Predictive Role Of Circulating Tumor Cells Research Articles

Prognostic and predictive role of CTCs and AR-V7+ CTCs expression in metastatic catrate resistant prostate cancer (mCRPC): A feasibility study.

367 Background: Circulating tumor cells (CTC) counts ≥ 5/7.5 mL predict shorter survival in patients (pts) with mCRPC. Moreover, the presence of androgen receptor splice variant-7 mRNA (AR-V7) in CTCs is thought to play a relevant role in the development of primary or acquired resistance to enzalutamide (E) or abiraterone (A). We developed a new immunofluorescence-based assay for AR-V7+ CTCs and tested its association with PFS and OS. Methods: We performed a single-centre observational prospective trial enrolling pts with mCRPC candidate to receive E or A. CTC samples have been collected at baseline, after 1 month (mo) and every 3 mos thereafter until progression or at 12 mos without progression. CTCs have been enumerated with CellSearch System. We integrated the standard assay with a mAb able to recognize the AR-V7 protein. Slides from samples underwent automated immunofluorescent staining and AR-V7+ CTCs were enumerated. Results: Since Sep 2016, 31 pts have been enrolled (Table). We compared CTC counts between standard and the integrated assay and found no differences in the mean total CTC number ± (Wilcoxon Signed Rank test, p= 0.31). 16 out of 28 evaluable pts (57%) had ≥ 1 CTCs at baseline, 9 pts (32%) had ≥ 5 CTCs/7.5 ml, 4 pts (14.3%) were AR-V7+ before any exposure to A or E. After a median follow-up time of 8.1 mos, 6 pts have progressed and 4 died. No association has been found between CTCs ≥ 5/7.5 mL and survival. The presence of at least 1 AR-V7+ CTC at baseline did not correlate with PSA response, but had a weak association with shorter PFS (log-rank test, p = 0.055) and a significant impact (p = 0.02) on OS. Conclusions: We developed a new integrated assay for AR-V7+ CTCs, based on an automated platform that permits serial sampling with low inter- / intra-test variability. The clinical utility in anticipating the resistance to E or A is under study. [Table: see text]

Abstract OT3-04-02: DETECT III and IV – Individualized CTC-based therapy of metastatic breast cancer

Abstract Background: Circulating tumor cells (CTCs) are found in patients with early and metastatic breast cancer (MBC), and both their prognostic and predictive value has been described already. There is growing evidence that CTC phenotype may differ from the primary tumor. However, CTC targeted therapy is not used in clinical routine, and treatment decisions often still are based on the primary tumor's phenotype without considering CTC-characteristics. The aim of the DETECT studies is to investigate and evaluate the role of presence and phenotype of CTC for guiding therapeutic decisions in women with HER2-negative MBC. Trial design and eligibility criteria: In a joint screening for DETECT III and IV, women with HER2-negative MBC are tested for CTCs and their HER2-phenotype. CTC detection is performed by the FDA-approved CellSearch System® (Janssen Diagnostics, Raritan, USA). Patients with HER2-positive CTCs are randomized in the multicenter Phase III study DETECT III to a physician's choice chemo- or endocrine therapy with or without additional HER2-targeted treatment with lapatinib. Women with only HER2-negative CTCs are recruited to the multicenter open-label phase II study DETECT IV. Postmenopausal women with hormone-receptor positive MBC are treated with everolimus and a physician's choice endocrine therapy in DETECT IVa. Patients with hormone-receptor positive MBC and an indication for chemotherapy and patients with triple-negative MBC receive mono-chemotherapy with eribulin in DETECT IVb. Treatment efficacy will be evaluated based on the early available CTC clearance rate (in DETECT III and DETECT IVa) and progression-free survival (in DETECT IVb) respectively, as the primary endpoint; secondary objectives will be to estimate disease control rate, progression-free (DETECT III and IVa) and overall survival, toxicity and tolerability of treatments with lapatinib, everolimus and eribulin, and quality of life. Specific aims: Changes in CTC-dynamics during therapy and their HER2-phenotype may influence following therapy decisions. The DETECT studies evaluate the prognostic and predictive role of CTCs as well as the efficacy of CTC based therapy to enable the establishment of a more personalized therapy for patients with MBC that might lead to prolonged progressive free survival and/or improved quality of life. The accompanying translational research programs investigate various markers for molecular characterization of CTCs and prediction of therapy response. Present accrual and target accrual: More than 1550 patients with HER2-negative MBC have already been screened within the DETECT study program. Thus, it is the worldwide largest study concept with therapy decisions resulting from CTC-testing and CTC-phenotypization. Contact: For further information on the DETECT study program please contact www.detect-studien.de or studienzentrale.ufk@uniklinik-ulm.de. Citation Format: Polasik A, Schramm A, Friedl TWP, Rack B, Trapp E, Fasching PA, Taran F-A, Hartkopf A, Schneeweiss A, Müller V, Aktas B, Pantel K, Meier-Stiegen F, Wimberger P, Janni W, Fehm T. DETECT III and IV – Individualized CTC-based therapy of metastatic breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr OT3-04-02.

