Gil-Jimenez Alberto, van Dorp Jeroen, Contreras-Sanz Alberto, van der Vos Kristan, Vis Daniel J, Braaf Linde, Broeks Annegien, Kerkhoven Ron, van Kessel Kim E M, Ribal María José, Alcaraz Antonio, Wessels Lodewyk F A, Seiler Roland, Wright Jonathan L, Mengual Lourdes, Boormans Joost, van Rhijn Bas W G, Black Peter C, van der Heijden Michiel S
Department of Molecular Carcinogenesis, Netherlands Cancer Institute, Amsterdam, The Netherlands; Oncode Institute, Utrecht, The Netherlands.
Department of Molecular Carcinogenesis, Netherlands Cancer Institute, Amsterdam, The Netherlands.
Eur Urol. 2023 Apr;83(4):313-317. doi: 10.1016/j.eururo.2022.07.023. Epub 2022 Aug 11.
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.
对于肌层浸润性膀胱癌（MIBC）患者，推荐采用以顺铂为基础的新辅助化疗（NAC），然后进行根治性膀胱切除术。研究表明，ERCC2的体细胞有害突变、ERBB2的功能获得性突变以及ATM、RB1和FANCC的改变与MIBC患者对NAC的病理反应相关。本研究的目的是在一个由165例MIBC患者组成的独立回顾性队列的预处理经尿道切除材料中验证这些基因组生物标志物，这些患者随后接受了NAC和根治性手术。术后ypT0/Tis/Ta/T1N0疾病的患者被定义为反应者。在68例（13%）可评估的反应者中有9例发现ERCC2的体细胞有害突变，在95例（2%）可评估的无反应者中有2例发现（p = 0.009；FDR = 0.03）。未观察到反应与ERBB2或ATM、RB1或FANCC单独或联合改变之间的相关性。在探索性分析中，没有其他基因组改变能区分NAC的反应者和无反应者。在上述生物标志物与术后病理完全缓解（ypT0N0）之间未发现进一步的关联。总之，我们观察到ERCC2的有害突变与对NAC的病理反应之间存在正相关，但与总生存期或无复发生存期无关。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在膀胱癌确定性手术前会对化疗有反应。先前的研究描述了膀胱癌中几种与化疗反应相关的基因突变。本研究证实，ERCC2基因突变的膀胱癌患者通常对化疗有反应。
