The clinical utility of tissue biopsies in cancer management will continue to expand, especially with the evolving role of targeted therapies. “Liquid biopsy” refers to testing a patient's biofluid samples such as blood or urine to detect tumor-derived molecules and cells that can be used diagnostically and prognostically in the assessment of cancer. Many proof-of-concept and pilot studies have shown the clinical potential of liquid biopsies as diagnostic and prognostic markers which would provide a surrogate for the conventional “solid biopsy”. In this review, we focus on three methods of liquid biopsy—circulating tumor cells, extracellular vesicles, and circulating tumor DNA—to provide a landscape view of their clinical applicability in cancer management and research.
Get full access to this article
View all access options for this article.
References
1.
AbboshC, BirkbakNJ, WilsonGA, et al. (2017) Phylogenetic ctDNA analysis depicts early-stage lung cancer evolution. Nature, 545:446-451.
2.
AiB, LiuH, HuangY, et al. (2016) Circulating cell-free DNA as a prognostic and predictive biomarker in non-small cell lung cancer. Oncotarget, 7:44583-44595.
3.
Alix-PanabieresC (2012) EPISPOT assay: detection of viable DTCs/CTCs in solid tumor patients. Recent Results Cancer Res, 195:69-76.
Alix-PanabieresC, PantelK (2016) Clinical applications of circulating tumor cells and circulating tumor DNA as liquid biopsy. Cancer Discov, 6:479-491.
6.
Alunni-FabbroniM, SandriMT (2010) Circulating tumour cells in clinical practice: methods of detection and possible characterization. Methods, 50:289-297.
7.
AntfolkM, MagnussonC, AugustssonP, et al. (2015) Acoustofluidic, label-free separation and simultaneous concentration of rare tumor cells from white blood cells. Anal Chem, 87:9322-9328.
8.
AntonarakisES, LuC, WangH, et al. (2014) AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer. N Engl J Med, 371:1028-1038.
9.
ArbelaizA, AzkargortaM, KrawczykM, et al. (2017) Serum extracellular vesicles contain protein biomarkers for primary sclerosing cholangitis and cholangiocarcinoma. Hepatology, 66:1125-1143.
10.
AshworthT (1869) A case of cancer in which cells similar to those in the tumours were seen in the blood after death. Aust Med J, 14:146.
BatesSE, LongoDL (1985) Tumor markers: value and limitations in the management of cancer patients. Cancer Treat Rev, 12:163-207.
13.
Bayarri-LaraC, OrtegaFG, Cueto Ladrón de GuevaraA, et al. (2016) Circulating tumor cells identify early recurrence in patients with non-small cell lung cancer undergoing radical resection. PLoS One, 11:e0148659.
14.
BeckerA, ThakurBK, WeissJM, et al. (2016) Extracellular vesicles in cancer: cell-to-cell mediators of metastasis. Cancer Cell, 30:836-848.
15.
BettegowdaC, SausenM, LearyRJ, et al. (2014) Detection of circulating tumor DNA in early- and late-stage human malignancies. Sci Transl Med, 6:224ra24.
16.
BockhornM, RobergeS, SousaC, et al. (2004) Differential gene expression in metastasizing cells shed from kidney tumors. Cancer Res, 64:2469-2473.
17.
BorkU, RahbariNN, SchölchS, et al. (2015) Circulating tumour cells and outcome in non-metastatic colorectal cancer: a prospective study. Br J Cancer, 112:1306-1313.
18.
BrawerMK (1999) Prostate-specific antigen: current status. CA Cancer J Clin, 49:264-281.
19.
CatarinoR, FerreiraMM, RodriguesH, et al. (2008) Quantification of free circulating tumor DNA as a diagnostic marker for breast cancer. DNA Cell Biol, 27:415-421.
20.
ChafferCL, WeinbergRA (2011) A perspective on cancer cell metastasis. Science, 331:1559-1564.
21.
ChanKC, JiangP, ZhengYW, et al. (2013) Cancer genome scanning in plasma: detection of tumor-associated copy number aberrations, single-nucleotide variants, and tumoral heterogeneity by massively parallel sequencing. Clin Chem, 59:211-224.
22.
ChenK, ZhangJ, GuanT, et al. (2017) Comparison of plasma to tissue DNA mutations in surgical patients with non-small cell lung cancer. J Thorac Cardiovasc Surg, 154:1123-1131.