Circulating Tumor Cells: Back to the Future.

Circulating tumor cells (CTCs) are rare and heterogeneous cells found in the peripheral blood of cancer patients. They are supposed to be a central component of metastatic dissemination and have been correlated with prognosis, progression-free survival, and treatment efficacy in different solid tumors (1, 2). Despite CTC significance, studies conducted on them still present considerable issues. In particular, regarding to how CTCs should be investigated and to their actual metastatic competence and tumor heterogeneity reflecting dissimilar cancer cell subpopulations. Importantly, CTCs’ clinical utility has not been demonstrated and they cannot be utilized to guide therapeutic decisions. As reviewed by others (3), recent and currently ongoing clinical trials are trying to determine the predictive role of CTCs, but they are apparently failing to support definitive conclusions. Nevertheless, the results of these trials could shed a light on the real possibilities of CTCs. In our opinion, CTC troubleshootings will depend on what scientific community will explore about CTCs and the metastatic process. Only a deeper insight in base knowledge about CTCs and their role in tumor biology may help us in overcoming such hurdles.

Abstract 3969: CTCs and CTC clusters in breast cancer patient-derived xenograft models

Abstract Breast cancer (BC) patient-derived xenograft (PDX) models represent a continuous and reproducible source of circulating tumor cells (CTCs). Using various BC PDX models, we describe the utility of CTCs and CTC clusters in detecting tumor-specific mutations and our preliminary results in understanding their predictive value for treatment response and long-term outcomes. CTCs were detected in 300-450 μl of blood of PDX-bearing mice using the RareCyte technology adapted for small blood volume. CTCs were isolated without cell surface marker-based enrichment and identified them as DAPI+, human Cytokeratin (CK)+, and mouse CD45-. Collective expression of cell surface markers (EpCAM, EGFR, and HER2) was assessed using a cocktail of target-specific antibodies in CTCs and primary PDX tumors. Individual CTCs and tumor cells from primary and metastatic tumors were isolated using CytePicker® for single cell analysis of tumor-specific mutations. Single CTCs (1-41 per mouse) and CTC clusters (1-2 per mouse) were detected in the blood of one ER+/PR+/HER2- (BCM-4888) and two triple-negative BC (TNBC, BCM-4272 and BCM-3887) PDX models. The PIK3CA T1035A mutation found in primary tumors of BCM-4888 was also detected in isolated CTCs and PDX primary and metastatic tumor cells. As a proof-of-principle experiment, we have evaluated numbers of single CTCs and CTC clusters at baseline and after treatment with 4 weekly cycles of vehicle (N = 5-6) or chemotherapy regimens (N = 2-3) [docetaxel or carboplatin or their combination] in TNBC PDX models BCM-4272 and BCM-3887. Preliminary analysis from these studies suggests dynamic and differential effects of chemotherapy regimens on single CTCs and CTC clusters, potentially reflecting the genetic characteristics of tumors and their unique response to the selected chemotherapy agents. Ongoing experiments in additional mice and PDX models will determine the predictive role of CTCs and CTC clusters in treatment response and long-term outcomes such as recurrence-free survival. In conclusion, we have demonstrated that RareCyte technology detects CTCs from small volumes of blood without the use of cell surface marker-based enrichment method. Furthermore, CTCs and CTC clusters can be used to assess the presence of tumor-specific mutations. Ongoing studies will fully reveal the potential of CTCs and CTC clusters as surrogate markers of treatment response and outcomes within PDX models. Citation Format: Debashish Sahay, Arturo B. Ramirez, Raksha R. Bhat, Lacey E. Dobrolecki, Agostina Nardone, Michael T. Lewis, C. Kent Osborne, Mothaffar Rimawi, Jackie L. Stilwell, Eric P. Kaldjian, Rachel Schiff, Meghana V. Trivedi. CTCs and CTC clusters in breast cancer patient-derived xenograft models. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3969.