Personalized ctDNA analysis for predicting outcomes and tracking response to therapy in localized sarcomas: randomized phase 2 SARC032 trial

Circulating tumor DNA (ctDNA) holds promise for prognostication and disease monitoring in solid tumors; however, rare and heterogenous tumors with low mutational burden like soft tissue sarcomas (STS) present a technical challenge for ctDNA analysis. Secondary analysis of the randomized phase 2 SARC032 trial evaluated personalized ctDNA analysis to predict outcomes and track response to radiotherapy (RT) and pembrolizumab in localized STS. The authors analyzed 313 plasma samples collected pretreatment, postradiotherapy/presurgery, and postsurgery from 106 patients treated with preoperative RT with or without perioperative pembrolizumab. Personalized ctDNA assays were designed to track a median of 46 somatic mutations per patient. Personalized ctDNA profiling detected baseline ctDNA in 85% of patients. Baseline ctDNA levels correlated with tumor size, grade 3 disease, and expression of genes related to hypoxia and the cell cycle. ctDNA levels pretreatment, after RT with or without immunotherapy but before surgery, and postsurgery were strongly associated with disease-free and overall survival. Patients treated with pembrolizumab, who had significantly better disease-free survival, had a greater decrease in their ctDNA levels after neoadjuvant therapy. Personalized ctDNA analysis enabled noninvasive subclone tracking; patients with multiple tumor clones detected by ctDNA analysis after surgery had inferior outcomes. The authors conclude that tumor-informed, personalized profiling enables sensitive ctDNA detection and quantitative monitoring in localized STS, providing independent prognostic information across the perioperative course.