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

Publication ,  Journal Article
Patel, R; Mowery, YM; Qi, Y; Bassil, AM; Holbrook, M; Xu, ES; Hong, CS; Himes, JE; Williams, NT; Everitt, J; Ma, Y; Luo, L; Selitsky, SR ...
Published in: Mol Cancer Ther
January 3, 2023

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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Published In

Mol Cancer Ther

DOI

EISSN

1538-8514

Publication Date

January 3, 2023

Volume

22

Issue

1

Start / End Page

112 / 122

Location

United States

Related Subject Headings

  • Tumor Suppressor Protein p53
  • Soft Tissue Neoplasms
  • Sarcoma
  • Retrospective Studies
  • Radiotherapy, Adjuvant
  • Progression-Free Survival
  • Oncology & Carcinogenesis
  • Neoplasm Recurrence, Local
  • Neoadjuvant Therapy
  • Mice
 

Citation

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Patel, R., Mowery, Y. M., Qi, Y., Bassil, A. M., Holbrook, M., Xu, E. S., … Badea, C. T. (2023). Neoadjuvant Radiation Therapy and Surgery Improves Metastasis-Free Survival over Surgery Alone in a Primary Mouse Model of Soft Tissue Sarcoma. Mol Cancer Ther, 22(1), 112–122. https://doi.org/10.1158/1535-7163.MCT-21-0991
Patel, Rutulkumar, Yvonne M. Mowery, Yi Qi, Alex M. Bassil, Matt Holbrook, Eric S. Xu, Cierra S. Hong, et al. “Neoadjuvant Radiation Therapy and Surgery Improves Metastasis-Free Survival over Surgery Alone in a Primary Mouse Model of Soft Tissue Sarcoma.Mol Cancer Ther 22, no. 1 (January 3, 2023): 112–22. https://doi.org/10.1158/1535-7163.MCT-21-0991.
Patel R, Mowery YM, Qi Y, Bassil AM, Holbrook M, Xu ES, et al. Neoadjuvant Radiation Therapy and Surgery Improves Metastasis-Free Survival over Surgery Alone in a Primary Mouse Model of Soft Tissue Sarcoma. Mol Cancer Ther. 2023 Jan 3;22(1):112–22.
Patel, Rutulkumar, et al. “Neoadjuvant Radiation Therapy and Surgery Improves Metastasis-Free Survival over Surgery Alone in a Primary Mouse Model of Soft Tissue Sarcoma.Mol Cancer Ther, vol. 22, no. 1, Jan. 2023, pp. 112–22. Pubmed, doi:10.1158/1535-7163.MCT-21-0991.
Patel R, Mowery YM, Qi Y, Bassil AM, Holbrook M, Xu ES, Hong CS, Himes JE, Williams NT, Everitt J, Ma Y, Luo L, Selitsky SR, Modliszewski JL, Gao J, Jung S-H, Kirsch DG, Badea CT. Neoadjuvant Radiation Therapy and Surgery Improves Metastasis-Free Survival over Surgery Alone in a Primary Mouse Model of Soft Tissue Sarcoma. Mol Cancer Ther. 2023 Jan 3;22(1):112–122.

Published In

Mol Cancer Ther

DOI

EISSN

1538-8514

Publication Date

January 3, 2023

Volume

22

Issue

1

Start / End Page

112 / 122

Location

United States

Related Subject Headings

  • Tumor Suppressor Protein p53
  • Soft Tissue Neoplasms
  • Sarcoma
  • Retrospective Studies
  • Radiotherapy, Adjuvant
  • Progression-Free Survival
  • Oncology & Carcinogenesis
  • Neoplasm Recurrence, Local
  • Neoadjuvant Therapy
  • Mice