Background and objective

Circulating tumor DNA (ctDNA) can be used for sensitive detection of minimal residual disease (MRD). However, the probability of detecting ctDNA in settings of low tumor burden is limited by the number of mutations analyzed and the plasma volume available. We used a whole-genome sequencing (WGS) approach for ctDNA detection in patients with urothelial carcinoma.

Methods

We used a tumor-informed WGS approach for ctDNA-based detection of MRD and evaluation of treatment responses. We analyzed 916 longitudinally collected plasma samples from 112 patients with localized muscle-invasive bladder cancer who received neoadjuvant chemotherapy (NAC) before radical cystectomy. Recurrence-free survival (primary endpoint), overall survival, and ctDNA dynamics during NAC were assessed.

Key findings and limitations

We found that WGS-based ctDNA detection is prognostic for patient outcomes with a median lead time of 131 d over radiographic imaging. WGS-based ctDNA assessment after radical cystectomy identified recurrence with sensitivity of 91% and specificity of 92%. In addition, genomic characterization of post-treatment plasma samples with a high ctDNA level revealed acquisition of platinum therapy–associated mutational signatures and copy number variations not present in the primary tumors. The sequencing depth is a limitation for studying tumor evolution.

Conclusions and clinical implications

Our results support the use of WGS for ultrasensitive ctDNA detection and highlight the possibility of plasma-based tracking of tumor evolution. WGS-based ctDNA detection represents a promising option for clinical use owing to the low volume of plasma needed and the ease of performing WGS, eliminating the need for personalized assay design.

中文翻译：

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全基因组突变分析用于尿路上皮癌患者循环肿瘤 DNA 的肿瘤知情检测

 背景和目标

循环肿瘤 DNA （ctDNA） 可用于灵敏检测微小残留病 （MRD）。然而，在低肿瘤负荷的情况下检测到 ctDNA 的可能性受到分析的突变数量和可用血浆量的限制。我们使用全基因组测序 （WGS） 方法对尿路上皮癌患者进行 ctDNA 检测。

 方法

我们使用肿瘤知情的 WGS 方法进行基于 ctDNA 的 MRD 检测和治疗反应评估。我们分析了 916 例纵向收集的血浆样本，这些样本来自 112 例在根治性膀胱切除术前接受新辅助化疗 （NAC） 的局限性肌层浸润性膀胱癌患者。评估 NAC 期间的无复发生存期 （主要终点） 、总生存期和 ctDNA 动力学。

主要发现和局限性

我们发现基于 WGS 的 ctDNA 检测对患者结局有预后作用，放射影像学成像的中位提前期为 131 d。根治性膀胱切除术后基于 WGS 的 ctDNA 评估发现复发，敏感性为 91%，特异性为 92%。此外，具有高 ctDNA 水平的治疗后血浆样本的基因组表征揭示了原发肿瘤中不存在的铂类治疗相关突变特征和拷贝数变异的获得。测序深度是研究肿瘤进化的一个限制。

结论和临床意义

我们的结果支持使用 WGS 进行超灵敏的 ctDNA 检测，并强调了基于血浆追踪肿瘤演变的可能性。基于 WGS 的 ctDNA 检测是一种很有前途的临床应用选择，因为所需的血浆量低且易于执行 WGS，无需个性化检测设计。