泌尿系肿瘤 DNA (utDNA) 分析可识别与尿路上皮癌相关的突变，可用于检测微小残留病 (MRD)。我们评估了 utDNA 分析在预测用 nadofaragene firadenovec 治疗的卡介苗无反应的高级 (HG) 非肌层浸润性膀胱癌 (NMIBC) 治疗失败中的效用。在诱导前收集参与者的尿液 (n = 32) 以及 nadofaragene firadenovec 平行组 2 期研究 (NCT01687244) 的 3 个月评估 (n = 18)。使用 UroAmp MRD 检测（Convergent Genomics，南旧金山，加利福尼亚州，美国）进行 utDNA 检测。使用两种算法版本确定 HG NMIBC 复发风险，并使用 Kaplan-Meier 分析评估无复发生存 (RFS)。TP53、TERT、PIK3CA、ARID1A、PLEKHS1、ELF3 和 ERBB2 是最常见的突变基因。对于治疗前尿液，经验证的 MRD 算法导致阴性患者的 12 个月 RFS 为 56%，阳性患者为 22%（p = 0.097）。实验性增强算法将另外两名患者分类为阳性，阴性患者的 RFS 为 71%，阳性患者的 RFS 为 20% (p = 0.012)。对于 3 个月的尿液，两种算法对于阴性患者的 RFS 均为 100%，对于阳性患者的 RFS 为 38% (p = 0.038)。纵向 utDNA 检测将患者分为阴性 (7%)、完全缓解 (13%)、部分缓解 (27%)、无缓解 (20%) 和扩大缓解 (33%)。 nadofaragene firadenovec 诱导后的尿液 MRD 检测提供了具有统计学意义的预测2 期试验参与者的复发率。通过分析尿源性肿瘤 DNA，我们可以帮助确定哪些患有高级别非肌层浸润性膀胱癌的患者在接受二线治疗时复发的风险最大。版权所有 © 2024作者。由 Elsevier B.V. 出版。保留所有权利。

Urinary tumor DNA (utDNA) profiling identifies mutations associated with urothelial carcinoma and can be used to detect minimal residual disease (MRD). We evaluate the utility of utDNA profiling to predict treatment failure in bacillus Calmette-Guérin-unresponsive high-grade (HG) non-muscle-invasive bladder cancer (NMIBC) treated with nadofaragene firadenovec.Urine was collected from participants prior to induction (n = 32) and at their 3-mo evaluation (n = 18) in the parallel-arm, phase 2 study (NCT01687244) of nadofaragene firadenovec. The UroAmp MRD assay (Convergent Genomics, South San Francisco, CA, USA) was used to perform utDNA testing. Risk of HG NMIBC recurrence was determined using two algorithm versions, and recurrence-free survival (RFS) was assessed using a Kaplan-Meier analysis.TP53, TERT, PIK3CA, ARID1A, PLEKHS1, ELF3, and ERBB2 were the most prevalently mutated genes. With pretreatment urine, the validated MRD algorithm resulted in 12-mo RFS of 56% for negative and 22% for positive patients (p = 0.097). The experimental, enhanced algorithm classified two additional patients as positive, giving RFS of 71% for negative and 20% for positive patients (p = 0.012). With 3-mo urine, both algorithms gave RFS of 100% for negative and 38% for positive patients (p = 0.038). Longitudinal utDNA testing classified patients as negative (7%), complete responders (13%), partial responders (27%), unresponsive (20%), and expanding (33%).Urinary MRD testing after nadofaragene firadenovec induction provided statistically significant prognostication of recurrence among phase 2 trial participants.By analyzing urine-borne tumor DNA, we can help determine which patients with high-grade non-muscle-invasive bladder cancer are at the greatest risk of recurrence when receiving second-line therapy.Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.