23.
ChoEH, WendelM, LuttgenM, et al. (2012) Characterization of circulating tumor cell aggregates identified in patients with epithelial tumors. Phys Biol, 9:016001.
24.
ChoiDS, KimDK, KimYK, et al. (2015) Proteomics of extracellular vesicles: exosomes and ectosomes. Mass Spectrom Rev, 34:474-490.
25.
ChoiJJ, Reich CFIII, PisetskyDS (2005) The role of macrophages in the in vitro generation of extracellular DNA from apoptotic and necrotic cells. Immunology, 115:55-62.
26.
CohenJD, LiL, WangY, et al. (2018) Detection and localization of surgically resectable cancers with a multi-analyte blood test. Science, 359:926-930.
27.
CohenSJ, PuntCJ, LannottiN, et al. (2008) Relationship of circulating tumor cells to tumor response, progression-free survival, and overall survival in patients with metastatic colorectal cancer. J Clin Oncol, 26:3213-3221.
28.
CrowleyE, Di NicolantonioF, LoupakisF, et al. (2013) Liquid biopsy: monitoring cancer-genetics in the blood. Nat Rev Clin Oncol, 10:472-484.
29.
DawsonSJ, RosenfeldN, CaldasC (2013a) Circulating tumor DNA to monitor metastatic breast cancer. N Engl J Med, 369:93-94.
30.
DawsonSJ, TsuiDW, MurtazaM, et al. (2013b) Analysis of circulating tumor DNA to monitor metastatic breast cancer. N Engl J Med, 368:1199-1209.
31.
De Mattos-ArrudaL, CaldasC (2016) Cell-free circulating tumour DNA as a liquid biopsy in breast cancer. Mol Oncol, 10:464-474.
32.
DenisJA, PatroniA, GuillermE, et al. (2016) Droplet digital PCR of circulating tumor cells from colorectal cancer patients can predict KRAS mutations before surgery. Mol Oncol, 10:1221-1231.
33.
DesitterI, GuerrouahenBS, Benali-FuretN, et al. (2011) A new device for rapid isolation by size and characterization of rare circulating tumor cells. Anticancer Res, 31:427-441.
34.
DiazLAJr., WilliamsRT, WuJ, et al. (2012) The molecular evolution of acquired resistance to targeted EGFR blockade in colorectal cancers. Nature, 486:537-540.
35.
DiehlF, LiM, DressmanD, et al. (2005) Detection and quantification of mutations in the plasma of patients with colorectal tumors. Proc Natl Acad Sci U S A, 102:16368-16373.
36.
DiehlF, SchmidtK, ChotiMA, et al. (2008) Circulating mutant DNA to assess tumor dynamics. Nat Med, 14:985-990.
37.
DouillardJY, OstorosG, CoboM, et al. (2014) Gefitinib treatment in EGFR mutated caucasian NSCLC: circulating-free tumor DNA as a surrogate for determination of EGFR status. J Thorac Oncol, 9:1345-1353.
38.
DraismaG, EtzioniR, TsodikovA, et al. (2009) Lead time and overdiagnosis in prostate-specific antigen screening: importance of methods and context. J Natl Cancer Inst, 101:374-383.
39.
FabbriF, CarloniS, ZoliW, et al. (2013) Detection and recovery of circulating colon cancer cells using a dielectrophoresis-based device: KRAS mutation status in pure CTCs. Cancer Lett, 335:225-231.
40.
FangS, TianH, LiX, et al. (2017) Clinical application of a microfluidic chip for immunocapture and quantification of circulating exosomes to assist breast cancer diagnosis and molecular classification. PLoS One, 12:e0175050.
41.
FiorelliA, AccardoM, CarelliE, et al. (2015) Circulating tumor cells in diagnosing lung cancer: clinical and morphologic analysis. Ann Thorac Surg, 99:1899-1905.
42.
FlaumenhaftR, DilksJR, RichardsonJ, et al. (2009) Megakaryocyte-derived microparticles: direct visualization and distinction from platelet-derived microparticles. Blood, 113:1112-1121.
43.
ForshewT, MurtazaM, ParkinsonC, et al. (2012) Noninvasive identification and monitoring of cancer mutations by targeted deep sequencing of plasma DNA. Sci Transl Med, 4:136ra68.
