FEATURE 10


by TR Ashworth about 150 years ago in a woman with metastatic breast cancer [4]. These detectable cancer cells are CTCs that represent a rare cell population in the circulation usually representing less than 10 cells/ml. These cells can originate from either the primary or metastatic tumor tissue and require special enrichment techniques for their detection [5]. These techniques are based either on the biological properties of the CTCs such as protein secretion or cell surface antigen expression or are based on the physical characteristics of these cells such as presence of electric charges, size of the cell, density or deformability. Currently the only FDA approved CTC enumeration technology is the CellSearch system that involves first immunomagnetic capturing of the CTCs using cell surface expression of EpCAM (epithelial cell adhesion molecule) followed by staining of the captured cells for epithelial keratins [6]. Over the last decade we have seen data reported from a number of important studies that looked at the prognostic and predictive role of CTCs in both early stage and metastatic breast cancer. The prognostic role of CTC in metastatic breast cancer was first defined in the pivotal trial by Cristofanilli and colleagues [6] in which women with metastatic breast cancer and an elevated CTC level (≥5 cells/7.5 ml of blood) were found to have a worse progression free and overall survival compared with women with CTC levels below this cut off threshold. The same group went on to show that baseline CTC levels prior to starting first-line therapy were highly predictive of prognostic outcome with elevated CTC levels at any time point during treatment being a good indicator of rapid disease progression [7,8]. Individual patient data pooled analysis of 1944 patients enrolled across 17 European centers has essentially confirmed the prognostic role of CTCs with the authors reporting that patients whose baseline CTC count was ≥5/7.5 ml of blood having a worse progression free (HR: 1.92, p < 0.0001) and overall survival (HR: 2.78, p < 0.0001) compared with those with a CTC count less than 5/7.5 ml [9]. The authors further reported that CTC levels at 3–5 and 6–8 weeks following start of treatment was also predictive of progression free and overall survival. The addition of CTC count to the clinicopathological models increased the predictive power of these models, however, interestingly the addition of tumor markers such CA 15–3 and CEA did not add significantly add to


the models. In the early stage setting CTC levels have also been shown to be associated with prognostic outcome [10,11]. Rack and colleagues [11] recently reported on a large prospective trial that enrolled over 2000 patients with early stage breast cancer. The authors observed that at baseline prior to starting adjuvant chemotherapy 21.5% of patients had CTCs detected with patients having at least 5 CTCs/30 ml of blood having worse prognostic outcome. The results of this study provided evidence for CTC levels being a prognostic marker in the early stage breast cancer setting. Having established the prognostic power of CTCs in both the metastatic and early stage setting the next question was to try and look at the clinical utility of CTC as a predictor of treatment efficacy thereby essentially guiding therapeutic management. In


The ideal technology would not only improve detection of CTCs over various time points during the course of treatment but would also allow for real time detection of changes in biological tumor characteristics thereby enabling dynamic genotype directed therapeutic approaches.


the metastatic setting changes in the levels of CTC counts have been shown in several studies to indicate treatment responses which could be as early as after the first cycle of treatment well before any change is detected on standard imaging modalities [12,13]. In the metastatic breast cancer setting several modalities have been investigated to try and individualize treatment management. Such modalities include molecular profiling that use next generation sequencing to identify targets associated with sensitivity to specific therapeutic agents [14]. Recently oncotype DX has also been investigated in the metastatic breast cancer setting to identify patients who would perhaps benefit from chemotherapy rather endocrine therapy [15]. The problem with


such techniques is that it involves using tissue biopsies taken at each time point of progression of disease as one would assume that targets within the tumor tissue do not remain static but are continuously evolving along the cancer progression continuum.


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