Combinatorial Power of cfDNA, CTCs and EVs in Oncology

Abstract

Liquid biopsy is a promising technique for clinical management of oncological patients. The diversity of analytes circulating in the blood useable for liquid biopsy testing is enormous. Circulating tumor cells (CTCs), cell-free DNA (cfDNA) and extracellular vesicles (EVs), as well as blood cells and other soluble components in the plasma, were shown as liquid biopsy analytes. A few studies directly comparing two liquid biopsy analytes showed a benefit of one analyte over the other, while most authors concluded the benefit of the additional analyte. Only three years ago, the first studies to examine the value of a characterization of more than two liquid biopsy analytes from the same sample were conducted. We attempt to reflect on the recent development of multimodal liquid biopsy testing in this review. Although the analytes and clinical purposes of the published multimodal studies differed significantly, the additive value of the analytes was concluded in almost all projects. Thus, the blood components, as liquid biopsy reservoirs, are complementary rather than competitive, and orthogonal data sets were even shown to harbor synergistic effects. The unmistakable potential of multimodal liquid biopsy testing, however, is dampened by its clinical utility, which is yet to be proven, the lack of methodical standardization and insufficiently mature reimbursement, logistics and data handling.

Beyond blood: Advancing the frontiers of liquid biopsy in oncology and personalized medicine

“…56 Their role in liquid biopsy complements ctDNA and CTC analysis, enhancing the diagnostic spectrum and offering a noninvasive avenue for comprehensive tumor evaluation. 29,57 While the value of traditional biopsies is unequivocal, the noninvasive nature of liquid biopsies allows for a complementary approach. They facilitate ongoing monitoring of genetic changes, enabling clinicians to adapt treatment strategies in real time.…”

Circulating Tumor Cells in Cancer Diagnostics and Prognostics by Single-Molecule and Single-Cell Characterization

“…To overcome these limitations for early cancer detection, a combination of other circulating biomarkers (e.g., ctDNA, extracellular vesicles-EVs, miRNAs, proteins, etc.) should be considered …”

“…should be considered. 182 Medical diagnosis based on CTC enumeration and characterization could also benefit from answering fundamental questions regarding biological features of CTCs throughout the metastatic cascade; for example, limited information is known regarding CTC life cycle or their dissemination rhythm in the bloodstream. A recent study observed accelerated CTC dissemination during sleep in mBRCA patients and that these rest-phase CTCs presented a higher metastatic potential compared to active-phase CTCs.…”

New Perspectives on the Importance of Cell-Free DNA Biology

“…Evidence suggests that the sensitivity and specificity of cfDNA assays may not only be augmented by the simultaneous interrogation of multiple cfDNA features, but also by the parallel characterization of cfDNA and other biomarkers, such as proteins [ 331 , 332 ], genomic DNA and RNA from circulating tumor cells (CTCs) [ 333 , 334 , 335 , 336 , 337 , 338 , 339 , 340 ], EVs [ 338 , 341 ], miRNAs [ 342 , 343 ], metabolites [ 344 ], or mRNA transcripts [ 345 ].…”