Translational Oncology (Oct 2021)

Genomic identification of sarcoma radiosensitivity and the clinical implications for radiation dose personalization

  • George Yang,
  • Zhigang Yuan,
  • Kamran Ahmed,
  • Eric A. Welsh,
  • William J. Fulp,
  • Ricardo J. Gonzalez,
  • John E. Mullinax,
  • Douglas Letson,
  • Marilyn Bui,
  • Louis B. Harrison,
  • Jacob G. Scott,
  • Javier F. Torres-Roca,
  • Arash O. Naghavi

Journal volume & issue
Vol. 14, no. 10
p. 101165

Abstract

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Background: Soft-tissue sarcomas (STS) are heterogeneous with variable response to radiation therapy (RT). Utilizing the radiosensitivity index (RSI) we estimated the radiobiologic ratio of lethal to sublethal damage (α/β), genomic-adjusted radiation dose(GARD), and in-turn a biological effective radiation dose (BED). Methods: Two independent cohorts of patients with soft-tissue sarcoma were identified. The first cohort included 217 genomically-profiled samples from our institutional prospective tissue collection protocol; RSI was calculated for these samples, which were then used to dichotomize the population as either highly radioresistant (HRR) or conventionally radioresistant (CRR). In addition, RSI was used to calculate α/β ratio and GARD, providing ideal dosing based on sarcoma genomic radiosensitivity. A second cohort comprising 399 non-metastatic-STS patients treated with neoadjuvant RT and surgery was used to validate our findings. Results: Based on the RSI of the sample cohort, 84% would historically be considered radioresistant. We identified a HRR subset that had a significant difference in the RSI, and clinically a lower tumor response to radiation (2.4% vs. 19.4%), 5-year locoregional-control (76.5% vs. 90.8%), and lower estimated α/β (3.29 vs. 5.98), when compared to CRR sarcoma. Using GARD, the dose required to optimize outcome in the HRR subset is a BEDα/β=3.29 of 97 Gy. Conclusions: We demonstrate that on a genomic scale, that although STS is radioresistant overall, they are heterogeneous in terms of radiosensitivity. We validated this clinically and estimated an α/β ratio and dosing that would optimize outcome, personalizing dose.

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