Cisplatin-based neoadjuvant chemotherapy (NAC) followed by radical cystectomy is recommended for patients with muscle-invasive bladder cancer (MIBC). It has been shown that somatic deleterious mutations in ERCC2, gain-of-function mutations in ERBB2, and alterations in ATM, RB1, and FANCC are correlated with pathological response to NAC in MIBC. The objective of this study was to validate these genomic biomarkers in pretreatment transurethral resection material from an independent retrospective cohort of 165 patients with MIBC who subsequently underwent NAC and radical surgery. Patients with ypT0/Tis/Ta/T1N0 disease after surgery were defined as responders. Somatic deleterious mutations in ERCC2 were found in nine of 68 (13%) evaluable responders and two of 95 (2%) evaluable nonresponders (p = 0.009; FDR = 0.03). No correlation was observed between response and alterations in ERBB2 or in ATM, RB1, or FANCC alone or in combination. In an exploratory analysis, no additional genomic alterations discriminated between responders and nonresponders to NAC. No further associations were identified between the aforementioned biomarkers and pathological complete response (ypT0N0) after surgery. In conclusion, we observed a positive association between deleterious mutations in ERCC2 and pathological response to NAC, but not overall survival or recurrence-free survival. Other previously reported genomic biomarkers were not validated.

Patient summary

It is currently unknown which patients will respond to chemotherapy before definitive surgery for bladder cancer. Previous studies described several gene mutations in bladder cancer that correlated with chemotherapy response. This study confirmed that patients with bladder cancer with a mutation in the ERCC2 gene often respond to chemotherapy.

中文翻译：

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评估预测性基因组生物标志物对膀胱癌中基于顺铂的新辅助化疗的反应

推荐对肌肉浸润性膀胱癌 (MIBC) 患者进行基于顺铂的新辅助化疗 (NAC)，然后进行根治性膀胱切除术。已经表明，ERCC2 中的体细胞有害突变、ERBB2中的功能获得性突变以及ATM、RB1和FANCC中的改变与 MIBC 中对 NAC 的病理反应相关。本研究的目的是验证这些基因组生物标志物在预处理经尿道切除材料中的有效性，这些材料来自 165 名随后接受 NAC 和根治性手术的 MIBC 患者的独立回顾性队列。手术后患有 ypT0/Tis/Ta/T1N0 疾病的患者被定义为反应者。ERCC2中的体细胞有害突变在 68 名可评估的反应者中有 9 名 (13%) 和 95 名可评估的无反应者中有两名 ( p  = 0.009；FDR = 0.03)。在ERBB2或ATM、RB1或FANCC单独或组合的反应和改变之间没有观察到相关性。在探索性分析中，没有额外的基因组改变区分对 NAC 的反应者和无反应者。上述生物标志物与手术后病理完全缓解 (ypT0N0) 之间未发现进一步关联。总之，我们观察到ERCC2中的有害突变之间存在正相关和对 NAC 的病理反应，但不是总生存期或无复发生存期。其他先前报道的基因组生物标志物未得到验证。

患者总结

目前尚不清楚哪些患者会在膀胱癌根治性手术前对化疗产生反应。先前的研究描述了膀胱癌中与化疗反应相关的几种基因突变。这项研究证实，具有ERCC2基因突变的膀胱癌患者通常对化疗有反应。