44.
FrattiniM, GallinoG, SignoroniS, et al. (2006) Quantitative analysis of plasma DNA in colorectal cancer patients: a novel prognostic tool. Ann N Y Acad Sci, 1075:185-190.
45.
FredebohmJ, MehnertDH, LöberAK, et al. (2016) Detection and quantification of KIT mutations in ctDNA by plasma safe-seqS. Adv Exp Med Biol, 924:187-189.
46.
FrenelJS, CarreiraS, GooddallJ, et al. (2015) Serial next-generation sequencing of circulating cell-free DNA evaluating tumor clone response to molecularly targeted drug administration. Clin Cancer Res, 21:4586-4596.
47.
GazzanigaP, GradiloneA, de BerardinisE, et al. (2012) Prognostic value of circulating tumor cells in nonmuscle invasive bladder cancer: a CellSearch analysis. Ann Oncol, 23:2352-2356.
48.
GerlingerM, RowanAJ, HorswellS, et al. (2012) Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med, 366:883-892.
49.
GholizadehS, Shehata DrazM, ZarghooniM, et al. (2017) Microfluidic approaches for isolation, detection, and characterization of extracellular vesicles: current status and future directions. Biosens Bioelectron, 91:588-605.
50.
GionM, MioneR, BarioliP, et al. (1996) Dynamic use of tumor markers, rationale-clinical applications and pitfalls. Anticancer Res, 16:2279-2284.
51.
GoldkornA, ElyB, QuinnDI, et al. (2014) Circulating tumor cell counts are prognostic of overall survival in SWOG S0421: a phase III trial of docetaxel with or without atrasentan for metastatic castration-resistant prostate cancer. J Clin Oncol, 32:1136-1142.
52.
GröbeA, BlessmannM, HankenH, et al. (2014) 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, 20:425-433.
53.
GuoW, YangXR, SunYF, et al. (2014) Clinical significance of EpCAM mRNA-positive circulating tumor cells in hepatocellular carcinoma by an optimized negative enrichment and qRT-PCR-based platform. Clin Cancer Res, 20:4794-4805.
54.
GyörgyB, PálócziK, KovácsA, et al. (2014) Improved circulating microparticle analysis in acid-citrate dextrose (ACD) anticoagulant tube. Thromb Res, 133:285-292.
55.
HashadD, SorourA, GhazalA, et al. (2012) Free circulating tumor DNA as a diagnostic marker for breast cancer. J Clin Lab Anal, 26:467-472.
56.
HigginsMJ, JelovacD, BarnathanE, et al. (2012) Detection of tumor PIK3CA status in metastatic breast cancer using peripheral blood. Clin Cancer Res, 18:3462-3469.
57.
HodgkinsonCL, MorrowCJ, LiY, et al. (2014) Tumorigenicity and genetic profiling of circulating tumor cells in small-cell lung cancer. Nat Med, 20:897-903.
58.
HoldhoffM, SchmidtK, DonehowerR, et al. (2009) Analysis of circulating tumor DNA to confirm somatic KRAS mutations. J Natl Cancer Inst, 101:1284-1285.
59.
HoshimotoS, FariesMB, MortonDL, et al. (2012) Assessment of prognostic circulating tumor cells in a phase III trial of adjuvant immunotherapy after complete resection of stage IV melanoma. Ann Surg, 255:357-362.
60.
HouHW, WarkianiMe, KhooBL, et al. (2013) Isolation and retrieval of circulating tumor cells using centrifugal forces. Sci Rep, 3:1259.
61.
HuangZH, HuY, HuaD, et al. (2011) Quantitative analysis of multiple methylated genes in plasma for the diagnosis and prognosis of hepatocellular carcinoma. Exp Mol Pathol, 91:702-707.
62.
HuangZH, LiLH, HuaD (2006) Quantitative analysis of plasma circulating DNA at diagnosis and during follow-up of breast cancer patients. Cancer Lett, 243:64-70.
63.
IlieM, HofmanV, Long-MiraE, et al. (2014) “Sentinel” circulating tumor cells allow early diagnosis of lung cancer in patients with chronic obstructive pulmonary disease. PLoS One, 9:e111597.
64.
InhesternJ, OertelK, StemmannV, et al. (2015) Prognostic role of circulating tumor cells during induction chemotherapy followed by curative surgery combined with postoperative radiotherapy in patients with locally advanced oral and oropharyngeal squamous cell cancer. PLoS One, 10:e0132901.
