Principles of blood based testing

Although being the standard in clinical oncology, analyzing mutations in tumor tissue comes with considerable drawbacks. Biopsies can significantly increase the costs of patient care, are inconvenient from a scheduling perspective and not without clinical complications (1). Moreover, they are subject to selection bias due to tumor heterogeneity, can be difficult to obtain in sufficient amounts and the information provided is restricted to a static time point (2-3). It is now well established that cells shed small DNA fragments into the circulation with most of this DNA being compartmentalized in the plasma component of whole blood (4-12). The specific detection of tumor-derived cell-free DNA has been shown to correlate with tumor burden, to a change in response to treatment or surgery, and to indicate that subpopulations of tumor cells that are resistant to treatment can proliferate in response to therapy (13,14). Therefore circulating tumor DNA can serve as liquid biopsy that can be used for a variety of clinical and investigational applications without the need for physical biopsies.

Advantages of blood-based testing

  • ctDNA provides real-time information about the current mutational status of the tumor•Non-invasive liquid biopsies minimize cost andrisk to patients
  • Easily performed in situations where no tumor tissue is available or accessible
  • Systemic approach assesses the mutational status of the tumor eliminating the selection bias inherent with tissue samples.



circulating cell-free tumor DNA


  1.  Overman MJ, Modak J, Kopetz S, et al: Use of research biopsies in clinical trials: Are risks and benefits adequately discussed? J Clin Oncol 31:17-22, 2013
  2.  Vogelstein B, Papadopoulos N, Velculescu VE, et al: Cancer genome landscapes. Science 339:1546-1558, 2013
  3.  Gerlinger M, Rowan AJ, Horswell S, et al: Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med 366:883-892, 2012
  4.  Delgado PO, Alves BC, Gehrke Fde S, et al: Characterization of cell-free circulating DNA in plasma in patients with prostate cancer. Tumour Biol 34:983-986, 2013
  5.  Hashad D, Sorour A, Ghazal A, et al: Free circulating tumor DNA as a diagnostic marker for breast cancer. J Clin Lab Anal 26:467-472, 2012
  6.  No JH, Kim K, Park KH, et al: Cell-free DNA level as a prognostic biomarker for epithelial ovarian cancer. Anticancer Res 32:3467-3471, 2012
  7. Park JL, Kim HJ, Choi BY, et al: Quantitative analysis of cell-free DNA in the plasma of gastric cancer patients. Oncol Lett 3:921-926, 2012
  8. Salvianti F, Pinzani P, Verderio P, et al: Multiparametric analysis of cell-free DNA in melanoma patients. PLoS One 7:e49843, 2012
  9.  Schwarzenbach H, Alix-Panabieres C, Mueller I, et al: Cell-free tumor DNA in blood plasma as a marker for circulating tumor cells in prostate cancer. Clin Cancer Res 15:1032-1038, 2009
  10. Schwarzenbach H, Mueller V, Milde-Langosch K, et al: Evaluation of cell-free tumour DNA and RNA in patients with breast cancer and benign breast disease. Mol Biosyst 7:2848-2854, 2011
  11. Schwarzenbach H, Stoehlmacher J, Pantel K,et al: Detection and monitoring of cell-free DNA in blood of patients with colorectal cancer. Ann N Y Acad Sci 1137:190-196, 2008
  12. Fleischhacker M, Schmidt B: Circulating nucleic acids (CNAs) and cancer: A survey. Biochim Biophys Acta 1775:181-232, 2007
  13. Diaz, L. A. Jr et al. The molecular evolution of acquired resistance to targeted EGFR blockade in colorectal cancers. Nature 486, 537–540 (2012).
  14. Misale, S. et al. Emergence of KRAS mutations and acquired resistance to anti-EGFR therapy in colorectal cancer. Nature 486, 532–536 (2012).

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