1932

Abstract

Circulating tumor DNA (ctDNA) is a component of the “naked” DNA found in blood. It can be isolated from plasma and represents combined genetic material from the primary tumor and metastases. Quantitative and qualitative information about a cancer, including mutations, can be derived using digital polymerase chain reaction and other technologies. This “liquid biopsy” is quicker and more easily repeated than tissue biopsy, yields real-time information about the cancer, and may suggest therapeutic options. All stages of cancer therapy have the ability to benefit from ctDNA, starting with screening for cancer before it is clinically apparent. During treatment of metastatic disease, it is useful to predict response and monitor disease progression. Currently, ctDNA is used in the clinic to select patients who may benefit from epidermal growth factor receptor–targeted therapy in non–small cell lung cancer. In the future, ctDNA technology promises useful applications in every part of clinical oncology care.

Loading

Article metrics loading...

/content/journals/10.1146/annurev-med-041316-085721
2018-01-29
2024-03-28
Loading full text...

Full text loading...

/deliver/fulltext/med/69/1/annurev-med-041316-085721.html?itemId=/content/journals/10.1146/annurev-med-041316-085721&mimeType=html&fmt=ahah

Literature Cited

  1. Mandel P, Métais P. 1.  1948. Les acides nucléiques du plasma sanguin chez l'homme. Comptes Rendus Seances Soc. Biol. Fil. 142:241–43 [Google Scholar]
  2. Tan EM, Schur PH, Carr RI, Kunkel HG. 2.  1966. Deoxyribonucleic acid (DNA) and antibodies to DNA in the serum of patients with systemic lupus erythematosus. J. Clin. Investig. 45:1732–40 [Google Scholar]
  3. Rous P. 3.  1959. Surmise and fact on the nature of cancer. Nature 183:1357–61 [Google Scholar]
  4. Leon SA, Shapiro B, Sklaroff DM, Yaros MJ. 4.  1977. Free DNA in the serum of cancer patients and the effect of therapy. Cancer Res 37:646–50 [Google Scholar]
  5. 5. US Food and Drug Administration. 2016. Cobas EGFR mutation test v2 Rep., US Food Drug Admin., Silver Spring, MD. https://www.fda.gov/drugs/informationondrugs/approveddrugs/ucm504540.htm
  6. 6. European Medicines Agency. 2014. Iressa: EPAR—product information Rep., Eur. Med. Agency, London. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/001016/WC500036358.pdf
  7. Ansari J, Yun JW, Kompelli AR. 7.  et al. 2016. The liquid biopsy in lung cancer. Genes Cancer 7:355–67 [Google Scholar]
  8. Thierry AR, El Messaoudi S, Gahan PB. 8.  et al. 2016. Origins, structures, and functions of circulating DNA in oncology. Cancer Metastasis Rev 35:347–76 [Google Scholar]
  9. Thierry AR, Mouliere F, Gongora C. 9.  et al. 2010. Origin and quantification of circulating DNA in mice with human colorectal cancer xenografts. Nucleic Acids Res 38:6159–75 [Google Scholar]
  10. Jahr S, Hentze H, Englisch S. 10.  et al. 2001. DNA fragments in the blood plasma of cancer patients: quantitations and evidence for their origin from apoptotic and necrotic cells. Cancer Res 61:1659–65 [Google Scholar]
  11. Diehl F, Schmidt K, Choti MA. 11.  et al. 2008. Circulating mutant DNA to assess tumor dynamics. Nat. Med. 14:985–90 [Google Scholar]
  12. Diehl F, Li M, Dressman D. 12.  et al. 2005. Detection and quantification of mutations in the plasma of patients with colorectal tumors. PNAS 102:16368–73 [Google Scholar]
  13. Diaz LA Jr., Bardelli A. 13.  2014. Liquid biopsies: genotyping circulating tumor DNA. J. Clin. Oncol. 32:579–86 [Google Scholar]
  14. Anker P, Stroun M, Maurice PA. 14.  1975. Spontaneous release of DNA by human blood lymphocytes as shown in an in vitro system. Cancer Res 35:2375–82 [Google Scholar]
