Cancer patients usually receive therapies according to their primary tumor's molecular traits. These characteristics may change during the molecular evolution of distant metastases as the leading cause of cancer deaths. Primary tumor tissue, if accessible at all, does not always provide enough information to stratify individual patients to the most promising therapy. Re-analysis of metastatic lesions by needle biopsy is possible but invasive, and limited by the known intra-patient heterogeneity of individual lesions. These hurdles might be overcome by analyzing tumor cells or tumor cell products in blood samples (liquid biopsy), which in principle might reflect all subclones present at that specific time point and allow sequential monitoring of disease evolution. Liquid biopsies inform on circulating tumor cells as well as tumor-derived cell-free nucleic acids, exosomes and platelets. Here, we introduce the different approaches of blood-based liquid biopsies and discuss the clinical applications in oncology.

Ferrari M, Carrera P, Lampasona V, Galbiati S: New trend in non-invasive prenatal diagnosis. Clin Chim Acta 2015;451:9-13.
Aragona CO, Imbalzano E, Mamone F, et al.: Endothelial progenitor cells for diagnosis and prognosis in cardiovascular disease. Stem Cells Int 2016;2016:8043792.
Nascimento da Silva M, Sicchieri LB, de Oliveira Silva FR, et al.: Liquid biopsy of atherosclerosis using protoporphyrin IX as a biomarker. Analyst 2014;139:1383-1388.
Speicher MR, Pantel K: Tumor signatures in the blood. Nat Biotechnol 2014;32:441-443.
Pantel K, Alix-Panabieres C: Real-time liquid biopsy in cancer patients: Fact or fiction? Cancer Res 2013;73:6384-6388.
Bedard PL, Hansen AR, Ratain MJ, Siu LL: Tumour heterogeneity in the clinic. Nature 2013;501:355-364.
De Luca F, Rotunno G, Salvianti F, et al.: Mutational analysis of single circulating tumor cells by next generation sequencing in metastatic breast cancer. Oncotarget 2016;7:26107-26119.
Brock G, Castellanos-Rizaldos E, Hu L, et al.: Liquid biopsy for cancer screening, patient stratification and monitoring. Translational Cancer Research 2015;4:280-290.
Ashworth T: A case of cancer in which cells similar to those in the tumors were seen in the blood after death. Aust Med J 1869;14:146-149.
Alix-Panabieres C, Pantel K: Circulating tumor cells: Liquid biopsy of cancer. Clin Chem 2013;59:110-118.
Baccelli I, Schneeweiss A, Riethdorf S, et al.: Identification of a population of blood circulating tumor cells from breast cancer patients that initiates metastasis in a xenograft assay. Nat Biotechnol 2013;31:539-544.
Pantel K, Speicher MR: The biology of circulating tumor cells. Oncogene 2016;35:1216-1224.
Alix-Panabieres C, Mader S, Pantel K: Epithelial-mesenchymal plasticity in circulating tumor cells. J Mol Med (Berl) 2017;95:133-142.
Alix-Panabieres C, Pantel K: Technologies for detection of circulating tumor cells: Facts and vision. Lab Chip 2014;14:57-62.
Zhang L, Riethdorf S, Wu G, et al.: Meta-analysis of the prognostic value of circulating tumor cells in breast cancer. Clin Cancer Res 2012;18:5701-5710.
Grobe A, Blessmann M, Hanken H, et al.: Prognostic relevance of circulating tumor cells in blood and disseminated tumor cells in bone marrow of patients with squamous cell carcinoma of the oral cavity. Clin Cancer Res 2014;20:425-433.
Rink M, Chun FK, Dahlem R, et al.: Prognostic role and HER2 expression of circulating tumor cells in peripheral blood of patients prior to radical cystectomy: A prospective study. Eur Urol 2012;61:810-817.
Antonarakis ES, Lu C, Wang H, et al.: AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer. N Engl J Med 2014;371:1028-1038.
Scher HI, Heller G, Molina A, et al.: Circulating tumor cell biomarker panel as an individual-level surrogate for survival in metastatic castration-resistant prostate cancer. J Clin Oncol 2015;33:1348-1355.
Bidard FC, Peeters DJ, Fehm T, et al.: Clinical validity of circulating tumour cells in patients with metastatic breast cancer: A pooled analysis of individual patient data. Lancet Oncol 2014;15:406-414.
Yu M, Bardia A, Wittner BS, et al.: Circulating breast tumor cells exhibit dynamic changes in epithelial and mesenchymal composition. Science 2013;339:580-584.
Cayrefourcq L, Mazard T, Joosse S, et al.: Establishment and characterization of a cell line from human circulating colon cancer cells. Cancer Res 2015;75:892-901.
Yu M, Bardia A, Aceto N, et al.: Cancer therapy. Ex vivo culture of circulating breast tumor cells for individualized testing of drug susceptibility. Science 2014;345:216-220.
Hodgkinson CL, Morrow CJ, Li Y, et al.: Tumorigenicity and genetic profiling of circulating tumor cells in small-cell lung cancer. Nat Med 2014;20:897-903.
Carter L, Rothwell DG, Mesquita B, et al.: Molecular analysis of circulating tumor cells identifies distinct copy-number profiles in patients with chemosensitive and chemorefractory small-cell lung cancer. Nat Med 2017;23:114-119.
