Zhang Ruiyun, Zang Jingyu, Jin Di, Xie Feng, Shahatiaili Akezhouli, Wu Guangyu, Zhang Lu, Wang Lu, Zhang Yue, Zhao Zhixin, Du Pan, Jia Shidong, Fan Jinhai, Zhuang Guanglei, Chen Haige
State Key Laboratory of Systems Medicine for Cancer, Department of Urology, Shanghai Cancer Institute, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China.
Department of Radiation Oncology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China.
Clin Cancer Res. 2023 Oct 13;29(20):4040-4046. doi: 10.1158/1078-0432.CCR-23-0513.
Bladder preservation is a viable option for some patients with muscle-invasive bladder cancer (MIBC), but an effective noninvasive biomarker test to accurately identify promising candidates is lacking. Here we present the clinical application of a novel tissue-agnostic, urine-based minimal residual disease (MRD) assay in the neoadjuvant setting for personalized disease surveillance and actionable target identification to facilitate bladder-sparing treatment approaches.
The urinary tumor DNA (utDNA) analysis was evaluated in an investigator-initiated phase I trial RJBLC-I2N003 in which 20 patients diagnosed with resectable MIBC were treated presurgically with the PD-1 inhibitor toripalimab followed by radical cystectomy (RC).
We showed that neoadjuvant toripalimab therapy was feasible, safe, and induced a 40% rate (8/20) of pathologic complete response. Longitudinal utDNA profiling outperformed radiographic assessment and conventional biomarkers to predict the pathologic outcome of immune checkpoint blockade. In addition to detecting 3 exceptional responders with molecular MRD-negative status, we identified 7 other individuals characterized for utDNA response and 4 harboring FGFR3 mutants, all of whom (60%, 12/20) could have postponed or avoided RC.
These findings demonstrate the safety and efficacy of neoadjuvant toripalimab, and suggest the immense potential of noninvasive utDNA MRD testing to guide tailored decision-making with regard to bladder preservation and change the current treatment paradigm for patients with MIBC.
对于一些肌层浸润性膀胱癌（MIBC）患者，膀胱保留是一种可行的选择，但目前缺乏一种有效的非侵入性生物标志物检测方法来准确识别有希望的候选者。在此，我们展示了一种新型的组织非特异性、基于尿液的微小残留病（MRD）检测方法在新辅助治疗中的临床应用，用于个性化疾病监测和可操作靶点识别，以促进膀胱保留治疗方法的实施。
在一项由研究者发起的I期试验RJBLC-I2N003中对尿肿瘤DNA（utDNA）分析进行了评估，该试验纳入了20例诊断为可切除MIBC的患者，术前接受PD-1抑制剂托瑞帕利单抗治疗，随后进行根治性膀胱切除术（RC）。
我们表明，新辅助托瑞帕利单抗治疗是可行、安全的，且病理完全缓解率为40%（8/20）。纵向utDNA分析在预测免疫检查点阻断的病理结果方面优于影像学评估和传统生物标志物。除了检测到3例分子MRD阴性状态的特殊缓解者外，我们还识别出另外7例具有utDNA反应特征的个体以及4例携带FGFR3突变的个体，所有这些人（60%，12/20）都可以推迟或避免RC。
这些发现证明了新辅助托瑞帕利单抗的安全性和有效性，并表明非侵入性utDNA MRD检测在指导膀胱保留的个性化决策以及改变MIBC患者当前治疗模式方面具有巨大潜力。