  15. Mouliere F, El Messaoudi S, Gongora C. 15.  et al. 2013. Circulating cell-free DNA from colorectal cancer patients may reveal high KRAS or BRAF mutation load. Transl. Oncol. 6:319–28 [Google Scholar]
  16. Mouliere F, Robert B, Arnau Peyrotte E. 16.  et al. 2011. High fragmentation characterizes tumour-derived circulating DNA. PLOS ONE 6:e23418 [Google Scholar]
  17. Underhill HR, Kitzman JO, Hellwig S. 17.  et al. 2016. Fragment length of circulating tumor DNA. PLOS Genet 12:e1006162 [Google Scholar]
  18. Lo YM, Zhang J, Leung TN. 18.  et al. 1999. Rapid clearance of fetal DNA from maternal plasma. Am. J. Hum. Genet. 64:218–24 [Google Scholar]
  19. Normanno N, Denis MG, Thress KS. 19.  et al. 2017. Guide to detecting epidermal growth factor receptor (EGFR) mutations in ctDNA of patients with advanced non-small-cell lung cancer. Oncotarget 8:12501–16 [Google Scholar]
  20. Benesova L, Belsanova B, Suchanek S. 20.  et al. 2013. Mutation-based detection and monitoring of cell-free tumor DNA in peripheral blood of cancer patients. Anal. Biochem. 433:227–34 [Google Scholar]
  21. Wan JC, Massie C, Garcia-Corbacho J. 21.  et al. 2017. Liquid biopsies come of age: towards implementation of circulating tumour DNA. Nat. Rev. Cancer 17:223–38 [Google Scholar]
  22. Lee TH, Montalvo L, Chrebtow V, Busch MP. 22.  2001. Quantitation of genomic DNA in plasma and serum samples: higher concentrations of genomic DNA found in serum than in plasma. Transfusion 41:276–82 [Google Scholar]
  23. Toro PV, Erlanger B, Beaver JA. 23.  et al. 2015. Comparison of cell stabilizing blood collection tubes for circulating plasma tumor DNA. Clin. Biochem. 48:993–98 [Google Scholar]
  24. Hrebien S, O'Leary B, Beaney M. 24.  et al. 2016. Reproducibility of digital PCR assays for circulating tumor DNA analysis in advanced breast cancer. PLOS ONE 11:e0165023 [Google Scholar]
  25. Malentacchi F, Pizzamiglio S, Verderio P. 25.  et al. 2015. Influence of storage conditions and extraction methods on the quantity and quality of circulating cell-free DNA (ccfDNA): the SPIDIA-DNAplas External Quality Assessment experience. Clin. Chem. Lab. Med. 53:1935–42 [Google Scholar]
  26. Sorber L, Zwaenepoel K, Deschoolmeester V. 26.  et al. 2017. A comparison of cell-free DNA isolation kits: isolation and quantification of cell-free DNA in plasma. J. Mol. Diagn. 19:162–68 [Google Scholar]
  27. Fong SL, Zhang JT, Lim CK. 27.  et al. 2009. Comparison of 7 methods for extracting cell-free DNA from serum samples of colorectal cancer patients. Clin. Chem. 55:587–89 [Google Scholar]
  28. Jung K, Stephan C, Lewandowski M. 28.  et al. 2004. Increased cell-free DNA in plasma of patients with metastatic spread in prostate cancer. Cancer Lett 205:173–80 [Google Scholar]
  29. Chun FK, Muller I, Lange I. 29.  et al. 2006. Circulating tumour-associated plasma DNA represents an independent and informative predictor of prostate cancer. BJU Int 98:544–48 [Google Scholar]
  30. Zanetti-Dallenbach R, Wight E, Fan AX. 30.  et al. 2008. Positive correlation of cell-free DNA in plasma/serum in patients with malignant and benign breast disease. Anticancer Res 28:921–25 [Google Scholar]
  31. Huang ZH, Li LH, Hua D. 31.  2006. Quantitative analysis of plasma circulating DNA at diagnosis and during follow-up of breast cancer patients. Cancer Lett 243:64–70 [Google Scholar]
  32. Gal S, Fidler C, Lo YM. 32.  et al. 2004. Quantitation of circulating DNA in the serum of breast cancer patients by real-time PCR. Br. J. Cancer 90:1211–15 [Google Scholar]
  33. Jung K, Fleischhacker M, Rabien A. 33.  2010. Cell-free DNA in the blood as a solid tumor biomarker—a critical appraisal of the literature. Clin. Chim. Acta 411:1611–24 [Google Scholar]
  34. Dressman D, Yan H, Traverso G. 34.  et al. 2003. Transforming single DNA molecules into fluorescent magnetic particles for detection and enumeration of genetic variations. PNAS 100:8817–22 [Google Scholar]
