我们以前报道过具有四种基因突变(ATM,RB1,FANCC,或ERCC2)可能对基于顺铂的新辅助化疗(NAC)有反应,导致在膀胱切除术时(pT0)的无癌手术标本。这里,我们报告我们对这一发现的验证。使用CARIS592基因面板(卡利斯生命科学,凤凰城,AZ,美国),我们分析了来自一项新辅助吉西他滨和顺铂(GC)的大型多中心试验(S1314)的105个NAC前肿瘤标本,或者剂量密集的甲氨蝶呤,长春碱,阿霉素,和顺铂(DDMVAC)。我们发现这四个基因中的任何一个在手术时预测pT0的突变(比值比=5.36;95%置信区间[CI]2.05,14.02;双侧p=0.0006)。生物标志物在预测疾病的存在方面更好(pT0的阴性预测值86%;95%CI73%,94%)比没有疾病(pT0的阳性预测值48%;95%CI35%,62%)。就pT0而言,没有证据表明治疗臂(DDMVACvsGC)与遗传变异之间存在相互作用。当与临床评估相结合时,这些发现有助于患者选择顺铂为基础的化疗后保留膀胱.患者总结: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。我们先前发现,在初次活检(经尿道膀胱肿瘤切除术)时收集的肿瘤样品中的特定DNA突变可以预测对NAC的完全反应。换句话说,有这些突变的患者在手术后发现膀胱无癌的可能性更大.在这项研究中,我们分析了一组更大的肿瘤样本,这些样本来自一项化疗后膀胱切除术的国家临床试验,以验证这些早期发现.我们得出结论,这种生物标志物测试,当结合仔细的临床评估,可用于将患者分配给仔细的膀胱监测,而不是手术。这一假设已在先前提出的RETAIN试验(NCT02710734)中得到检验。
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).