我们之前报道过，含有四种基因突变（ATM、RB1、FANCC 或 ERCC2）中任何一种的肿瘤可能对基于顺铂的新辅助化疗 (NAC) 产生反应，从而在膀胱切除术时获得无癌手术标本 (pT0) ）。在这里，我们报告了对这一发现的验证。使用 CARIS 592 基因面板（Caris Life Sciences，凤凰城，亚利桑那州，美国），我们分析了来自新辅助吉西他滨和顺铂 (GC) 或剂量密集甲氨蝶呤的大型多中心试验 (S1314) 的 105 个 NAC 前肿瘤标本，长春花碱、阿霉素和顺铂 (DDMVAC)。我们发现这四个基因中任何一个的突变都可以预测手术时的 pT0（比值比 = 5.36；95% 置信区间 [CI] 2.05, 14.02；两侧 p = 0.0006）。该生物标志物在预测疾病存在方面（pT0 阴性预测值 86%；95% CI 73%、94%）优于预测不存在疾病（pT0 阳性预测值 48%；95% CI 35%、62%） ）。就 pT0 而言，没有证据表明治疗组（DDMVAC 与 GC）与遗传变异之间存在相互作用。与临床评估相结合，这些发现有助于患者在顺铂化疗后选择保留膀胱。患者摘要：肌层浸润性膀胱癌患者的常见护理标准是新辅助化疗 (NAC)，然后进行膀胱切除术以实现治愈。我们之前发现，初始活检（经尿道膀胱肿瘤切除术）收集的肿瘤样本中的特定 DNA 突变可以预测 NAC 的完全缓解。换句话说，携带这些突变的患者更有可能在手术后发现膀胱没有癌症。在这项研究中，我们分析了来自一项国家化疗随后膀胱切除术临床试验的更大组肿瘤样本，以验证这些早期发现。我们的结论是，这种生物标志物测试与仔细的临床评估相结合，可用于将患者分配给仔细的膀胱监测而不是手术。这一假设已在之前提出的 RETAIN 试验 (NCT02710734) 中得到检验。版权所有 © 2024 欧洲泌尿外科协会。由 Elsevier B.V. 出版。保留所有权利。

We previously reported that tumors harboring any one of four gene mutations (ATM, RB1, FANCC, or ERCC2) were likely to respond to neoadjuvant cisplatin-based chemotherapy (NAC), resulting in cancer-free surgical specimens at the time of cystectomy (pT0). Here, we report our validation of this finding. Using the CARIS 592 Gene Panel (Caris Life Sciences, Phoenix, AZ, USA), we analyzed 105 pre-NAC tumor specimens from a large multicenter trial (S1314) of either neoadjuvant gemcitabine and cisplatin (GC), or dose-dense methotrexate, vinblastine, Adriamycin, and cisplatin (DDMVAC). We found that a mutation in any one of these four genes predicted for pT0 at surgery (odds ratio = 5.36; 95% confidence interval [CI] 2.05, 14.02; two-sided p = 0.0006). The biomarker was better at predicting the presence of disease (negative predictive value for pT0 86%; 95% CI 73%, 94%) than the absence of disease (positive predictive value for pT0 48%; 95% CI 35%, 62%). There was no evidence of an interaction between the treatment arm (DDMVAC vs GC) and the genetic variant in terms of pT0. When combined with clinical assessment, these findings help inform patient selection for bladder preservation after cisplatin-based chemotherapy. PATIENT SUMMARY: A common standard of care for patients with muscle-invasive bladder cancer is neoadjuvant chemotherapy (NAC) followed by cystectomy to achieve cure. We previously discovered that specific DNA mutations in tumor samples collected at initial biopsy (transurethral resection of a bladder tumor) were predictive of a complete response to NAC. In other words, patients with these mutations were more likely to have a bladder found to be cancer free after surgery. In this study, we analyzed a larger set of tumor samples from a national clinical trial of chemotherapy followed by cystectomy to validate these earlier findings. We conclude that this biomarker test, when combined with careful clinical assessment, can be used to allocate patients to careful bladder surveillance instead of surgery. This hypothesis has been tested in the RETAIN trial presented previously (NCT02710734).Copyright © 2024 European Association of Urology. Published by Elsevier B.V. All rights reserved.