65.
JahrS, HentzeH, EnglischS, 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, 61:1659-1665.
66.
JakobsenKR, PaulsenBS, BaekR, et al. (2015) Exosomal proteins as potential diagnostic markers in advanced non-small cell lung carcinoma. J Extracell Vesicles, 4:26659.
67.
KarachaliouN, Mayo-de las CasasC, QueraltC, et al. (2015) Association of EGFR L858R mutation in circulating free DNA with survival in the EURTAC trial. JAMA Oncol, 1:149-157.
68.
KawakamiK, FujitaY, MatsudaY, et al. (2017) Gamma-glutamyltransferase activity in exosomes as a potential marker for prostate cancer. BMC, Cancer17:316.
69.
KhooBL, WarkianiME, TanDS, et al. (2014) Clinical validation of an ultra high-throughput spiral microfluidics for the detection and enrichment of viable circulating tumor cells. PLoS One, 9:e99409.
70.
KimTM, JungSH, AnCH, et al. (2015) Subclonal genomic architectures of primary and metastatic colorectal cancer based on intratumoral genetic heterogeneity. Clin Cancer Res, 21:4461-4472.
71.
KindeI, WuJ, PapadopoulosN, et al. (2011) Detection and quantification of rare mutations with massively parallel sequencing. Proc Natl Acad Sci U S A, 108:9530-9535.
72.
KleinCA, SeidlS, Petat-DutterK, et al. (2002) Combined transcriptome and genome analysis of single micrometastatic cells. Nat Biotechnol, 20:387-392.
73.
KohlerC, RadpourR, BarekatiZ, et al. (2009) Levels of plasma circulating cell free nuclear and mitochondrial DNA as potential biomarkers for breast tumors. Mol Cancer, 8:105.
74.
KrebsMG, SloaneR, PriestL, et al. (2011) Evaluation and prognostic significance of circulating tumor cells in patients with non-small-cell lung cancer. J Clin Oncol, 29:1556-1563.
75.
KulasingheA, TranTH, BlickT, et al. (2017) Enrichment of circulating head and neck tumour cells using spiral microfluidic technology. Sci Rep, 7:42517.
76.
LabiancaR, NordlingerB, BerettaGD, et al. (2013) Early colon cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 24 Suppl, 6:vi64-vi72.
77.
LaneRE, KorbieD, HillMM, et al. (2018) Extracellular vesicles as circulating cancer biomarkers: opportunities and challenges. Clin Transl Med, 7:14.
78.
LigthartST, CoumansFA, BidardFC, et al. (2013) Circulating tumor cells count and morphological features in breast, colorectal and prostate cancer. PLoS One, 8:e67148.
79.
LiljaH, UlmertD, VickersAJ (2008) Prostate-specific antigen and prostate cancer: prediction, detection and monitoring. Nat Rev Cancer, 8:268-278.
80.
LogozziM, AngeliniDF, IessiE, et al. (2017) Increased PSA expression on prostate cancer exosomes in in vitro condition and in cancer patients. Cancer Lett, 403:318-329.
81.
LymanGH, TeminS, EdgeSB, et al. (2014) Sentinel lymph node biopsy for patients with early-stage breast cancer: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol, 32:1365-1383.
MaddenLA, VinceRV, SandströmME, et al. (2008) Microparticle-associated vascular adhesion molecule-I and tissue factor follow a circadian rhythm in healthy human subjects. Thromb Haemost, 99:909-915.
84.
MadicJ, KiialainenA, BidardFC, et al. (2015) Circulating tumor DNA and circulating tumor cells in metastatic triple negative breast cancer patients. Int J Cancer, 136:2158-2165.
85.
MaheswaranS, SequistLV, NagrathS, et al. (2008) Detection of mutations in EGFR in circulating lung-cancer cells. N Engl J Med, 359:366-377.
86.
MaoC, YuanJQ, YangZY, et al. (2015) Blood as a substitute for tumor tissue in detecting EGFR mutations for guiding EGFR TKIs treatment of nonsmall cell lung cancer: a systematic review and meta-analysis. Medicine (Baltimore). 94:e775.
87.
