FEATURE


The concept of the use of CTCs to guide changes in therapeutic management is an interesting one. The ease with which CTCs can be measured, the fact that it can be measured at various time points during treatment and at the time of progression of


CTC measurements at various time points functions as a sort of a real time ‘liquid biopsy’ that allows for rapid assessment at multiple time points.


disease and the fact that one could test several targets on the CTC itself make it a unique test that is easier to use than having to attain several tissue biopsies and as such several studies have attempted to study its predictive power. Smerage and colleagues [16] recently reported on the final results of the SWOG S0500 study the aim of which was to look at whether changes in chemotherapeutic regimens among women with metastatic breast cancer based on changes in the levels of CTCs measured 21 days after commencing first-line therapy could improve prognostic outcome in this cohort. Unfortunately the authors observed early changing of therapy did not impact either progression-free or overall survival in this cohort. Whether an early change in chemotherapy regimen based on CTC levels in the third line or later setting would impact prognostic outcome is currently being investigated in the CirCe01 trial. Technology is rapidly evolving and indeed technologies with CTC analytic capabilities have progressed beyond the currently available CellSearch technology [17,18]. 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. Key CTC markers that are likely to impact therapeutic decisions include expression of estrogen receptor, mutations in the estrogen receptor gene ESR1, changes in expression of or gene copy number of HER2 and mutations in the PIK3CA gene. Furthermore, one could envision that molecular characterization of CTC would also allow for identification of actionable mutations as well as enabling serial tumor monitoring for detection of acquisition of mutations that would render tumors resistant to certain therapeutic agents [19]. Taking this concept one step further Paoletti and colleagues [20] using an assay based both on CTC enumeration (using CellSearch) and measuring of protein expression developed the Circulating Tumor Cell-Endocrine Therapy Index (CTC-ETI) to help identify patients with endocrine resistant tumors earlier. CTCs were assessed for four endocrine therapy specific markers including estrogen receptor, Bcl-2, HER2 and Ki67 with low expression of these markers hypothesized to be associated with endocrine therapy resistance. The CTC-ETI was categorized into three groups based on a derived score (low was 0.3, intermediate was 4–6 and high


was -14) with a high score indicating resistance to endocrine therapy. The investigators established the analytic validity of this test on a small cohort of 50 patients with metastatic breast cancer. Interestingly they identified that 39% of the population studied had a high CTC-ETI score suggesting that a significant subset of patients


had endocrine therapy resistant tumors. Such information, if formally validated, would allow oncologists to effectively individualize therapeutic strategies among patients with hormone receptor positive metastatic breast cancer at various time points during the natural course of the disease. Clinical validation of the CTC-ETI test is currently being conducted through two randomized clinical trials (COMETI P2 and SWOG S1222). So where do we go from here? As we formally enter an era


where the majority of the treatment for patients with breast cancer will be based on specific targets real time identification of these targets would certainly be facilitated by genotyping of CTCs allowing for a personalized approach to management. Trials such as the SAFIR-01 and the I-SPY studies have used technologies that require tissue biopsies to identify evolving targets and personalizing treatment based on these targets among patients with metastatic breast cancer. Attaining such biopsies are cumbersome and may not always be feasible. CTC measurements at various time points functions as a sort of a real time ‘liquid biopsy’ that allows for rapid assessment at multiple time points. The information derived from these ‘liquid biopsies’ would not only service as a powerful prognostic marker that could help in risk stratification but would also play a major role in the application and monitoring of personalized therapeutic approaches to the management of patients with metastatic breast cancer. However, is it ready for prime time use? Can we effectively replace tissue biopsies with analysis of CTCs? As of now the simple answer would be no. We will need to wait for confirmatory studies to clearly elucidate its clinical utility and define the role of CTCs both as a predictive and prognostic tool.


Financial & competing interests disclosure M Cristofanilli is a Cynvenio scientific board member. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.


To see the full article, please go to: www.oncology-central.com/2016/04/25/ using-circulating-tumor-cells-to-guide-therapy-in-breast-cancer-could-this- replace-biopsies


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