Prostate cancer is the most common malignancy and the second highest cause of cancer mortality in American men. New prognostic and predictive biomarkers are urgently needed to better inform our treatment decisions. Recent studies have demonstrated that quantification of peripheral blood circulating tumor cells (CTCs) predicts response to therapy and overall survival in advanced prostate cancer. However, present methods for CTC collection are limited by low yield, complex techniques, and expensive equipment, and they provide little phenotypic information about the CTCs themselves. To address these limitations, we have developed a new microfilter device that is fitted to an ordinary syringe and reliably traps and enriches the CTC population from peripheral blood, enabling enumeration and further study of these cells, such as characterization of therapeutic targets. It is our hypothesis that quantification and characterization of CTC can determine prognosis and predict response to therapy early in the course of the therapeutic regimen, and that the microfilter can serve as a simple yet reliable new platform for CTC collection, quantification, and phenotypic analysis in a large clinical trial setting. To test this hypothesis, we propose a correlative study that would "piggyback" onto S0421, an active SWOG cooperative group protocol studying atrasentan in combination with docetaxel in castration resistant prostate cancer. This proposal has been reviewed by SWOG and has received executive approval. At 3 time points pre-designated by S0421, pre-treatment (day 1) and during treatment (days 21 and 63, that is at the time of the second and fourth of 4 treatments), blood samples will be drawn and processed through the microfilter device, and the captured CTCs will be analyzed to address the following specific aims: 1. Do absolute CTC counts and post-treatment changes in CTC counts accurately predict clinical outcome and response to therapy? As further validation of microfilter CTC capture, parallel samples will be analyzed using the FDA approved Cell Search CTC collection platform;2. Does the expression of relevant biomarkers on microfilter-trapped CTCs predict clinical outcome and response to therapy? We will specifically assess endothelin receptor A for atrasentan response, type III 2-tubulin for docetaxel response, and CD44 for an aggressive progenitor/metastatic phenotype;and 3. Does the presence and level of telomerase activity (an established cancer marker) in microfilter-enriched cells correlate with the presence and number of captured CTCs, and can it be used to predict clinical outcome and response to therapy? In summary, our goal will be to determine if the quantity and characteristics of CTCs captured on our novel platform can predict clinical outcome and response to therapy in S0421. Ultimately, the results of this study will significantly inform our treatment decisions in prostate cancer and profoundly enhance our ability to assess therapeutic efficacy in real time, thus constituting a major stride towards optimized, evidence-based, individualized patient management.
We propose to quantify and characterize peripheral blood circulating tumor cells (CTCs) as a marker to predict therapeutic response and survival in advanced prostate cancer using a novel microfilter device that traps and enriches circulating CTCs in patients enrolled in the SWOG clinical trial, S0421. We will analyze if CTC counts, expression of relevant biomarkers, and telomerase activity (an established cancer marker) in microfilter- enriched CTCs can predict outcome and response to therapy. We expect this study to significantly help prostate cancer management and enhance real time assessment of therapeutic efficacy.
|Goldkorn, Amir; Ely, Benjamin; Quinn, David I et al. (2014) Circulating tumor cell counts are prognostic of overall survival in SWOG S0421: a phase III trial of docetaxel with or without atrasentan for metastatic castration-resistant prostate cancer. J Clin Oncol 32:1136-42|
|Balic, Marija; Williams, Anthony; Lin, Henry et al. (2013) Circulating tumor cells: from bench to bedside. Annu Rev Med 64:31-44|