MarchettiA, Del GrammastroM, FelicioniL, et al. (2014) Assessment of EGFR mutations in circulating tumor cell preparations from NSCLC patients by next generation sequencing: toward a real-time liquid biopsy for treatment. PLoS One, 9:e103883.
88.
MarrinucciD, BethelK, KolatkarA, et al. (2012) Fluid biopsy in patients with metastatic prostate, pancreatic and breast cancers. Phys Biol, 9:016003.
89.
McKiernanJ, DonovanMJ, O'NeillV, et al. (2016) A novel urine exosome gene expression assay to predict high-grade prostate cancer at initial biopsy. JAMA Oncol, 2:882-889.
90.
MeloSA, LueckeLB, KahlertC, et al. (2015) Glypican-1 identifies cancer exosomes and detects early pancreatic cancer. Nature, 523:177-182.
91.
MengS, TripathyD, FrenkelEP, et al.Circulating tumor cells in patients with breast cancer dormancy. Clin Cancer Res, 10:8152-8162.
92.
MillerMC, DoyleGV, TerstappenLW, Significance of circulating tumor cells detected by the cellsearch system in patients with metastatic breast colorectal and prostate cancer. J Oncol, 2010:617421.
93.
MinciacchiVR, FreemanMR, Di VizioD (2015) Extracellular vesicles in cancer: exosomes, microvesicles and the emerging role of large oncosomes. Semin Cell Dev Biol, 40:41-51.
94.
MisaleS, YaegerR, HoborS, et al. (2012) Emergence of KRAS mutations and acquired resistance to anti-EGFR therapy in colorectal cancer. Nature, 486:532-536.
95.
MitrugnoA, TormoenGW, KuhnP, et al. (2016) The prothrombotic activity of cancer cells in the circulation. Blood Rev, 30:11-19.
96.
MiyamotoDT, ZhengY, WittnerBS, et al. (2015) RNA-Seq of single prostate CTCs implicates noncanonical Wnt signaling in antiandrogen resistance. Science, 349:1351-1356.
97.
MoonPG, LeeJE, ChoYE, et al. (2016) Identification of developmental endothelial locus-1 on circulating extracellular vesicles as a novel biomarker for early breast cancer detection. Clin Cancer Res, 22:1757-1766.
98.
MurtazaM, DawsonSJ, TsuiDW, et al. (2013) Non-invasive analysis of acquired resistance to cancer therapy by sequencing of plasma DNA. Nature, 497:108-112.
99.
NaitoY, YoshiokaY, YamamotoY, et al. (2017) How cancer cells dictate their microenvironment: present roles of extracellular vesicles. Cell Mol Life Sci, 74:697-713.
100.
Nana-SinkamSP, PowellCA (2013) Molecular biology of lung cancer: diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 143 Suppl, 5:e30S-e39S.
101.
NastalyP, RufC, BeckerP, et al. (2014) Circulating tumor cells in patients with testicular germ cell tumors. Clin Cancer Res, 20:3830-3841.
102.
NewmanAM, BratmanSV, ToJ, et al. (2014) An ultrasensitive method for quantitating circulating tumor DNA with broad patient coverage. Nat Med, 20:548-554.
103.
NewmanAM, LovejoyAF, KlassDM, et al. (2016) Integrated digital error suppression for improved detection of circulating tumor DNA. Nat Biotechnol, 34:547-555.
104.
OshiroC, KagaraN, NaoiY, et al. (2015) PIK3CA mutations in serum DNA are predictive of recurrence in primary breast cancer patients. Breast Cancer Res Treat, 150:299-307.
105.
OxnardGR, PaweletzCP, KuangY, et al. (2014) Noninvasive detection of response and resistance in EGFR-mutant lung cancer using quantitative next-generation genotyping of cell-free plasma DNA. Clin Cancer Res, 20:1698-1705.
106.
PaillerE, AdamJ, BarthélémyA, et al. (2013) Detection of circulating tumor cells harboring a unique ALK rearrangement in ALK-positive non-small-cell lung cancer. J Clin Oncol, 31:2273-2281.
107.
PatelGK, KhanMA, BhardwajA, et al. (2017) Exosomes confer chemoresistance to pancreatic cancer cells by promoting ROS detoxification and miR-155-mediated suppression of key gemcitabine-metabolising enzyme, DCK. Br J Cancer, 116:609-619.
108.
