Personalized Circulating Tumor DNA Analysis for Predicting Outcomes and Tracking Response to Radiotherapy and Pembrolizumab in Localized Sarcomas: Analysis of the SU2C-SARC032 Trial.

However, rare and heterogenous tumors with low mutational burden like soft tissue sarcomas (STS) present a technical challenge for ctDNA analysis.

然而，像软组织肉瘤（STS）这样的罕见且异质性肿瘤，具有低突变负荷，为ctDNA分析带来了技术挑战。

We investigated the ability of personalized ctDNA analysis to predict outcomes and track response to radiotherapy and pembrolizumab in patients with localized STS.

我们研究了个性化ctDNA分析预测结果和追踪对放疗和pembrolizumab反应的能力，针对的是接受放疗和/或围手术期pembrolizumab治疗的局部性STS患者。

Methods

We analyzed 313 plasma samples collected pretreatment, postradiotherapy/presurgery, and postsurgery from 106 patients treated with preoperative radiotherapy with or without perioperative pembrolizumab for high-risk, localized STS in the SU2C-SARC032 phase II randomized trial. Personalized ctDNA assays were designed to track a median of 46 somatic mutations per patient.

我们分析了313个血浆样本，这些样本是在106名接受术前放疗，有或没有围手术期pembrolizumab治疗的高风险局部性STS患者中收集的，这些患者参与了SU2C-SARC032第二阶段随机试验。个性化ctDNA检测被设计来追踪每个患者中位数为46个的体细胞突变。

Associations between ctDNA levels and outcomes were assessed using univariable and multivariable models adjusting for clinical risk factors.

使用单变量和多变量模型调整临床风险因素后，评估了ctDNA水平与结果之间的关联。

Results

Personalized ctDNA profiling detected baseline ctDNA in 85% of patients.

个性化ctDNA分析在85%的患者中检测到基线ctDNA。

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 radiotherapy with or without immunotherapy but before surgery, and postsurgery were strongly associated with disease-free and overall survivalon univariable and multivariable analyses.

基线ctDNA水平与肿瘤大小、3级疾病以及与缺氧和细胞周期相关的基因表达相关。术前、放疗后（无论是否接受免疫治疗）和术后的ctDNA水平与无病生存期和总生存期在单变量和多变量分析中密切相关。

Patients treated with pembrolizumab, who had significantly better disease-free survival, had a greater decrease in their ctDNA levels after neoadjuvant therapy.

接受pembrolizumab治疗的患者，其无病生存期显著改善，他们的ctDNA水平在新辅助治疗后有更大的下降。

Finally, personalized ctDNA analysis enabled noninvasive subclone tracking and patients with multiple tumor clones detected by ctDNA analysis after surgery had inferior outcomes.

最终，个性化的循环肿瘤DNA（ctDNA）分析使得非侵入性地追踪亚克隆成为可能，通过ctDNA分析在手术后检测到多个肿瘤克隆的患者预后较差。

Conclusions

Tumor-informed, personalized profiling enables sensitive ctDNA detection and quantitative monitoring in localized STS, providing independent prognostic information across the perioperative course.

基于肿瘤信息的个性化分析使得在局部软组织肉瘤（STS）中敏感地检测ctDNA并进行定量监测成为可能，这在整个围手术期提供了独立的预后信息。

These findings support prospective ctDNA-guided interventional trials in STS.

这些发现支持在软组织肉瘤（STS）中进行前瞻性ctDNA指导的干预性试验。