Somatic alterations of TP53 and MDM2 associated with response to enfortumab vedotin in patients with advanced urothelial cancer.
Somatic alterations of TP53 and MDM2 associated with response to enfortumab vedotin in patients with advanced urothelial cancer.
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DOI：
10.3389/fonc.2023.1161089
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发表时间：
2023
影响因子：
4.7
通讯作者：
中科院分区：
文献类型：
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作者：
Enfortumab vedotin （EV）是一种被批准用于治疗难治性晚期尿路上皮癌（aUC）患者的抗体-药物偶联物，然而缺乏生物标志物的应答数据。我们回顾性地确定了我院所有接受EV单药治疗并有下一代测序（NGS）数据的aUC患者。如果患者在治疗期间的重新扫描中有完全反应或部分反应，则认为患者有反应。观察有效率（ORR）由当地调查员评估，并采用卡方检验比较反应者和无反应者。采用Cox比例风险试验进行单变量分析，以评估基线特征和最常见的躯体改变（≥10%的患者）与患者生存结局[无进展生存期（PFS）和总生存期（OS）]之间的关系。然后在单独的多变量模型中单独评估体细胞改变，同时使用Cox回归模型考虑患者和临床特征。在29例接受EV单药治疗的患者中，27例有可用的NGS数据。中位年龄为70岁，男性24例（83%），白种人19例（62%），纯尿路上皮组织学15例（52%），膀胱原发肿瘤22例（76%）。ORR为41%，总体队列的PFS和OS分别为5.1个月和10.2个月。在TP53、KDM6A和MDM2改变的患者中，应答者较多。有这些改变的患者，以及TP53/MDM2复合改变的患者（TP53或MDM2的改变），与没有这些改变的患者相比，EV治疗的ORR也增加了。在单变量分析中，基线白蛋白水平≥3.0g/dL和TP53/MDM2复合改变的存在与延长的OS相关。基线ECOG 0/1、TP53改变和TP53/MDM2改变与PFS延长相关。在多变量分析中，考虑到相关临床特征后，TP53和TP53/MDM2改变是预测PFS改善的基因组标记。在这项对接受EV治疗的aUC患者的单中心回顾性分析中，存在TP53或MDM2体细胞改变、较低的ECOG PS评分（ECOG 0或1）和较高的白蛋白水平（≥3 g/dL）与EV治疗的改善结果相关。在更大的队列中对这些发现进行前瞻性和外部验证是有必要的。
Enfortumab vedotin (EV) is an antibody-drug conjugate approved for patients with treatment-refractory advanced urothelial carcinoma (aUC), however data on biomarkers of response is lacking. We retrospectively identified all aUC patients at our institution who received EV monotherapy and had next-generation sequencing (NGS) data available. Patients were considered responders if they had a complete response or partial response on restaging scans during treatment. Observed response rate (ORR) was evaluated by local investigator and compared between responders and non-responders using Chi-squared test. A univariable analysis was conducted using the Cox proportional hazard test to assess for associations between baseline characteristics and most common somatic alterations (in ≥10% of patients) with patient survival outcomes [progression-free survival (PFS) and overall survival (OS)]. Somatic alterations were then individually evaluated in separate multivariate models while accounting for patient and clinical characteristics using Cox regression models. Among 29 patients treated with EV monotherapy, 27 had available NGS data. Median age was 70, 24 (83%) were men, 19 (62%) were Caucasian, 15 (52%) had pure urothelial histology and 22 (76%) had primary tumor in the bladder. ORR was 41%, and PFS and OS for the overall cohort were 5.1 months and 10.2 months. Responders were enriched among patients with TP53, KDM6A and MDM2 alterations. Patients with these alterations, as well as those with composite TP53/MDM2 alterations (alterations in either TP53 or MDM2), also had increased ORR with EV treatment compared to patients without these alterations. In the univariable analysis, baseline albumin level ≥ 3.0g/dL and presence of composite TP53/MDM2 alterations were associated with a prolonged OS. Baseline ECOG 0/1, TP53 alterations and TP53/MDM2 alterations were associated with a prolonged PFS. In the multivariable analysis, TP53 and TP53/MDM2 alterations were genomic markers predictive of improved PFS after accounting for the relevant clinical characteristics. In this single-center retrospective analysis of aUC patients treated with EV, presence of TP53 or MDM2 somatic alterations, lower ECOG PS scores (ECOG 0 or 1) and higher albumin levels (≥3 g/dL) were associated with improved outcomes with EV treatment. Prospective and external validation of these findings in larger cohorts is warranted.
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影响因子：
7.3
作者：
Gao J;Aksoy BA;Dogrusoz U;Dresdner G;Gross B;Sumer SO;Sun Y;Jacobsen A;Sinha R;Larsson E;Cerami E;Sander C;Schultz N
通讯作者：
Schultz N
铂衰竭后转移性尿路上皮癌的AVELUMAB（标枪实体瘤）：汇总的结果是两个开放标签1期试验的两个膨胀队列的结果。
DOI：
10.1016/s1470-2045(17)30900-2
发表时间：
2018-01
期刊：
The Lancet. Oncology
影响因子：
--
作者：
Patel MR;Ellerton J;Infante JR;Agrawal M;Gordon M;Aljumaily R;Britten CD;Dirix L;Lee KW;Taylor M;Schöffski P;Wang D;Ravaud A;Gelb AB;Xiong J;Rosen G;Gulley JL;Apolo AB
通讯作者：
Apolo AB
影响因子：
45.3
作者：
Bellmunt, Joaquim;Choueiri, Toni K.;Rosenberg, Jonathan E.
通讯作者：
Rosenberg, Jonathan E.
DOI：
10.1056/nejmoa2034442
发表时间：
2021-06-03
期刊：
The New England journal of medicine
影响因子：
--
作者：
Bajorin DF;Witjes JA;Gschwend JE;Schenker M;Valderrama BP;Tomita Y;Bamias A;Lebret T;Shariat SF;Park SH;Ye D;Agerbaek M;Enting D;McDermott R;Gajate P;Peer A;Milowsky MI;Nosov A;Neif Antonio J Jr;Tupikowski K;Toms L;Fischer BS;Qureshi A;Collette S;Unsal-Kacmaz K;Broughton E;Zardavas D;Koon HB;Galsky MD
通讯作者：
Galsky MD
影响因子：
4.7
作者：
Natesan D;Zhang L;Martell HJ;Jindal T;Devine P;Stohr B;Espinosa-Mendez C;Grenert J;Van Ziffle J;Joseph N;Umetsu S;Onodera C;Turski M;Chan E;Desai A;Aggarwal R;Wong A;Porten S;Chou J;Friedlander T;Fong L;Small EJ;Sweet-Cordero A;Koshkin VS
通讯作者：
Koshkin VS