PearlML, DongH, TulleyS, et al. (2015) Treatment monitoring of patients with epithelial ovarian cancer using invasive circulating tumor cells (iCTCs). Gynecol Oncol, 137:229-238.
109.
PenfornisP, VallabhaneniKC, WhittJ, et al. (2016) Extracellular vesicles as carriers of microRNA, proteins and lipids in tumor microenvironment. Int J Cancer, 138:14-21.
110.
PhallenJ, SausenM, AdleffV, et al. (2017) Direct detection of early-stage cancers using circulating tumor DNA. Sci Transl Med, 9:pii:eaan2415.
111.
PolyakK, WeinbergRA (2009) Transitions between epithelial and mesenchymal states: acquisition of malignant and stem cell traits. Nat Rev Cancer, 9:265-273.
112.
PovedaA, KayeSB, McCormackR, et al. (2011) Circulating tumor cells predict progression free survival and overall survival in patients with relapsed/recurrent advanced ovarian cancer. Gynecol Oncol, 122:567-572.
113.
PunnooseEA, AtwalS, LiuW, et al. (2012) Evaluation of circulating tumor cells and circulating tumor DNA in non-small cell lung cancer: association with clinical endpoints in a phase II clinical trial of pertuzumab and erlotinib. Clin Cancer Res, 18:2391-2401.
114.
QiaoY, LiJ, ShiC, et al. (2017) Prognostic value of circulating tumor cells in the peripheral blood of patients with esophageal squamous cell carcinoma. Onco Targets Ther, 10:1363-1373.
115.
QinL, ZhongW, ZhangL, et al. (2011) Comparison of three methods for detecting epidermal growth factor receptor mutations in plasma DNA samples of Chinese patients with advanced non-small cell lung cancer. Chin Med J (Engl), 124:887-891.
116.
QuailMA, KozarewaI, SmithF, et al. (2008) A large genome center's improvements to the Illumina sequencing system. Nat Methods, 5:1005-1010.
117.
RackB, SchindlbeckC, JückstockJ, et al. (2014) Circulating tumor cells predict survival in early average-to-high risk breast cancer patients. J Natl Cancer Inst. 106.
118.
ReinertT, SchølerLV, ThomsenR, et al. (2016) Analysis of circulating tumour DNA to monitor disease burden following colorectal cancer surgery. Gut, 65:625-634.
119.
RemonJ, CaramellaC, JoveletC, et al. (2017) Osimertinib benefit in EGFR-mutant NSCLC patients with T790M-mutation detected by circulating tumour DNA. Ann Oncol, 28:784-790.
120.
RiethdorfS, FritscheH, MüllerV, et al. (2007) Detection of circulating tumor cells in peripheral blood of patients with metastatic breast cancer: a validation study of the CellSearch system. Clin Cancer Res, 13:920-928.
121.
RinkM, ChunFK, DahlemR, et al. (2012) Prognostic role and HER2 expression of circulating tumor cells in peripheral blood of patients prior to radical cystectomy: a prospective study. Eur Urol, 61:810-817.
122.
RobbinsPD, MorelliAE (2014) Regulation of immune responses by extracellular vesicles. Nat Rev Immunol, 14:195-208.
123.
SariogluAF, AcetoN, KojicN, et al. (2015) A microfluidic device for label-free, physical capture of circulating tumor cell clusters. Nat Methods, 12:685-691.
124.
SatoS, WeaverAM (2018) Extracellular vesicles: important collaborators in cancer progression. Essays Biochem, 62:149-163.
125.
Saucedo-ZeniN, MewesS, NiestrojR, et al. (2012) A novel method for the in vivo isolation of circulating tumor cells from peripheral blood of cancer patients using a functionalized and structured medical wire. Int J Oncol, 41:1241-1250.
126.
SchiavonG, HrebienS, Garcia-MurillasI, et al. (2015) Analysis of ESR1 mutation in circulating tumor DNA demonstrates evolution during therapy for metastatic breast cancer. Sci Transl Med, 7:313ra182.
127.
SeverinoV, DumonceauJM, DelhayeM, et al. (2017) Extracellular vesicles in bile as markers of malignant biliary stenoses. Gastroenterology, 153:495-504.e8.
128.
ShahR, PatelT, FreedmanJE (2018) Circulating extracellular vesicles in human disease. N Engl J Med, 379:958-966.
129.