  35. Vogelstein B, Kinzler KW. 35.  1999. Digital PCR. PNAS 96:9236–41 [Google Scholar]
  36. Li J, Wang L, Mamon H. 36.  et al. 2008. Replacing PCR with COLD-PCR enriches variant DNA sequences and redefines the sensitivity of genetic testing. Nat. Med. 14:579–84 [Google Scholar]
  37. Marziali A, Pel J, Bizzotto D, Whitehead LA. 37.  2005. Novel electrophoresis mechanism based on synchronous alternating drag perturbation. Electrophoresis 26:82–90 [Google Scholar]
  38. Song C, Liu Y, Fontana R. 38.  et al. 2016. Elimination of unaltered DNA in mixed clinical samples via nuclease-assisted minor-allele enrichment. Nucleic Acids Res 44:e146 [Google Scholar]
  39. Forshew T, Murtaza M, Parkinson C. 39.  et al. 2012. Noninvasive identification and monitoring of cancer mutations by targeted deep sequencing of plasma DNA. Sci. Transl. Med. 4:136ra68 [Google Scholar]
  40. Kinde I, Wu J, Papadopoulos N. 40.  et al. 2011. Detection and quantification of rare mutations with massively parallel sequencing. PNAS 108:9530–35 [Google Scholar]
  41. Murtaza M, Dawson SJ, Tsui DW. 41.  et al. 2013. Non-invasive analysis of acquired resistance to cancer therapy by sequencing of plasma DNA. Nature 497:108–12 [Google Scholar]
  42. Newman AM, Bratman SV, To J. 42.  et al. 2014. An ultrasensitive method for quantitating circulating tumor DNA with broad patient coverage. Nat. Med. 20:548–54 [Google Scholar]
  43. Lanman RB, Mortimer SA, Zill OA. 43.  et al. 2015. Analytical and clinical validation of a digital sequencing panel for quantitative, highly accurate evaluation of cell-free circulating tumor DNA. PLOS ONE 10:e0140712 [Google Scholar]
  44. Tie J, Kinde I, Wang Y. 44.  et al. 2015. Circulating tumor DNA as an early marker of therapeutic response in patients with metastatic colorectal cancer. Ann. Oncol. 26:1715–22 [Google Scholar]
  45. Schmitt MW, Kennedy SR, Salk JJ. 45.  et al. 2012. Detection of ultra-rare mutations by next-generation sequencing. PNAS 109:14508–13 [Google Scholar]
  46. Hoang ML, Kinde I, Tomasetti C. 46.  et al. 2016. Genome-wide quantification of rare somatic mutations in normal human tissues using massively parallel sequencing. PNAS 113:9846–51 [Google Scholar]
  47. Heitzer E, Ulz P, Belic J. 47.  et al. 2013. Tumor-associated copy number changes in the circulation of patients with prostate cancer identified through whole-genome sequencing. Genome Med 5:30–45 [Google Scholar]
  48. Leary RJ, Kinde I, Diehl F. 48.  et al. 2010. Development of personalized tumor biomarkers using massively parallel sequencing. Sci. Transl. Med. 2:20ra14 [Google Scholar]
  49. Kinde I, Papadopoulos N, Kinzler KW, Vogelstein B. 49.  2012. FAST-SeqS: a simple and efficient method for the detection of aneuploidy by massively parallel sequencing. PLOS ONE 7:e41162 [Google Scholar]
  50. Belic J, Koch M, Ulz P. 50.  et al. 2015. Rapid identification of plasma DNA samples with increased ctDNA levels by a modified FAST-SeqS approach. Clin. Chem. 61:838–49 [Google Scholar]
  51. Jin J. 51.  2014. Breast cancer screening: benefits and harms. JAMA patient page. JAMA 312:2585 [Google Scholar]
  52. Fernandez-Cuesta L, Perdomo S, Avogbe PH. 52.  et al. 2016. Identification of circulating tumor DNA for the early detection of small-cell lung cancer. EBioMedicine 10:117–23 [Google Scholar]
  53. Gormally E, Vineis P, Matullo G. 53.  et al. 2006. TP53 and KRAS2 mutations in plasma DNA of healthy subjects and subsequent cancer occurrence: a prospective study. Cancer Res 66:6871–76 [Google Scholar]
  54. De Mattos-Arruda L, Weigelt B, Cortes J. 54.  et al. 2014. Capturing intra-tumor genetic heterogeneity by de novo mutation profiling of circulating cell-free tumor DNA: a proof-of-principle. Ann. Oncol. 25:1729–35 [Google Scholar]
