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Prospective Characterization of Circulating Tumor Cell Kinetics in Patients with Oligometastatic Disease Receiving Definitive Intent Radiation Therapy

Shivani Sud, Michael J Poellmann, Jacob Hall, Xianming Tan, Jiyoon Bu, Ja Hye Myung, Andrew Z Wang, Seungpyo Hong, Dana L. Casey

 

PURPOSE

There are currently no predictive molecular biomarkers to identify patients with oligometastatic disease (OMD) who will benefit from definitive-intent radiation therapy (RT). We prospectively characterized circulating tumor cell (CTC) kinetics in patients with OMD undergoing definitive-intent RT.

METHODS

This prospective correlative biomarker study included patients with any solid malignancy ≤5 metastatic sites in ≤3 anatomic organ systems undergoing definitive-intent RT to all disease sites. Circulating tumor cells (CTCs) were captured and enumerated using a biomimetic cell rolling and nanotechnology-based assay functionalized with antibodies against epithelial cell adhesion molecule, against human epidermal growth factor receptor 2, and against epidermal growth factor receptor before and during RT and at follow-up visits up to 2 years post-RT.

RESULTS

We enrolled 43 patients with a median follow-up of 14.3 months. The pretreatment CTC level (cells captured/mL) was not associated with the number of disease sites (median one metastatic site/patient, range 1-5) or metastasis location (bone, brain, visceral) on Wilcoxon signed-rank test, P > .05. Post-RT, 56% of patients received systemic therapy, and 72% of patients experienced subsequent local or systemic progression. For 90% of patients, a CTC level <15 within 130 days post-RT corresponded to a durable control of irradiated lesions. Patients with a favorable versus an unfavorable clearance profile experienced significantly longer progression-free survival after RT (median 13 v 4 months, log-rank test, P = .0011). On logistic regression, CTC level >15 at a given time point was associated with clinical disease progression within the subsequent 6 months (odds ratio 3.31, P = .007). In 26% of patients with disease progression, a CTC level >15 preceded radiographic or clinical progression.

CONCLUSION

CTCs may serve as a biomarker for disease control in OMD and may predict disease progression before standard assessments for patients receiving diverse cancer-directed therapies.

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JCO Precision Oncology 2023 7:e2300303.

DOI:10.1200/PO.23.00303

Cancer Letters Journal Cover.jpg
Circulating tumor cell abundance in head and neck squamous cell carcinoma decreases with successful chemoradiation and cetuximab treatment

Michael J Poellmann, Jiyoon Bu, DaWon Kim, Mari Iida, Heejoo Hong, Andrew Z Wang, Deric Wheeler, Randall J Kimple, Seungpyo Hong

 

Abstract

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Head and neck squamous cell carcinoma (HNSCC) is a common and deadly cancer. Circulating tumor cell (CTC) abundance may a valuable, prognostic biomarker in low- and intermediate-risk patients. However, few technologies have demonstrated success in detecting CTCs in these populations. We prospectively collected longitudinal CTC counts from two cohorts of patients receiving treatments at our institution using a highly sensitive device that purifies CTCs using biomimetic cell rolling and dendrimer-conjugated antibodies. In patients with intermediate risk human papillomavirus (HPV)-positive HNSCC, elevated CTC counts were detected in 13 of 14 subjects at screening with a median of 17 CTC/ml (range 0.2–2986.5). A second cohort of non-metastatic, HPV- HNSCC subjects received cetuximab monotherapy followed by surgical resection. In this cohort, all subjects had elevated baseline CTC counts median of 73 CTC/ml (range 5.4–332.9) with statistically significant declines during treatment. Interestingly, two patients with recurrent disease had elevated CTC counts during and following treatment, which also correlated with growth of size and ki67 expression in the primary tumor. The results suggest that our device may be a valuable tool for evaluating the success of less intensive treatment regimens.

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Cancer Letters 2023 562:216187.