ShapiroHM, SchildkrautER, CurbeloR, et al. (1976) Combined blood-cell counting and classification with fluorochrome stains and flow instrumentation. J Histochem Cytochem, 24:396-411.
130.
Shaw BagnallJ, ByunS, BegumS, et al. (2015) Deformability of tumor cells versus blood cells. Sci Rep, 5:18542.
131.
ShinozakiM, O'DaySJ, KitagoM, et al. (2007) Utility of circulating B-RAF DNA mutation in serum for monitoring melanoma patients receiving biochemotherapy. Clin Cancer Res, 13:2068-2074.
132.
SiegelRL, MillerKD, JemalA (2016) Cancer statistics, 2016. CA Cancer J Clin, 66:7-30.
133.
SmerageJB, BarlowWE, HortobagyiGN, et al. (2014) Circulating tumor cells and response to chemotherapy in metastatic breast cancer: SWOG S0500. J Clin Oncol, 32:3483-3489.
134.
SoresiM, MagliarisiC, CampagnaP, et al. (2003) Usefulness of alpha-fetoprotein in the diagnosis of hepatocellular carcinoma. Anticancer Res, 23:1747-1753.
135.
SpindlerKL, PallisgaardN, VogeliusI, et al. (2012) Quantitative cell-free DNA, KRAS, and BRAF mutations in plasma from patients with metastatic colorectal cancer during treatment with cetuximab and irinotecan. Clin Cancer Res, 18:1177-1185.
136.
SteinbichlerTB, DudásJ, RiechelmannH, et al. (2017) The role of exosomes in cancer metastasis. Semin Cancer Biol, 44:170-181.
137.
StolierA, SkinnerJ, LevineEA (2000) A prospective study of seeding of the skin after core biopsy of the breast. Am J Surg, 180:104-107.
138.
SunW, HuangT, LiG, et al. (2013) The advantage of circulating tumor cells over serum carcinoembryonic antigen for predicting treatment responses in rectal cancer. Future Oncol, 9:1489-1500.
139.
TaberneroJ, LenzHJ, SienaS, 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, 16:937-948.
140.
ThelwellN, MillingtonS, SolinasA, et al. (2000) Mode of action and application of Scorpion primers to mutation detection. Nucleic Acids Res, 28:3752-3761.
141.
TherkildsenC, BergmannTK, Henrichsen-SchnackT, et al. (2014) The predictive value of KRAS, NRAS, BRAF, PIK3CA and PTEN for anti-EGFR treatment in metastatic colorectal cancer: a systematic review and meta-analysis. Acta Oncol, 53:852-864.
142.
ThieleJA, BethelK, KrálíčkováM, et al. (2017) Circulating tumor cells: fluid surrogates of solid tumors. Annu Rev Pathol, 12:419-447.
143.
ThressKS, BrantR, CarrTH, et al. (2015) EGFR mutation detection in ctDNA from NSCLC patient plasma: a cross-platform comparison of leading technologies to support the clinical development of AZD9291. Lung Cancer, 90:509-515.
144.
TieJ, KindeI, WangY, et al. (2015) Circulating tumor DNA as an early marker of therapeutic response in patients with metastatic colorectal cancer. Ann Oncol, 26:1715-1722.
145.
TrevisaniF, D'IntinoPE, Morselli-LabateAM, et al. (2001) Serum alpha-fetoprotein for diagnosis of hepatocellular carcinoma in patients with chronic liver disease: influence of HBsAg and anti-HCV status. J Hepatol, 34:570-575.
146.
UmerM, VaidyanathanR, NguyenNT, et al. (2018) Circulating tumor microemboli: progress in molecular understanding and enrichment technologies. Biotechnol Adv, 36:1367-1389.
147.
UnderhillHR, KitzmanJO, HellwigS, et al. (2016) Fragment length of circulating tumor DNA. PLoS Genet, 12:e1006162.
148.
van der PolE, BöingAN, GoolEL, et al. (2016) Recent developments in the nomenclature, presence, isolation, detection and clinical impact of extracellular vesicles (vol 14, pg 48, 2016). J Thromb Haemost, 14:2087.
149.
van NielG, D'AngeloG, RaposoG (2018) Shedding light on the cell biology of extracellular vesicles. Nat Rev Mol Cell Biol, 19:213-228.
150.
