Neoadjuvant Radiation Therapy and Surgery Improves Metastasis-Free Survival over Surgery Alone in a Primary Mouse Model of Soft Tissue Sarcoma.

Abstract

This study aims to investigate whether adding neoadjuvant radiotherapy (RT), anti-programmed cell death protein-1 (PD-1) antibody (anti-PD-1), or RT + anti-PD-1 to surgical resection improves disease-free survival for mice with soft tissue sarcomas (STS). We generated a high mutational load primary mouse model of STS by intramuscular injection of adenovirus expressing Cas9 and guide RNA targeting Trp53 and intramuscular injection of 3-methylcholanthrene (MCA) into the gastrocnemius muscle of wild-type mice (p53/MCA model). We randomized tumor-bearing mice to receive isotype control or anti-PD-1 antibody with or without radiotherapy (20 Gy), followed by hind limb amputation. We used micro-CT to detect lung metastases with high spatial resolution, which was confirmed by histology. We investigated whether sarcoma metastasis was regulated by immunosurveillance by lymphocytes or tumor cell-intrinsic mechanisms. Compared with surgery with isotype control antibody, the combination of anti-PD-1, radiotherapy, and surgery improved local recurrence-free survival (P = 0.035) and disease-free survival (P = 0.005), but not metastasis-free survival. Mice treated with radiotherapy, but not anti-PD-1, showed significantly improved local recurrence-free survival and metastasis-free survival over surgery alone (P = 0.043 and P = 0.007, respectively). The overall metastasis rate was low (∼12%) in the p53/MCA sarcoma model, which limited the power to detect further improvement in metastasis-free survival with addition of anti-PD-1 therapy. Tail vein injections of sarcoma cells into immunocompetent mice suggested that impaired metastasis was due to inability of sarcoma cells to grow in the lungs rather than a consequence of immunosurveillance. In conclusion, neoadjuvant radiotherapy improves metastasis-free survival after surgery in a primary model of STS.

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Citation

Published Version (Please cite this version)

10.1158/1535-7163.mct-21-0991

Publication Info

Patel, Rutulkumar, Yvonne M Mowery, Yi Qi, Alex M Bassil, Matt Holbrook, Eric S Xu, Cierra S Hong, Jonathon E Himes, et al. (2023). Neoadjuvant Radiation Therapy and Surgery Improves Metastasis-Free Survival over Surgery Alone in a Primary Mouse Model of Soft Tissue Sarcoma. Molecular cancer therapeutics, 22(1). pp. 112–122. 10.1158/1535-7163.mct-21-0991 Retrieved from https://hdl.handle.net/10161/26764.

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Scholars@Duke

Mowery

Yvonne Marie Mowery

Butler Harris Assistant Professor in Radiation Oncology
Everitt

Jeffrey Ira Everitt

Professor Emeritus in Pathology
Jung

Sin-Ho Jung

Professor of Biostatistics & Bioinformatics

Design of Clinical Trials
Survival Analysis
Longitudinal Data Analysis
Clustered Data Analysis
ROC Curve Analysis
Design and Analysis of Microarray Studies
Big Data Analysis

Kirsch

David Guy Kirsch

Adjunct Professor in the Department of Radiation Oncology

My clinical interests are the multi-modality care of patients with bone and soft tissue sarcomas and developing new sarcoma therapies. My laboratory interests include utilizing mouse models of cancer to study cancer and radiation biology in order to develop new cancer therapies in the pre-clinical setting.

Badea

Cristian Tudorel Badea

Professor in Radiology

  • Our lab's research focus lies primarily in developing novel quantitative imaging systems, reconstruction algorithms and analysis methods.  My major expertise is in preclinical CT.
  • Currently, we are particularly interested in developing novel strategies for spectral CT imaging using nanoparticle-based contrast agents for theranostics (i.e. therapy and diagnostics).
  • We are also engaged in developing new approaches for multidimensional CT image reconstruction suitable to address difficult undersampling cases in cardiac and spectral CT (dual energy and photon counting) using compressed sensing and/or deep learning.



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