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

Patel, Rutulkumar

Mowery, Yvonne M

Qi, Yi

Bassil, Alex M

Holbrook, Matt

Xu, Eric S

Hong, Cierra S

Himes, Jonathon E

Williams, Nerissa T

Everitt, Jeffrey

Ma, Yan

Luo, Lixia

Selitsky, Sara R

Modliszewski, Jennifer L

Gao, Junheng

Jung, Sin-Ho

Kirsch, David G

Badea, Cristian T

2023-03-27T13:12:28Z

2023-03-27T13:12:28Z

2023-01

2023-03-27T13:12:26Z

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.

711999

1535-7163

1538-8514

https://hdl.handle.net/10161/26763

eng

American Association for Cancer Research (AACR)

Molecular cancer therapeutics

10.1158/1535-7163.mct-21-0991

Animals

Mice

Sarcoma

Soft Tissue Neoplasms

Neoplasm Recurrence, Local

Disease-Free Survival

Neoadjuvant Therapy

Radiotherapy, Adjuvant

Retrospective Studies

Tumor Suppressor Protein p53

Progression-Free Survival

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

Journal article

Mowery, Yvonne M|0000-0002-9839-2414

Everitt, Jeffrey|0000-0003-0273-6284

Jung, Sin-Ho|0000-0002-1473-7236

Badea, Cristian T|0000-0002-1850-2522

112

122

1

Duke

Pratt School of Engineering

School of Medicine

Basic Science Departments

Clinical Science Departments

Institutes and Centers

Biostatistics & Bioinformatics

Pharmacology & Cancer Biology

Biomedical Engineering

Pathology

Radiation Oncology

Radiology

Duke Cancer Institute

Head and Neck Surgery & Communication Sciences

Regeneration Next Initiative

Published

22