  55. Wu YL, Sequist LV, Hu CP. 55.  et al. 2017. EGFR mutation detection in circulating cell-free DNA of lung adenocarcinoma patients: analysis of LUX-Lung 3 and 6. Br. J. Cancer 116:175–85 [Google Scholar]
  56. Jenkins S, Yang JC, Ramalingam SS. 56.  et al. 2017. Plasma ctDNA analysis for detection of the EGFR T790M mutation in patients with advanced non-small cell lung cancer. J. Thorac. Oncol. 12:1061–70 [Google Scholar]
  57. Mok T, Wu YL, Lee JS. 57.  et al. 2015. Detection and dynamic changes of EGFR mutations from circulating tumor DNA as a predictor of survival outcomes in NSCLC patients treated with first-line intercalated erlotinib and chemotherapy. Clin. Cancer Res. 21:3196–203 [Google Scholar]
  58. Spindler KL, Pallisgaard N, Appelt AL. 58.  et al. 2015. 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 51:2678–85 [Google Scholar]
  59. Jovelet C, Ileana E, Le Deley MC. 59.  et al. 2016. Circulating cell-free tumor DNA analysis of 50 genes by next-generation sequencing in the prospective MOSCATO trial. Clin. Cancer Res. 22:2960–68 [Google Scholar]
  60. Tabernero J, Lenz HJ, Siena S. 60.  et al. 2015. 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 16:937–48 [Google Scholar]
  61. Dawson SJ, Tsui DW, Murtaza M. 61.  et al. 2013. Analysis of circulating tumor DNA to monitor metastatic breast cancer. N. Engl. J. Med. 368:1199–209 [Google Scholar]
  62. Frenel JS, Carreira S, Goodall J. 62.  et al. 2015. Serial next-generation sequencing of circulating cell-free DNA evaluating tumor clone response to molecularly targeted drug administration. Clin. Cancer Res. 21:4586–96 [Google Scholar]
  63. Goyal L, Saha SK, Liu LY. 63.  et al. 2017. Polyclonal secondary FGFR2 mutations drive acquired resistance to FGFR inhibition in patients with FGFR2 fusion-positive cholangiocarcinoma. Cancer Discov 7:252–63 [Google Scholar]
  64. Hong DS, Morris VK, El Osta B. 64.  et al. 2016. Phase IB study of vemurafenib in combination with irinotecan and cetuximab in patients with metastatic colorectal cancer with BRAFV600E mutation. Cancer Discov 6:1352–65 [Google Scholar]
  65. Toy W, Shen Y, Won H. 65.  et al. 2013. ESR1 ligand-binding domain mutations in hormone-resistant breast cancer. Nat. Genet. 45:1439–45 [Google Scholar]
  66. Guttery DS, Page K, Hills A. 66.  et al. 2015. Noninvasive detection of activating estrogen receptor 1 (ESR1) mutations in estrogen receptor-positive metastatic breast cancer. Clin. Chem. 61:974–82 [Google Scholar]
  67. Chu D, Paoletti C, Gersch C. 67.  et al. 2016. ESR1 mutations in circulating plasma tumor DNA from metastatic breast cancer patients. Clin. Cancer Res. 22:993–99 [Google Scholar]
  68. Sefrioui D, Perdrix A, Sarafan-Vasseur N. 68.  et al. 2015. Short report: monitoring ESR1 mutations by circulating tumor DNA in aromatase inhibitor resistant metastatic breast cancer. Int. J. Cancer 137:2513–19 [Google Scholar]
  69. Fribbens C, O'Leary B, Kilburn L. 69.  et al. 2016. Plasma ESR1 mutations and the treatment of estrogen receptor-positive advanced breast cancer. J. Clin. Oncol. 34:2961–68 [Google Scholar]
  70. Chandarlapaty S, Chen D, He W. 70.  et al. 2016. Prevalence of ESR1 mutations in cell-free DNA and outcomes in metastatic breast cancer: a secondary analysis of the BOLERO-2 clinical trial. JAMA Oncol 2:1310–15 [Google Scholar]
  71. Parsons HA, Beaver JA, Cimino-Mathews A. 71.  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. 23:379–86 [Google Scholar]
  72. Lebofsky R, Decraene C, Bernard V. 72.  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. 9:783–90 [Google Scholar]
/content/journals/10.1146/annurev-med-041316-085721
Loading
/content/journals/10.1146/annurev-med-041316-085721
Loading

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error