Sizing up circulating tumor cells for personalized therapy

Most deaths resulting from solid cancers are not caused by the primary tumor but by metastases to distant organs.1 Such metastases require that the cancer escapes the primary microenvironment and spreads via the bloodstream. The study of such blood-borne cancer cells (circulating tumor cells,CTCs) offers a unique window into the process of metastasis. Although CTCs have been postulated to exist since the 19th century, it was not until the past decade that several groups have combined to develop a wide array of technologies to capture, enumerate, and characterize these cells. Approaches that capitalize on epithelial antigens,2 electromagnetic properties of cells,3 and blood flow dynamics4 have all been explored as means to separate CTCs from whole blood. The greatest success has been achieved with antigen-based capture: based on a set of landmark studies,5,6 the US Food and Drug Administration (FDA) approved the clinical use of the Veridex CellSearch System (which enumerates CTCs separated from blood based on their epithelial properties) for use in patient prognosis. It is becoming abundantly clear that the biological and clinical value of CTCs exceeds their mere enumeration. For example, a recent study by Liu et al. demonstrated that HER2-positive breast cancer patients with HER2-positive CTCs have longer progression-free survival (PFS) after anti-HER2 therapies than HER2-positive patients with HER2-negative CTCs.7 Emerging evidence indicates that CTCs, much like the primary tumor, are heterogeneous in nature and may include subsets of cells that can successfully form metastases and/or cells that may be capable of re-seeding the primary tumor. Most existing technologies do not allow for capture of live/viable cells that would enable the functional determination of such metastatic potential, aggressiveness, and/or chemotherapeutic sensitivity. Technologies that are dependent on epithelial markers are likewise ineffective or will likely be minimally effective in capturing cells that are losing epithelial properties and gaining mesenchymal properties, cells that are not of epithelial origin such as melanomas (or other solid cancers of neural crest origin), or cells that have low expression of epithelial antigens such as triple-negative breast cancers. To overcome the limitations of other CTC enrichment methods, to capture the heterogeneity of CTCs, and to broaden the functional utility of these cells, Gallant et al. have utilized a unique approach to enrich for these rare cells based on size and deformability.8 Using a novel technology, the FMSA device, Gallant et al. show how CTCs can be isolated from blood, potentially cultured in vitro and in vivo and thereafter used to evaluate the sensitivity of a patient’s own CTCs to anticancer therapeutics. Notably, the FMSA device (along with cancer cells isolated from blood) was implanted into a mouse and tumors grew. There is potential for patient CTCs (after isolation via the FMSA or similar devices) to similarly be implanted. Such an approach has the potential to deliver in vivo chemosensitivity information and lead to the establishment of CTC-cell lines from freshly isolated tumor cells. By allowing for the capture and maintenance of viable patient-derived CTCs, Gallant et al.’s approach should allow for functional studies not possible with other technologies. Major hurdles remain, including the need for expansion, proliferation, and growth of live/viable patient CTCs. However, cell proliferation and growth is not a limitation for genomic and biological studies of these cells. Although studying the heterogeneity of CTCs adds another layer of complexity to our understanding of cancer, it opens up a new therapeutic possibility: personalized therapeutic targeting of blood-borne cancer cells before occult metastases.