G, Jess P. Low number of detectable circulating tumor cells in non-metastatic colon cancer. Anticancer Res. 2011;31(2):613–617.

    PubMed  Google Scholar 

  8. Cohen SJ, Punt CJ, Iannotti N, et al. 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. Tol J, Koopman M, Miller MC, et al. Circulating tumour cells early predict progression-free and overall survival in advanced colorectal cancer patients treated with chemotherapy and targeted agents. Ann Oncol. 2010;21(5):1006–1012.

    Article  CAS  PubMed  Google Scholar 

  10. Sastre J, Maestro ML, Gomez MA, et al. Enumeration circulating tumor cells (CTCs) is a prognostic and predictive factor for progression free survival (PFS) and overall survival in colon cancer patients receiving first-line chemotherapy plus bevacizumab. A TTD Spanish group cooperative study. Ann Oncol. 2010;21(Suppl. 8):viii63–viii77.

    Google Scholar 

  11. Smerage JB, Barlow WE, Hortobagyi GN, et al. Circulating tumor cells and response to chemotherapy in metastatic breast cancer: SWOG S050. J Clin Oncol. 2014;32(31):3483–3489.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Huang MY, Wang HM, Chang HJ, et al. Overexpression of S100B, TM4SF4, and OLFM4 genes is correlated with liver metastasis in Taiwanese colorectal cancer patients. DNA Cell Biol. 2012;31(1):43–49.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Bettegowda C, Sausen M, Leary RJ, et al. Detection of circulating tumor DNA in early- and late-stage human malignancies. Sci Transl Med. 2014;6:224ra24.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Mandel PM, Métais P. Les acides nucleiques du plasma sanguine chez l’homme. CR Acad Sci Paris. 1947;142:241–253.

    Google Scholar 

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

    CAS  PubMed  Google Scholar 

  16. Hibi K, Robinson CR, Booker S, et al. Molecular detection of genetic alterations in the 505 serum of colorectal cancer patients. Cancer Res. 1998;58:1405–1407.

    CAS  PubMed  Google Scholar 

  17. Lecomte T, Ceze N, Dorval E, Laurent-Puig P. Circulating free tumor DNA and colorectal cancer. Gastroenterol Clin Biol. 2010;34:662–681.

    Article  CAS  PubMed  Google Scholar 

  18. Sikora A, Zimmermann BG, Rusterholz C, et al. Detection of increased amounts of cell-free fetal DNA with short PCR amplicons. Clin Chem. 2010;56:136–138.

    Article  CAS  PubMed  Google Scholar 

  19. Jung K, Fleischhacker M, Rabien A. Cell-free DNA in the blood as a solid tumor biomarker – a critical appraisal of the literature. Clin Chim Acta. 2010;411:1611–1624.

    Article  CAS  PubMed  Google Scholar 

  20. Danese E, Minicozzi AM, Benati M, et al. Comparison of genetic and epigenetic alterations of primary tumors and matched plasma samples in patients with colorectal cancer. PLoS ONE. 2015;10(5):e0126417 doi:10.1371/journal.pone.0126417.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Kuo YB, Chen JS, Li YS, Chan EC. Comparison of KRAS mutation analysis of primary tumors and matched 2 circulating cell-free DNA in plasmas of patients with colorectal cancer. Clin Chim Acta. 2014;433:284–289.

    Article  CAS  PubMed  Google Scholar 

  22. Heitzer E, Ulz P, Geigl JB. Circulating tumor DNA as a liquid biopsy for cancer. Clin Chem. 2015;61(1):112–123.

    Article  CAS  PubMed  Google Scholar 

  23. Spindler KLG, Appelt AL, Pallisgaard N, et al. Cell-free DNA levels in colorectal cancer patients treated with irinotecan, healthy controls, and non-cancer patients with comorbidity. J Clin Oncol. 2014;32(5s):suppl; abstr 3559.

    Google Scholar 

  24. Danese E, Montagnana M, Minicozzi AM, et al. Real-time polymerase chain reaction quantification of free DNA in serum of patients with polyps and colorectal cancers. Clin Chem Lab Med. 2010;48(11):1665–1668.

    Article  CAS  PubMed  Google Scholar 

  25. Tie J, Kinde I, Wang Y, et al. Circulating tumor DNA (ctDNA) as a marker of recurrence risk in stage II colon cancer (CC). J Clin Oncol. 2014;33(suppl 5):abstr 11015.

    Google Scholar 

  26. Mouliere F, Thierry AR. The importance of examining the proportion of circulating DNA originating from tumor, microenvironment and normal cells in colorectal cancer patients. Expert Opin Biol Ther. 2012;12(Suppl.1):209–215.