DOI:10.1016/j.canlet.2023.216187

Nanotechnology and machine learning enable circulating tumor cells as a reliable biomarker for radiotherapy responses of gastrointestinal cancer patients

Michael J Poellmann, Jiyoon Bu, Stanley Liu, Andrew Z Wang, Steven N Seyedin, Chandrikha Chandrasekharan, Heejoo Hong, YoungSoo Kim, Joseph M Caster, Seungpyo Hong

 

Abstract

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A highly sensitive, circulating tumor cell (CTC)-based liquid biopsy was used to monitor gastrointestinal cancer patients during treatment to determine if CTC abundance was predictive of disease recurrence. The approach used a combination of biomimetic cell rolling on recombinant E-selectin and dendrimer-mediated multivalent immunocapture at the nanoscale to purify CTCs from peripheral blood mononuclear cells. Due to the exceptionally high numbers of CTCs captured, a machine learning algorithm approach was developed to efficiently and reliably quantify abundance of immunocytochemically-labeled cells. A convolutional neural network and logistic regression model achieved 82.9% true-positive identification of CTCs with a false positive rate below 0.1% on a validation set. The approach was then used to quantify CTC abundance in peripheral blood samples from 27 subjects before, during, and following treatments. Samples drawn from the patients either prior to receiving radiotherapy or early in chemotherapy had a median 50 CTC ml−1 whole blood (range 0.6–541.6). We found that the CTC counts drawn 3 months post treatment were predictive of disease progression (p = .045). This approach to quantifying CTC abundance may be a clinically impactful in the timely determination of gastrointestinal cancer progression or response to treatment.

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Biosensors and Bioelectronics 2023 226:115117

DOI:10.1016/j.bios.2023.115117

Biosensors and Bioelectronics Journal Cover.jpg

Publications List

  1. "Prospective Characterization of Circulating Tumor Cell Kinetics in Patients with Oligometastatic Disease Receiving Definitive Intent Radiation Therapy" S. Sud, M.J. Poellmann, J. Hall, X. Tan, J. Bu, J.H. Myung, A.Z. Wang, S. Hong, and D.L. Casey. JCO Precision Oncology 2023, 7:e2300303.

  2. "Circulating Tumor Cell Abundance in Head and Neck Squamous Cell Carcinoma Decreases with Successful Chemoradiation and Cetuximab Treatment" M.J. Poellmann, J. Bu, D.W. Kim, M.Iida, H.Hong, A.Z. Wang, D. Wheeler, R.J.Kimple, and S. Hong. Cancer Letters 2023, 562:216187.

  3. "Nanotechnology and Machine Learning Enable Circulating Tumor Cells as a Reliable Biomarker for Radiotherapy Responses of Gastrointestinal Cancer Patients" M.J. Poellmann, J. Bu, S. Liu, A.Z. Wang, S.N. Seyedin, C. Chandrasekharan, H. Hong, Y.S. Kim, J.M. Caster, and S. Hong. Biosensors and Bioelectronics 2023, 226:115117.

  4. "Branched, Dendritic, and Hyperbranched Polymers in Liquid Biopsy Device Design" M.J. Poellmann, P. Rawding, D.W. Kim, J. Bu, Y.S. Kim, and S. Hong. Wiley Interdisciplinary Reviews: Nanomedicine and Nanobiotechnology 2022, 14(3):e1770.

  5. "Surface Engineering for Efficient Capture of Circulating Tumor Cells in Renal Cell Carcinoma: From Nanoscale Analysis to Clinical Application" J. Bu, A. Nair, L.J. Kubiatowicz, M.J. Poellmann, W.J. Jeong, M. Reyes-Martinez, A.J. Armstrong, D.J. George, A.Z. Wang, T. Zhang, and S. Hong. Biosensors and Bioelectronics 2020, 162:112250.

  6. "Immunoavidity-Based Capture of Tumor Exosomes Using Poly (amidoamine) Dendrimer Surfaces" M.J. Poellmann, A. Nair, J. Bu, J.K.H. Kim, R.J. Kimple, and S. Hong. Nano Letters 2020, 20(8):5685-5692.

  7. "Dendrimer-Based Platform for Effective Capture of Tumor Cells after TGFβ1-Induced Epithelial–Mesenchymal Transition" J.H. Myung, A. Cha, K.A. Tam, M. Poellmann, A. Borgeat, R. Sharifi, R.E. Molokie, G. Votta-Velis, and S. Hong. Analytical Chemistry 2019, 91(13):8374-8382.

