浸润性膀胱癌的预后标志物：FGFR3突变状态与P53和KI-67表达的比较：一项针对1058例根治性膀胱切除术患者的多中心、多实验室分析
Prognostic markers in invasive bladder cancer: FGFR3 mutation status versus P53 and KI-67 expression: a multi-center, multi-laboratory analysis in 1058 radical cystectomy patients.
作者信息
Mertens Laura S, Claps Francesco, Mayr Roman, Bostrom Peter J, Shariat Shahrokh F, Zwarthoff Ellen C, Boormans Joost L, Abas Cheno, van Leenders Geert J L H, Götz Stefanie, Hippe Katrin, Bertz Simone, Neuzillet Yann, Sanders Joyce, Broeks Annegien, Peters Dennis, van der Heijden Michiel S, Jewett Michael A S, Stöhr Robert, Zlotta Alexandre R, Eckstein Markus, Soorojebally Yanish, van der Schoot Deric K E, Wullich Bernd, Burger Maximilian, Otto Wolfgang, Radvanyi François, Sirab Nanour, Pouessel Damien, van der Kwast Theo H, Hartmann Arndt, Lotan Yair, Allory Yves, Zuiverloon Tahlita C M, van Rhijn Bas W G
机构信息
Dept. Urology, Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands.
Dept. Urology, Caritas St Josef Medical Center, University of Regensburg, Regensburg, Germany.
出版信息
Urol Oncol. 2022 Mar;40(3):110.e1-110.e9. doi: 10.1016/j.urolonc.2021.10.010. Epub 2021 Dec 11.
OBJECTIVES
To determine the association between the FGFR3 mutation status and immuno-histochemistry (IHC) markers (p53 and Ki-67) in invasive bladder cancer (BC), and to analyze their prognostic value in a multicenter, multi-laboratory radical cystectomy (RC) cohort.
PATIENTS AND METHODS
We included 1058 cN0M0, chemotherapy-naive BC patients who underwent RC with pelvic lymph-node dissection at 8 hospitals. The specimens were reviewed by uro-pathologists. Mutations in the FGFR3 gene were examined using PCR-SNaPshot; p53 and Ki-67 expression were determined by standard IHC. FGFR3 mutation status as well as p53 (cut-off>10%) and Ki-67 (cut-off>20%) expression were correlated to clinicopathological parameters and disease specific survival (DSS).
RESULTS
pT-stage was <pT2 in 80, pT2 in 266, pT3 in 513 and pT4 in 199 patients, respectively. Cancer-positive nodes were found in 410 (39%) patients. An FGFR3 mutation was detected in 107 (10%) and aberrant p53 and Ki-67 expression in 718 (68%) and 581(55%) tumors, respectively. The FGFR3 mutation was associated with lower pT-stage (P<0.001), lower grade (P<0.001), pN0 (P=0.001) and prolonged DSS (P<0.001). Aberrant Ki-67 and p53 expression were associated with higher pT-stage and G3-tumors, but not with pN-stage or worse DSS, even if these IHC-biomarkers were combined (P=0.81). Significant predictors for DSS in multivariable analysis were pT-stage (HR1.5, 95%CI:1.3-1.6; P<0.001), lympho-vascular invasion (LVI) (HR1.4, 95%CI:1.2-1.7; P=0.001), pN-stage (HR1.9, 95%CI:1.6-2.4; P<0.001) and FGFR3 mutation status (HR1.6, 95%CI:1.1-2.2; P=0.011).
CONCLUSION
The FGFR3 mutation selectively identified patients with favorable BC at RC while p53 and Ki-67 were only associated with adverse tumor characteristics. Our results suggest that, besides tumor-stage, nodal-status and LVI, the oncogenic FGFR3 mutation may represent a valuable tool to guide adjuvant treatment and follow-up strategies after RC.
目的
确定浸润性膀胱癌（BC）中FGFR3突变状态与免疫组织化学（IHC）标志物（p53和Ki-67）之间的关联，并分析它们在多中心、多实验室根治性膀胱切除术（RC）队列中的预后价值。
患者与方法
我们纳入了1058例cN0M0、未接受过化疗的BC患者，这些患者在8家医院接受了RC及盆腔淋巴结清扫术。标本由泌尿病理学家进行复查。使用PCR-SNaPshot检测FGFR3基因的突变；通过标准IHC测定p53和Ki-67的表达。FGFR3突变状态以及p53（临界值>10%）和Ki-67（临界值>20%）的表达与临床病理参数和疾病特异性生存（DSS）相关。
结果
分别有80例、266例、513例和199例患者的pT分期<pT2、pT2、pT3和pT4。410例（39%）患者发现癌阳性淋巴结。107例（10%）肿瘤检测到FGFR3突变，分别有718例（68%）和581例（55%）肿瘤存在p53和Ki-67异常表达。FGFR3突变与较低的pT分期（P<0.001）、较低分级（P<0.001）、pN0（P=0.001）和较长的DSS（P<0.001）相关。Ki-67和p53异常表达与较高的pT分期和G3肿瘤相关，但与pN分期或更差的DSS无关，即使将这些IHC生物标志物联合起来也是如此（P=0.81）。多变量分析中DSS的显著预测因素为pT分期（HR1.5，95%CI：1.3 - 1.6；P<0.001）、淋巴管浸润（LVI）（HR1.4，95%CI：1.2 - 1.7；P=0.001）、pN分期（HR1.9，95%CI：1.6 - 2.4；P<0.001）和FGFR3突变状态（HR1.6，95%CI：1.1 - 2.2；P=0.011）。
结论
FGFR3突变可选择性地识别出RC时BC预后良好的患者，而p53和Ki-67仅与不良肿瘤特征相关。我们的结果表明，除了肿瘤分期、淋巴结状态和LVI外，致癌性FGFR3突变可能是指导RC术后辅助治疗和随访策略的有价值工具。
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