Clinical and Genomic Landscape of FGFR3-Altered Urothelial Carcinoma and Treatment Outcomes with Erdafitinib: A Real-World Experience.
Clinical and Genomic Landscape of FGFR3-Altered Urothelial Carcinoma and Treatment Outcomes with Erdafitinib: A Real-World Experience.
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FGFR3 改变的尿路上皮癌的临床和基因组景观以及 Erdafitinib 的治疗结果：真实世界的经验。
DOI：
10.1158/1078-0432.ccr-23-1283
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Lenis,Andr
中科院分区：
文献类型：
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作者：
Guercio,BrendanJ;Sarfaty,Michal;Teo,MinYuen;Ratna,Neha;Duzgol,Cihan;Funt,SamuelA;Lee,Chung-Han;Aggen,DavidH;Regazzi,AshleyM;Chen,Ziyu;Lattanzi,Michael;Al-Ahmadie,HikmatA;Brannon,ARose;Shah,Ronak;Chu,Carissa;Lenis,Andr
目的Erdafitinib是FDA批准的治疗FGFR2/3基因改变的转移性尿路上皮癌的唯一靶向疗法。我们描述了FGFR基因改变的尿路上皮癌的遗传图景和使用厄达非替尼的真实世界的临床结果，包括正在治疗的基因组进化。实验设计前瞻性收集的临床数据与机构基因组数据整合，以定义FGFR2/3改变的尿路上皮癌图景。结果39%(199/504)的非肌肉侵袭性肿瘤患者、14%(75/526)的肌肉侵袭性肿瘤患者、43%(81/187)的上尿路肿瘤患者和26%(59/228)的转移性肿瘤患者存在预测厄达非替尼敏感性的FGFR3改变。一名患者有潜在的致敏FGFR2融合。在27例原发肿瘤和异时转移的FGFR3改变的病例中，7对标本(26%)显示FGFR3状态不一致。Erdafitinib的有效率为40%，但中位无进展生存期和总生存期分别为2.8个月和6.6个月(n=32)。剂量减少(38%，12/32)和中断(50%，16/32)是常见的。CfDNA中可能的耐药突变包括TP53(n=5)、AKT1(n=1)和FGFR3第二位点突变(n=2)。结论FGFR3突变在尿路上皮癌中常见，而FGFR2突变很少见。原发肿瘤和转移性肿瘤之间FGFR3突变状态的不一致经常发生，并引起了人们对原发肿瘤测序的关注，以指导患者选择厄达菲替尼治疗。Erdafitinib的反应通常很短，剂量受到毒性的限制。在cfDNA中检测到的FGFR3、AKT1和TP53突变代表获得性厄达非替尼耐药的可能机制。
PurposeErdafitinib is the only FDA-approved targeted therapy for FGFR2/3-altered metastatic urothelial cancer. We characterized the genetic landscape of FGFR-altered urothelial carcinoma and real-world clinical outcomes with erdafitinib, including on-treatment genomic evolution.Experimental DesignProspectively collected clinical data were integrated with institutional genomic data to define the landscape of FGFR2/3-altered urothelial carcinoma. To identify mechanisms of erdafitinib resistance, a subset of patients underwent prospective cell-free (cf) DNA assessment.ResultsFGFR3 alterations predictive of erdafitinib sensitivity were identified in 39% (199/504) of patients with non-muscle invasive, 14% (75/526) with muscle-invasive, 43% (81/187) with localized upper tract, and 26% (59/228) with metastatic specimens. One patient had a potentially sensitizing FGFR2 fusion. Among 27 FGFR3-altered cases with a primary tumor and metachronous metastasis, 7 paired specimens (26%) displayed discordant FGFR3 status. Erdafitinib achieved a response rate of 40% but median progression-free and overall survival of only 2.8 and 6.6 months, respectively (n= 32). Dose reductions (38%, 12/32) and interruptions (50%, 16/32) were common. Putative resistance mutations detected in cfDNA involved TP53 (n= 5), AKT1 (n= 1), and second-site FGFR3 mutations (n= 2).ConclusionsFGFR3 mutations are common in urothelial carcinoma, whereas FGFR2 alterations are rare. Discordance of FGFR3 mutational status between primary and metastatic tumors occurs frequently and raises concern over sequencing archival primary tumors to guide patient selection for erdafitinib therapy. Erdafitinib responses were typically brief and dosing was limited by toxicity. FGFR3, AKT1, and TP53 mutations detected in cfDNA represent putative mechanisms of acquired erdafitinib resistance.