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

Highlights

• •

  Soft tissue sarcomas have traditionally been treated with a one-size fits all approach, despite a wide range of histologies and clinical outcomes.

• •

  The radiosensitivity index has demonstrated that soft tissue sarcomas are in general radioresistant, however exhibit a wide range of radiosensitivity.

• •

  These differences in radiosensitivity are associated with decreased locoregional control in patients with radioresistant histologies.

• •

  Using the radiosensitivity index we identify specific histologies of soft tissue sarcoma that may be more radioresistant, and suggest a genomic-based radiation dosing framework.

Abstract

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 BED _{α/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.