Molecular biomarkers impact survival after neoadjuvant chemoradiation in locally advanced soft tissue sarcoma patients

Background Locally advanced, marginally resectable soft tissue sarcomas (STS) are frequently treated with multimodal neoadjuvant strategies to enable limb-sparing, R0 resection. However, pathological response (PR) to neoadjuvant chemoradiation is heterogeneous, and robust molecular predictors of response are lacking. We performed comprehensive DNA/RNA profiling to identify genomic correlates of PR and clinical outcomes in a real-world cohort treated with a uniform neoadjuvant chemoradiation regimen. Methods We retrospectively analyzed pre-treatment biopsies from 27 patients with high-grade, marginally resectable STS treated at a single sarcoma center (median age 55 years; range 28–74; 62.96% male). Histological subtypes included undifferentiated pleomorphic sarcoma (44.44%), myxofibrosarcoma (29.63%), malignant peripheral nerve sheath tumor (14.82%), myxoid liposarcoma (7.41%), and pleomorphic liposarcoma (3.70%). Targeted DNA/RNA sequencing was performed using the TruSight Oncology 500 assay to identify single-nucleotide variants (SNV), copy number variation (CNV), and gene fusions. Pathological response was assessed in resection specimens based on the proportion of viable tumor. Overall survival (OS), local recurrence-free survival (LRFS), and distant metastasis-free survival (DMFS) were estimated using the Kaplan–Meier method. Results The cohort displayed a complex genomic landscape with recurrent SNV/CNV events and frequent fusion calls across STS subtypes. Presence of gene fusions was associated with improved OS ( p  = 0.043), whereas PR itself was not significantly associated with survival ( p  = 0.427). Exploratory analyses identified molecular features related to PR: ROS1 -associated gene fusions were observed exclusively in tumors with favorable PR, while MDM2 gene amplification and PTEN deletion were linked to poor PR. Additionally, likely pathogenic variants of TP53, PLCG2, PIK3C2B, GABRA6 , and KMT2C genes were clustered in poor-response cases. Molecular profiling also flagged potential diagnostic reclassification in selected tumors via highly specific fusion events, underscoring its value beyond prognostication. Conclusions Comprehensive DNA/RNA profiling in locally advanced STS treated with neoadjuvant chemoradiation suggests that fusion status and specific actionable alterations may stratify response biology and survival. These hypothesis-generating biomarkers, particularly ROS1 -associated gene fusions, MDM2 gene amplification, and PTEN loss — require validation in larger, histology-controlled cohorts and may inform future molecularly guided neoadjuvant strategies. Trial registration NCT03651375.