VogelzangNJ, FizaziK, BurkeJM, et al. (2017) Circulating tumor cells in a phase 3 study of docetaxel and prednisone with or without lenalidomide in metastatic castration-resistant prostate cancer. Eur Urol, 71:168-171.
151.
VonaG, EstepaL, BéroudC, et al. (2004) Impact of cytomorphological detection of circulating tumor cells in patients with liver cancer. Hepatology, 39:792-797.
152.
WangS, ThomasA, LeeE, et al. (2016) Highly efficient and selective isolation of rare tumor cells using a microfluidic chip with wavy-herringbone micro-patterned surfaces. Analyst, 141:2228-2237.
153.
WangZ, ChenR, WangS, et al. (2014) Quantification and dynamic monitoring of EGFR T790M in plasma cell-free DNA by digital PCR for prognosis of EGFR-TKI treatment in advanced NSCLC. PLoS One, 9:e110780.
154.
WarkianiME, KhooBL, WuL, et al. (2016) Ultra-fast, label-free isolation of circulating tumor cells from blood using spiral microfluidics. Nat Protoc, 11:134-148.
155.
WebberJ, YeungV, ClaytonA (2015) Extracellular vesicles as modulators of the cancer microenvironment. Semin Cell Dev Biol, 40:27-34.
156.
WentPT, LugliA, MeierS, et al. (2004) Frequent EpCam protein expression in human carcinomas. Hum Pathol, 35:122-128.
157.
WuKR, XingF, WuSY, et al. (2017) Extracellular vesicles as emerging targets in cancer: recent development from bench to bedside. Biochim Biophys Acta Rev Cancer, 1868:538-563.
158.
XuR, RaiA, ChenM, et al. (2018) Extracellular vesicles in cancer - implications for future improvements in cancer care. Nat Rev Clin Oncol, 15:617-638.
159.
XuRH, WeiW, KrawczykM, et al. (2017a) Circulating tumour DNA methylation markers for diagnosis and prognosis of hepatocellular carcinoma. Nat Mater, 16:1155-1161.
160.
XuT, KangX, YouX, et al. (2017b) Cross-platform comparison of four leading technologies for detecting EGFR mutations in circulating tumor DNA from non-small cell lung carcinoma patient plasma. Theranostics, 7:1437-1446.
161.
YangSJ, WangDD, LiJ, et al. (2017) Predictive role of GSTP1-containing exosomes in chemotherapy-resistant breast cancer. Gene, 623:5-14.
162.
YokoyamaS, TakeuchiA, YamaguchiS, et al. (2017) Clinical implications of carcinoembryonic antigen distribution in serum exosomal fraction-Measurement by ELISA. PLoS One, 12:e0183337.
163.
YuM, StottS, TonerM, et al. (2011) Circulating tumor cells: approaches to isolation and characterization. J Cell Biol, 192:373-382.
164.
YuanaY, SturkA, NieuwlandR (2013) Extracellular vesicles in physiological and pathological conditions. Blood Rev, 27:31-39.
165.
Zanetti-DällenbachR, WightE, FanAX, et al. (2008) Positive correlation of cell-free DNA in plasma/serum in patients with malignant and benign breast disease. Anticancer Res, 28:921-925.
166.
ZhangCF, GuanY, SunY, et al. (2016) Tumor heterogeneity and circulating tumor cells. Cancer Lett, 374:216-223.
167.
ZhangW, CaiX, YuJ, et al. (2018) Exosome-mediated transfer of lncRNA RP11838N2.4 promotes erlotinib resistance in non-small cell lung cancer. Int J Oncol, 53:527-538.
168.
ZhangW, XiaW, LvZ, et al. (2017) Liquid biopsy for cancer: circulating tumor cells, circulating free DNA or exosomes?. Cell Physiol Biochem, 41:755-768.
169.
ZhangX, YuanX, ShiH, et al. (2015) Exosomes in cancer: small particle, big player. J Hematol Oncol, 8:83.
170.
ZhaoR, CaiZ, LiS, et al. (2017) Expression and clinical relevance of epithelial and mesenchymal markers in circulating tumor cells from colorectal cancer. Oncotarget, 8:9293-9302.
171.
ZhouY, BianB, YuanX, et al. (2015) Prognostic value of circulating tumor cells in ovarian cancer: a meta-analysis. PLoS One, 10:e0130873.
