Circulating tumor cells/dna/etc for Radiation Oncologists Andrew Z. Wang, M.D. Associate Professor Director of Clinical and Translational Research Department of Radiation Oncology Carolina Center for Cancer Nanotechnology Excellence Lineberger Comprehensive Cancer Center University of North Carolina Chapel Hill Disclosure Information I have the following financial relationships to disclose: Consultant for: Cerulean Pharma Speaker s Bureau for: N/A Grant/Research support from: Acuray and Cerulean Pharma Stockholder/Co-founder in: Capio BioSciences - and - I will not discuss off label use and/or investigational use in my presentation. 1
UNC-Duke-NC State-Wake Forest Spring 2017 Circulating stuff Tumors shed Circulating tumor cells Circulating DNA/other nucleic acids Applications Liquid biopsy Real-time biomarker Tumor Cell Release from Primary Tumor P. Carmeliet, R.K. Jain, Nature 2000, 407, 249-257. 2
1036 had T1N0 disease and received no chemo 25 of 229 patients with bone marrow micrometastasis (10.9 percent) and 46 of 807 without such micrometastasis (5.7 percent) developed metastatic disease CTC capture technologies Many platforms Most use microfluidics to capture EPIC: brute force relies on high res imaging to find 1 in 1 billion 3
CellSearch Only FDA approved device Prognostic biomarker for prostate, breast and colorectal cancers Relatively low sensitivity Limited use since it is not predicative nor does it affect treatment decisions 4
Major Challenges in CTC Detection Extreme rarity of CTCs in blood - As few as one out of a billion cells Heterogeneous phenotypes of CTCs - Epithelial-mesenchymal transition: epithelial cell-like to stem cell-like phenotypical transition A capture device with high sensitivity/selectivity, along with expandability to multiple cancer cell markers, may be ideal. 5
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Epic Biosciences 7
Only detected CTC in 17/27 patients From buffy coat 8
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Tracking viable circulating tumor cells (CTCs) in the peripheral blood of non small cell lung cancer (NSCLC) patients undergoing definitive radiation therapy: Pilot study results Cancer Volume 121, Issue 1, pages 139-149, 19 SEP 2014 DOI: 10.1002/cncr.28975 http://onlinelibrary.wiley.com/doi/10.1002/cncr.28975/full#cncr28975-fig-0001 Tracking viable circulating tumor cells (CTCs) in the peripheral blood of non small cell lung cancer (NSCLC) patients undergoing definitive radiation therapy: Pilot study results Cancer Volume 121, Issue 1, pages 139-149, 19 SEP 2014 DOI: 10.1002/cncr.28975 http://onlinelibrary.wiley.com/doi/10.1002/cncr.28975/full#cncr28975-fig-0002 10
OncoSense CTC a) b) c) d) e) Sensitive nanotechnology-based CTC detection system Utilizes multi-antibody dendrimers to capture f) tumor cells g) Flow direction Leukocytes E-selectin for cell rolling Antibodydendrimers for CTC capture G7 -(CH 2 CH 2 O) n - PEG CTCs Captured CTCs LCCC 1408-HNSCC Prospective evaluation in nonmetastatic H&N cancer patients CTCs detected in 100% of patients Mean 133 CTCs per ml CTCs decreased with treatment Post-treatment mean 27 CTCs per ml Changes in CTCs may correlate with clinical outcomes 11
CTC Blood Collection Time Points Peripheral blood collected during RT (n=41) Baseline Prior to RT During 1 st Week of RT Mid-Point of RT Final Week of RT Peripheral blood collected post-rt (n=25) 4 Weeks post-rt 3 Months post-rt 6 Months post-rt 12 Months post-rt 24 Months post-rt 48 Months post-rt Detection of Baseline CTCs (per ml) Before RT CTCs detected in all patients (100%) Average CTCs per ml (±SEM) = 131 ± 27 Median CTCs per ml = 67 Range CTCs per ml = 7 849 Interquartile Range (IQR) = 33 121 12
Can CTC Changes Be Useful for Disease Surveillance After Treatment? CTC declined to 3 per ml (18% of baseline, 31% of end-rt level) CTC increased to 29 per ml (145% of baseline, 176% of end-rt level) Pathologic Complete Response Pathologic Residual Disease Approach Exploratory, prospective pilot study Oligometastatic patients (19) 1-3 sites of disease Surgery or definitive dose RT to all evaluable sites Peripheral blood collected before, during, at end of treatment, q4-8 weeks thereafter Assess correlations between CTCs, patient/clinical characteristics, and clinical outcomes 13
Decreasing CTCs During RT C T C s p e r m L 1 5 0 1 0 0 5 0 CTC Count (per ml blood) Medi an Pre-RT 25 Rang e 3 124 End-RT 12 6 59 0 P r e - T r e a t m e n t P o s t - T r e a t m e n t P = 0.037 (Wilcoxon signed-rank test) Oligometastatic patients currently NED P e r ip h e r a l C T C s /m L 5 0 4 0 3 0 2 0 1 0 0 0 2 0 4 0 6 0 8 0 1 0 0 D a y s P o s t-t r e a tm e n t 14
CTCs increased with or before disease progression UNC 35- SCC OP lung met UNC 54 CRC lung me P e rip h e ra l C T C s /m L 1 0 0 5 0 P ro g re s s io n - s ta rt c h e m o 0 0 5 0 1 0 0 1 5 0 P e rip h e ra l C T C s /m L 1 0 0 R a d io g ra p h ic p ro g re s s io n 7 5 5 0 2 5 0 0 2 0 4 0 6 0 D a y s P o s t-t re a tm e n t D a y s P o s t-t re a tm e n t CTCs increased with or before disease progression 15
Circulating DNA/RNA etc Doesn t require new device development Can be amplified easily with existing technology Can provide rapid mutational analysis 16
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Many Technologies 18
RainDance/RainDrop 19
UNC-Duke-NC State-Wake Forest Spring 2017 20
Summary Circulating tumor cells and circulating DNA are both powerful biomarkers/tools They are likely complementary DNA is more sensitive but you need to know what to look for and more prone to error CTCs are less sensitive but more specific Full clinical impacts will be realized in the coming decade 21