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. 2022 Dec 9;23(2):95–111. doi: 10.1038/s41568-022-00536-4

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Fig. 3 — Available circulating tumour cell (CTC) detection technologies and examples of how CTCs can be included in clinical trial designs. a, CTC capture tools include antigen-dependent technologies (for example, immune capture via immobilized antibodies, antibody coated beads or coated intravascular guidewires) and antigen-independent technologies (for example, density gradient centrifugation, microfluidic systems based on deformability and size, size-based filtration systems, electrical charge-based technologies or cytapheresis). The latter do not require a priori knowledge of phenotypic profiles and are thought to capture more heterogeneous CTC populations compared with antigen-dependent methods. Downstream analysis of CTCs includes direct drug phenotyping, the creation of CTC-derived xenograft ‘avatar’ models and multi-omics interrogations at the single cell-level: epigenomic, proteomic, genomic and transcriptomic. b, Validation of the use of CTCs in the setting of innovative clinical trials includes randomizing and benchmarking CTCs against standard-of-care (SOC) diagnostic and therapeutic approaches or other liquid biopsy analytes (for example, circulating tumour DNA (ctDNA)) and testing of CTC-based treatment strategies. The figure shows various possibilities for CTC-based clinical trial design: randomization of CTC-based liquid biopsies versus tissue biopsies to guide the choice of therapy; randomization based on the presence of CTCs (positive versus negative) to guide the choice of therapy (that is, experimental or targeted versus SOC); randomization of patients who are positive for CTCs to treatment with different targeted or experimental drugs; randomization according to longitudinal or repeated CTC assessment to guide subsequent lines of therapy (for example, targeted or experimental treatment versus SOC); randomized trials which compare either use of CTCs alone with SOC diagnostic approaches (for example, medical imaging) or use of other liquid biopsy analytes (for example, ctDNA) or each individual modality with combined use of modalities.