免疫检查点抑制剂（ICIs）可以在转移性尿路上皮癌（mUC）中引起持久的疾病控制，但仅有20-25％的患者有响应。早期确定非持久性响应将改善管理策略。本研究旨在调查治疗期间循环肿瘤DNA（ctDNA）的测量是否可以预测mUC患者对ICI的响应。该研究包括40例mUC患者的发现队列和16例mUC患者的前瞻性多中心验证队列。收集骨髓基质细胞无胞质DNA样品在治疗开始时以及用药后3周和6周。ctDNA浓度通过靶向测序进行计算。结果测量指标包括无进展生存期（PFS）、总生存期（OS）和非持久性响应（PFS≤6个月）。使用Cox回归分析评估与ctDNA的关系。根据相对于基线的上升或下降将3周和6周的ctDNA水平变化分为两类。在发现队列中，常见ctDNA基线检出率为37/40（93％）。观察到12/15 （80％）和10/12（83％）的患者在3周和6周处出现非持久性响应时的ctDNA增加。其中，94％的持久性响应（PFS> 6个月）的患者显示出ctDNA的降低。在独立于临床预后变量的情况下，3周时的ctDNA上升与PFS（风险比[HR] 7.8，95％置信区间[CI] 3.1-19.5）和OS（HR 8.0，95％CI 3.0-21.0）较短相关。6周时也观察到类似的结果。在前瞻性队列中，3周与PFS的关联得到了验证（HR 7.5，95％CI 1.3-42.6）。局限性包括患者数量有限。ctDNA水平的早期变化与mUC ICI受益的持续时间密切相关，并可能有助于及时的治疗调整。通过调查血液中的肿瘤DNA，可以在治疗后仅3周预测免疫治疗的效应。这有助于对于免疫治疗受益有限的尿路上皮癌患者进行及时治疗策略的改变。© 2023年作者。Elsevier B.V.发表。保留所有权利。

Immune checkpoint inhibitors (ICIs) can induce durable disease control in metastatic urothelial cancer (mUC), but only 20-25% of patients respond. Early identification of a nondurable response will improve management strategies.To investigate whether on-treatment circulating tumor DNA (ctDNA) measurements can predict ICI responsiveness in mUC patients.This study consists of a discovery cohort of 40 mUC patients and a prospective multicenter validation cohort of 16 mUC patients. Plasma cell-free DNA was collected at baseline and after 3 and 6 wk on ICIs. The ctDNA levels were calculated from targeted sequencing.Outcome measurements were progression-free survival (PFS), overall survival (OS), and nondurable response (PFS ≤6 mo). Relationships with ctDNA were assessed using Cox regression. Changes in ctDNA level at 3 and 6 wk were categorized by an increase or decrease relative to baseline.In the discovery cohort, ctDNA was detected in 37/40 (93%) of patients at baseline. A ctDNA increase was observed in 12/15 (80%) and ten of 12 (83%) patients with a nondurable response at 3 and 6 wk, respectively. Of patients with a durable response (PFS >6 mo), 94% showed a decrease. A ctDNA increase at 3 wk was associated with shorter PFS (hazard ratio [HR] 7.8, 95% confidence interval [CI] 3.1-19.5) and OS (HR 8.0, 95% CI 3.0-21.0), independent of clinical prognostic variables. Similar results were observed at 6 wk. The 3-wk association with PFS was validated in a prospective cohort (HR 7.5, 95% CI 1.3-42.6). Limitations include the limited number of patients.Early changes in ctDNA levels are strongly linked to the duration of ICI benefit in mUC and may contribute to timely therapy modifications.Benefit from immunotherapy can be predicted after only 3 wk of treatment by investigating cancer DNA in blood. This could help in timely therapy changes for urothelial cancer patients with limited benefit from immunotherapy.Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.