Schwarzenbach H, Hoon DS, Pantel K: Cell-free nucleic acids as biomarkers in cancer patients. Nat Rev Cancer 2011;11:426-437.
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.
Bardelli A, Pantel K: Liquid biopsies, what we do not know (yet). Cancer Cell 2017;31:172-179.
Leung F, Kulasingam V, Diamandis EP, et al.: Circulating tumor DNA as a cancer biomarker: Fact or fiction? Clin Chem 2016;62:1054-1060.
Heitzer E, Ulz P, Geigl JB: Circulating tumor DNA as a liquid biopsy for cancer. Clin Chem 2015;61:112-123.
Murtaza M, Dawson SJ, Tsui DW, et al.: Non-invasive analysis of acquired resistance to cancer therapy by sequencing of plasma DNA. Nature 2013;497:108-112.
Douillard JY, Ostoros G, Cobo M, et al.: Gefitinib treatment in EGFR mutated caucasian NSCLC: Circulating-free tumor DNA as a surrogate for determination of EGFR status. J Thorac Oncol 2014;9:1345-1353.
Webb S: The cancer bloodhounds. Nat Biotechnol 2016;34:1090-1094.
Qin J, Williams TL, Fernando MR: A novel blood collection device stabilizes cell-free RNA in blood during sample shipping and storage. BMC Res Notes 2013;6:380.
Pucciarelli S, Rampazzo E, Briarava M, et al.: Telomere-specific reverse transcriptase (hTERT) and cell-free RNA in plasma as predictors of pathologic tumor response in rectal cancer patients receiving neoadjuvant chemoradiotherapy. Ann Surg Oncol 2012;19:3089-3096.
Olmos D, Brewer D, Clark J, et al.: Prognostic value of blood mRNA expression signatures in castration-resistant prostate cancer: A prospective, two-stage study. Lancet Oncol 2012;13:1114-1124.
Croce CM: Causes and consequences of microRNA dysregulation in cancer. Nat Rev Genet 2009;10:704-714.
Schwarzenbach H, Nishida N, Calin GA, Pantel K: Clinical relevance of circulating cell-free microRNAs in cancer. Nat Rev Clin Oncol 2014;11:145-156.
Mitchell PS, Parkin RK, Kroh EM, et al.: Circulating micrornas as stable blood-based markers for cancer detection. Proc Natl Acad Sci USA 2008;105:10513-10518.
Kalluri R: The biology and function of exosomes in cancer. J Clin Invest 2016;126:1208-1215.
Greening DW, Xu R, Ji H, et al.: A protocol for exosome isolation and characterization: Evaluation of ultracentrifugation, density-gradient separation, and immunoaffinity capture methods. Methods Mol Biol 2015;1295:179-209.
Hoshino A, Costa-Silva B, Shen TL, et al.: Tumour exosome integrins determine organotropic metastasis. Nature 2015;527:329-335.
Peinado H, Aleckovic M, Lavotshkin S, et al.: Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through met. Nat Med 2012;18:883-891.
Joosse SA, Pantel K: Tumor-educated platelets as liquid biopsy in cancer patients. Cancer Cell 2015;28:552-554.
Nilsson RJ, Balaj L, Hulleman E, et al.: Blood platelets contain tumor-derived RNA biomarkers. Blood 2011;118:3680-3683.
Best MG, Sol N, Kooi I, et al.: RNA-Seq of tumor-educated platelets enables blood-based pan-cancer, multiclass, and molecular pathway cancer diagnostics. Cancer Cell 2015;28:666-676.
Newman AM, Bratman SV, To J, et al.: An ultrasensitive method for quantitating circulating tumor DNA with broad patient coverage. Nat Med 2014;20:548-554.
Newman AM, Lovejoy AF, Klass DM, et al.: Integrated digital error suppression for improved detection of circulating tumor DNA. Nat Biotechnol 2016;34:547-555.
Alix-Panabieres C, Pantel K: Clinical applications of circulating tumor cells and circulating tumor DNA as liquid biopsy. Cancer Discov 2016;6:479-491.
Tug S, Helmig S, Deichmann ER, et al.: Exercise-induced increases in cell free DNA in human plasma originate predominantly from cells of the haematopoietic lineage. Exerc Immunol Rev 2015;21:164-173.
Heidary M, Auer M, Ulz P, et al.: The dynamic range of circulating tumor DNA in metastatic breast cancer. Breast Cancer Res 2014;16:421.
Alix-Panabieres C, Pantel K: Clinical prospects of liquid biopsies. Nat Biomed Eng 2017[Epub ahead of print].
Alix-Panabieres C, Pantel K: Challenges in circulating tumour cell research. Nat Rev Cancer 2014;14:623-631.
Wan JC, Massie C, Garcia-Corbacho J, et al.: Liquid biopsies come of age: Towards implementation of circulating tumour DNA. Nat Rev Cancer 2017;17:223-238.
Wan L, Pantel K, Kang Y: Tumor metastasis: Moving new biological insights into the clinic. Nat Med 2013;19:1450-1464.
Pantel K, Alix-Panabieres C: Tumour microenvironment: Informing on minimal residual disease in solid tumours. Nat Rev Clin Oncol 2017;14:325-326.
You do not currently have access to this content.