  8. "Multivalent binding and biomimetic cell rolling improves the sensitivity and specificity of circulating tumor cell capture" J.H. Myung, M.J. Eblan, J.M. Caster, S.J. Park, M.J. Poellmann, K. Wang, K.A. Tam, S.M. Miller, C. Shen, R.C. Chen, T. Zhang, J.E. Tepper, B.S. Chera, A.Z Wang and S. Hong. Clinical Cancer Research 2018, 24(11):2539-2547.

  9. "Noncatalytic Endosialidase Enables Surface Capture of Small-Cell Lung Cancer Cells Utilizing Strong Dendrimer-Mediated Enzyme-Glycoprotein Interactions" H.J. Hsu, H. Palka-Hamblin, G.P. Bhide, J.H. Myung, M. Cheong, K.J. Colley, and S. Hong. Analytical Chemistry 2018, 90 (6):3670–3675.

  10. "Integration of Biomimicry and Nanotechnology for Significantly Improved Detection of Circulating Tumor Cells (CTCs)" J.H. Myung, S.J. Park, A.Z. Wang, and S. Hong, Advanced Drug Delivery Reviews 2018, 125:36-47.

  11. “Recent Advances in Nanotechnology-based Detection and Separation of Circulating Tumor Cells” J.H. Myung, K.A. Tam, S.J. Park, A. Cha, and S. Hong, Wiley Interdisciplinary Reviews: Nanomedicine and Nanobiotechnology 2016, 8(2):223-239. 

  12. “Microfluidic Devices to Enrich and Isolate Circulating Tumor Cells” J.H. Myung and S. Hong. Lab on a Chip 2015, 15:4500-4511.

  13. “Effective Capture of Circulating Tumor Cells from a Transgenic Mouse Lung Cancer Model using Dendrimer Surfaces Immobilized with anti-EGFR” J.H. Myung, M. Roengvoraphoj, K.A. Tam, T. Ma, V.A. Memoli, E. Dmitrovsky, S.J. Freemantle, and S. Hong. Analytical Chemistry 2015, 87(19):10096-100102.

  14. “Differential Detection of Tumor Cells Using a Combination of Cell Rolling, Multivalent Binding, and Multiple Antibodies” J.H. Myung, K.A. Gajjar, J. Chen, R.E. Molokie, and S. Hong. Analytical Chemistry 2014, 86(12):6088-6094.

  15. “Epithelial-Mesenchymal Transition Enhances Nano-scale Actin Filament Dynamics of Ovarian Cancer Cells” S. Lee, Y. Yang, D. Fishman, M.M. Banaszak Holl, and S. Hong. Journal of Physical Chemistry B 2013, 117(31):9233-9240.

  16. “The Role of Polymers in Detection and Isolation of Circulating Tumor Cells” J.H. Myung, K.A. Gajjar, Y.E. Han, and S. Hong. Polymer Chemistry 2012, 3(9):2336-2341.

  17. “Channel Surface Patterning of Alternating Biomimetic Protein Combinations for Enhanced Microfluidic Tumor Cell Isolation” C.A. Launiere, M. Gaskill, G. Czaplewski, J.H. Myung, S. Hong, and D.T. Eddington. Analytical Chemistry 2012, 84(9):4022-8.

  18. “Dendrimer-mediated Multivalent Binding for Enhanced Capture of Tumor Cells” J.H. Myung, K.A. Gajjar, J. Saric, D.T. Eddington, and S. Hong. Angewandte Chemie International Edition 2011, 50(49):11769-11772.

  19. “Rheologically Biomimetic Cell Suspensions for Decreased Cell Settling in Microfluidic Devices” C.A. Launiere, G.J. Czaplewski, J.H. Myung, S. Hong, and D.T. Eddington. Biomedical Microdevices 2011, 13(3):549-557.

  20. “Direct Measurements on CD24-Mediated Rolling of Human Breast Cancer MCF-7 Cells on E-selectin” J.H. Myung, K.A. Gajjar, R.M. Pearson, C.A. Launiere, D.T. Eddington, and S. Hong. Analytical Chemistry 2011, 83(3):1078-1083.

  21. “Enhanced Tumor Cell Isolation by a Biomimetic Combination of E-selectin and anti-EpCAM: Implication for Effective Separation of Circulating Tumor Cells (CTCs)” J.H. Myung, C.A. Launiere, D.T. Eddington, and S. Hong. Langmuir 2010, 26(11):8589-8596.

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