    Article  Google Scholar 

  27. Tabernero J, Lenz HJ, Siena S, et al. Analysis of circulating DNA and protein biomarkers to predict the clinical activity of regorafenib and assess prognosis in patients with metastatic colorectal cancer: a retrospective, exploratory analysis of the CORRECT trial. Lancet Oncol. 2015;: doi:10.1016/S1470-2045(15)00138-2

    Google Scholar 

  28. Wong ALA, Lim JSJ, Sinha A, et al. Tumour pharmacodynamics and circulating cell free DNA in patients with refractory colorectal carcinoma treated with regorafenib. J Transl Med. 2015;13:57.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Teufel M, Kalmus J, Rutstein M. et al. Analysis of biomarkers in circulating tumor DNA from the phase 3 CONCUR study of regorafenib in Asian patients with metastatic colorectal cancer (mCRC): Correlation with clinical outcome ECOO2015 congress. vol abctract#2013. 2015.

    Google Scholar 

  30. Andersen RF, Spindler KL, Brandslund I, et al. Improved sensitivity of circulating tumor DNA measurement using short PCR amplicons. Clin Chim Acta. 2015;439:97–101.

    Article  CAS  PubMed  Google Scholar 

  31. Morelli MP, Overman MJ, Sanchez EV, et al. Frequency of concurrent gene mutations and copy number alterations in circulating cell-free DNA (cfDNA) from refractory metastatic CRC patients. J Clin Oncol. 2014;32(5s):abstr 11117.

    Google Scholar 

  32. Marziali A, Vysotskaia V, Wiggin M, et al. Circulating tumor DNA as a highly specific diagnostic marker for colorectal cancer. J Clin Oncol. 2014;32(suppl):abstr e22126.

    Google Scholar 

  33. Sefrioui D, Vasseur N, Sesboüé R, et al. Plasma cell-free DNA and fraction of circulating KRAS mutations as prognostic in patients with metastatic colorectal cancer. J Clin Oncol. 2014;32(suppl 3):abstr 490.

    Google Scholar 

  34. Liu F, Li C, Zhao J. et al. Detection of KRAS mutations in plasma from patients with metastatic colorectal cancer by the next-generation sequencing ECOO2015 congress. vol abctract#2185. 2015.

    Google Scholar 

  35. Jones F, Edelstein D, Wichner K. et al. Concordance of RAS mutation status in metastatic CRC patients by comparison of results from circulating tumor DNA and tissue-based RAS testing ECOO2015 congress. vol abctract#2012. 2015.

    Google Scholar 

  36. Yamada T, Kan H, Matsumoto S, et al. Liquid biopsy detection of KRAS and BRAF mutations may be useful as a prognostic or predictive marker. Ann Oncol. 2014;25(suppl_4):iv58–iv84. doi:10.1093/annonc/mdu326.

    Google Scholar 

  37. Poole JC, Vibat CRT, Benesova L, et al. Highly sensitive quantitative detection of circulating tumor DNA in urine and plasma from advanced colorectal cancer patients in aid of early diagnosis of clinically relevant KRAS mutations. J Clin Oncol. 2015;33(suppl 3):abstr 654.

    Google Scholar 

  38. Kopreski MS, Benko FA, Borys DJ, et al. Somatic mutation screening: identification of individuals harboring K‑ras mutations with the use of plasma DNA. J Natl Cancer Inst. 2000;92:918–923.

    Article  CAS  PubMed  Google Scholar 

  39. Nowell PC. The clonal evolution of tumor cell populations. Science. 1976;194:23–28.

    Article  CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Mohan S, Heitzer E, Ulz P, et al. Changes in colorectal carcinoma genomes under anti-EGFR therapy identified by whole-genome plasma DNA sequencing. PLoS Genet. 2014;10:e1004271.

    Article  PubMed  PubMed Central  Google Scholar 

  42. 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;21:795–801.

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Clinical Pharmacology and Chemotherapy, Russian Cancer Research Center named after N.N. Blokhin, Kashirskoye shosse 23, 115478, Moscow, Russia

    Mikhail Fedyanin MD, PhD, Elizaveta Polyanskaya MD & Sergei Tjulandin MD, PhD

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  1. Mikhail Fedyanin MD, PhD
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  2. Elizaveta Polyanskaya MD
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  3. Sergei Tjulandin MD, PhD
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Correspondence to Mikhail Fedyanin MD, PhD, Elizaveta Polyanskaya MD or Sergei Tjulandin MD, PhD.

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M. Fedyanin, E. Polyanskaya, and S. Tjulandin declare that they have no competing interests.

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Fedyanin, M., Polyanskaya, E. & Tjulandin, S. Circulating tumor cells and circulating tumor DNA in colon cancer. memo 9, 88–92 (2016). https://doi.org/10.1007/s12254-016-0263-7

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  • DOI: https://doi.org/10.1007/s12254-016-0263-7

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