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. 2019 Dec 19;12(1):17. doi: 10.3390/cancers12010017

Table 3.

Summary of the main highlights and challenges of the circulating markers.

Source Highlights Challenges
CTCs Peripheral blood CTC number correlates with PFS and OS;
Dynamic monitoring of molecular alterations during therapy;
Assessment of tumor markers (e.g., PD-L1) at baseline and during therapy;		 No FDA-approved technology for isolation;
Rare events;
Lack of reliable cut-off;
cfDNA ctDNA Plasma, Serum,
Cerebrospinal fluid,
Pleural effusion,
Ascites		 Flexibility in processing (stable for up to 2 days in blood sample);
No specific device required for isolation (benchtop centrifugation);
cfDNA level correlates with PFS and OS;
ctDNA reflects tumor heterogeneity;
Dynamic monitoring of molecular alterations during therapy;
Identification of novel targetable resistance mutations;		 Lack of reliable cut-off;
Contamination of germinal cfDNA;
cfDNA level reflects changes in ctDNA and patient characteristics as well as medical conditions;
Low portion of ctDNA in plasma;
Not all gene mutations are expressed in ctDNA;
Ci-miRNAs Plasma,
Serum		 More resistant to RNases than mRNA;
No specific device required for isolation (benchtop centrifugation);
Ci-miRNAs reflect the biology of the tumor;
Ci-miRNAs can discriminate healthy individual
from patients and early stage from advanced patients;
Ci-miRNA expression correlates with tumor development,
progression and metastases;		 Lack of standardization (e.g., RNA isolation, quantification);
High variability;
Lack of large prospective studies;
Exosomes Almost all body fluids Stable sources of tumor-derived genetic material
(e.g., DNA, RNA, miRNAs, and proteins);
Exosome number is higher in patients than in healthy controls;
Exosome size correlates with unfavorable outcome;
Exo-miRNAs can discriminate healthy individual from patients
and early stage from advanced patients;
Exo-RNA and Exo-DNA have a higher sensitivity in detection
of somatic mutations than plasma ctDNA;		 Unreliable isolation procedures;
Minimal overlap among exo-miRNA signatures;
Lack of large prospective studies;
TEP Peripheral blood No specific device required for isolation (benchtop centrifugation);
TEP-RNA reflects tumor transcriptome;
TEP-RNA can discriminate healthy individual from patients and early stage from advanced patients; 		Lack of large retrospective and prospective studies;

Abbreviations: CTC: circulating tumor cells; PFS: progression free survival; OS: overall survival; cfDNA: circulating cell-free DNA; ctDNA: circulating tumor DNA; ci-miRNA: circulating miRNA; Exo-DNA: Exosome DNA; Exo-RNA: Exosome RNA; TEP: tumor educated platelets.