Genomic Predictors of Recurrence Patterns in Localized Soft Tissue Sarcoma Treated With Radiation Therapy.

Purpose/objective(s) Soft tissue sarcomas (STSs) are diverse mesenchymal tumors that are primarily managed with surgery. Radiation therapy (RT) is frequently added pre- or post-operatively for localized disease but uncommonly used as definitive treatment because the majority of unresected tumors progress with RT alone. Advances in next-generation sequencing have led to the widespread use of clinical genomic profiling, but the genetic determinants of radiation response in STSs are unknown. We hypothesized that integrating patient outcome data and clinical tumor mutation profiling could identify genomic predictors of recurrence patterns after RT for localized STS. Materials/methods We retrospectively identified 31 patients treated at our institution with definitive RT with or without surgery for localized STS who underwent tumor genomic profiling using a sequencing platform. For genes altered in at least 10% of patients, the associations between genetic alterations and local failure or distant metastasis were analyzed with univariable and multivariable competing risk regression adjusted for the competing risk of death. Age, maximum tumor diameter, tumor grade, and extent of resection were included as co-variables, and P values were adjusted for multiple hypothesis testing. Results Median follow up was 24 months, and the median RT dose was 50.4 Gy in 28 fractions. The most common histologies were leiomyosarcoma (n = 4) and myxofibrosarcoma (n = 4). The majority of tumors were located in the trunk and extremities (68%) with the remaining tumors originating in the head and neck (16%) or abdomen and pelvis (16%). 48% of patients underwent margin-negative resection, 36% had microscopically positive margins, and 16% were unresected or had gross residual disease following surgery. Median age was 58, median tumor size was 7.5 cm, and 65% of tumors were high grade. On univariable analysis, younger age (P = 0.02) and extent of resection (P = 0.0002) were significantly associated with local recurrence, and there was a trend towards association between higher grade and distant metastasis (P = 0.09). On univariable analysis, amplification of FRS2 in isolation or in combination with MDM2 and CDK4 was associated with a significantly increased risk of local recurrence (n = 4, HR 4.3), and genetic alterations in FBXO11 were associated with a significantly increased risk of distant metastasis (n = 4, HR 3.9). On multivariable analysis, FBXO11 alterations continued to predict for distant metastasis (HR 5.7, P = 0.0002), but there were no significant predictors of local recurrence. Conclusion Our results suggest that somatic tumor mutations may contribute to the risk of local recurrence and distant metastasis in patients treated with RT for localized STS. Additional analysis and validation in larger multi-institutional cohorts will be critical to identify molecular predictors of prognosis and patterns of recurrence.