High hopes abound for the anticipated clinical value of information garnered from circulating tumor cells (CTCs). However, despite plentiful encouraging early reports of ties between the presence of CTCs and clinicopathologic presentations in known cancer patients, more needs to be understood about the basic biology of CTCs and their presumed role in metastasis. Among the conceivable clinical applications of CTCs include their use as a noninvasive, real-time marker to predict disease progression; as a therapeutic management tool including as an evaluator of therapeutic effectiveness and drug resistance both in clinical practice and as a surrogate end point in clinical trials; as a component of tumor staging criteria; as a means to identify tissue of origin through expression profiling for detection of organ-specific metastatic signatures; and as a screening tool to identify early-stage cancer patients. “CTC genomics is still in its infancy, mainly due to a lack of technologies capable of isolating sufficient numbers of CTCs to analyze somatic mutations, and the lack of suitable material with which to compare results due to CTC heterogeneity,” writes  lead author Vicki Plaks, from the University of California, San Francisco, in a perspective piece published in the Sept. 13 issue of Science. “The next frontier in the CTC field is their characterization using the constantly improving single-cell “omics” techniques. This will ultimately determine the clinical value of CTCs as biomarkers and therapeutic targets.” Early studies, though, are emerging that demonstrate preliminary signs of the clinical value of. Among the studies linking the presence of CTC to disease progression and survival are the following that were presented at the European Cancer Congress 2013 (Amsterdam; Sept. 27-Oct. 1):

• François-Clément Bidard, M.D., Ph.D., from the Institute Curie in France, led an international effort to contact all European laboratories using CellSearch (Veridex) to gather individual data on metastatic breast cancer patients for pooled analysis. The researchers found that baseline CTC count was significantly associated with patient performance status, synchronous metastasis, tumor subtype, liver and bone metastases, and carcinoembryonic antigen (CEA) and cancer antigen 15.3 (CA 15–3) levels. Baseline CTC values of greater than 5 CTCs/7.5mL was a significant independent predictor of overall survival. The addition of CEA to the clinicopathological model plus baseline CTC score had a small added effect for overall survival. There was also a significantly added prognostic value of overall survival by incorporating early changes in CTC status at week three to five to the model of clinicopathological factors and baseline CTC scores. This research (which was sponsored by Veridex) the authors say attains a previously unreached statistical power and provides level 1 evidence of the independent prognostic value of CTCs before and during treatment for metastatic breast cancer.

• Researchers led by Sumanta Pal, M.D., from City of Hope in Duarte, Calif., prospectively followed 35 patients with high-risk, localized prostate cancer who had undergone prostatectomy. Based on four sequential 30mL blood draws (two weeks prior and immediately prior to surgery and at four weeks and 12 weeks following surgery), CTCs were detectable in 49 percent of patients prior to surgery (mean cell count, 2.5 cells) and their presence was correlated pathologically to seminal vesicle involvement.

Despite these promising indicators of CTCs pathological significance, challenges remain in understanding the extent to which CTCs are actually predictive of cancer’s course and the extent to which CTCs are applicable across a spectrum of cancer subtypes. For instance Plaks points out that variations likely exist in the spatial and temporal distributions of CTCs within the circulation, and that it is plausible that only extremely small and/or plastic CTCs can keep circulating as opposed to those that are possibly filtered by smaller capillaries. This, she argues, could translate into logistical considerations when sampling for CTCs, including the possible need for multiple sampling sites to overcome the filtration and the competing desire to create CTC detection devices that can still identify these very rare cells in small sample volumes to maintain the minimally invasive nature of sample collection. Further, the pathogenic significance of captured CTCs is complicated by the differential gene expression between primary tumors and CTCs, as well as heterogeneity within the CTC population. “That some CTCs are undetectable and not all detected CTCs have metastatic potential indicates that CTC enumeration is not a good marker for disease staging and prognosis,” Plaks writes. “Instead, it is instrumental to design biomarkers based on the gene sets and genomic profile of CTC subsets that predict homing and colonization to specific distant metastatic sites or even sites of primary tumor origin. Advanced CTC analysis is being made possible by constant technical improvements in CTC detection and isolation, although there are still unresolved issues, specifically the need to standardize detection assays.” Takeaway: In order to realize the promise of CTCs much more needs to be understood about their biology and pathogenic role in metastasis. Yet, researchers are encouraged by emerging studies linking the presence of CTCs to clinicopathological presentation in a variety of cancers.

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