Molecular Subtypes Are Associated With Clinical Benefit in Cisplatin-Treated Metastatic Urothelial Cancer Patients.

IF 5.3 2区 医学 Q1 ONCOLOGY JCO precision oncology Pub Date : 2024-10-01 Epub Date: 2024-10-02 DOI:10.1200/PO.24.00209
Karin Holmsten, Gottfrid Sjödahl, Johan Abrahamsson, Carina Bernardo, Pontus Eriksson, Mattias Höglund, Fredrik Liedberg, Anders Ullén
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Abstract

Purpose: Cisplatin-based combination chemotherapy (CHT) is standard of care in metastatic urothelial cancer (mUC); however, no predictive molecular biomarkers are available for clinical use. The aim of this study was to investigate the impact of molecular subtypes in relation to treatment response and survival in patients with mUC treated with first-line CHT.

Patients and methods: Molecular subtype classification according to the Lund Taxonomy (LundTax) was performed by tumor transcriptomic profiling and immunostaining in a retrospective cohort. Molecular subtypes were investigated in relation to the primary end point overall response rate (ORR) and secondary end points progression-free survival (PFS) and overall survival (OS). Differential gene expression and association to treatment response were explored.

Results: Ninety-five patients with mUC were classified into urothelial-like (Uro, 43%), genomically unstable (GU, 26%), basal squamous-like (Ba/Sq, 20%), mesenchymal-like (Mes-like, 8%), and small cell neuroendocrine-like (Sc/NE, 3%) subtypes. Patients with Mes-like tumors had lower ORR (14%) compared with Uro (70%), GU (77%), Ba/Sq (75%), and Sc/NE (67%; odds ratio, 0.06 [95% CI, 0.01 to 0.54], P = .012). Furthermore, patients with Mes-like tumors had significantly shorter PFS (hazard ratio [HR], 5.18 [95% CI, 2.28 to 11.76], P < .001) and OS (HR, 3.19 [95% CI, 1.45 to 7.03], P = .004). Patients with Uro and GU showed the longest survival. In responders, an enrichment of downregulated stromal- and immune-related genes was seen. Downregulation of interferon-induced transmembrane protein 2 was associated with increased ORR and improved OS.

Conclusion: This study identifies different CHT responses by LundTax molecular subtypes in patients with mUC, where the Mes-like subtype was associated with lower response rate and shorter survival.

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分子亚型与顺铂治疗转移性尿路上皮癌患者的临床获益有关
目的:以顺铂为基础的联合化疗(CHT)是转移性尿路上皮癌(mUC)的标准治疗方法;然而,目前尚无可用于临床的预测性分子生物标记物。本研究旨在调查分子亚型对接受一线CHT治疗的mUC患者的治疗反应和生存期的影响:在一个回顾性队列中,通过肿瘤转录组学分析和免疫染色,根据隆德分类法(LundTax)进行分子亚型分类。研究了分子亚型与主要终点总反应率(ORR)及次要终点无进展生存期(PFS)和总生存期(OS)的关系。研究还探讨了基因表达的差异及其与治疗反应的关系:95名mUC患者被分为尿路上皮样(Uro,43%)、基因组不稳定(GU,26%)、基底鳞状细胞样(Ba/Sq,20%)、间质样(Mes,8%)和小细胞神经内分泌样(Sc/NE,3%)亚型。Mes样肿瘤患者的ORR(14%)低于Uro(70%)、GU(77%)、Ba/Sq(75%)和Sc/NE(67%;几率比为0.06 [95% CI, 0.01 to 0.54],P = .012)。此外,Mes 样肿瘤患者的 PFS(危险比 [HR],5.18 [95% CI,2.28 至 11.76],P < .001)和 OS(HR,3.19 [95% CI,1.45 至 7.03],P = .004)明显较短。泌尿系统和生殖系统疾病患者的生存期最长。在应答者中,基质和免疫相关基因的下调幅度较大。干扰素诱导跨膜蛋白2的下调与ORR增加和OS改善有关:这项研究发现了mUC患者中LundTax分子亚型的不同CHT反应,其中Mes样亚型与较低的反应率和较短的生存期相关。
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来源期刊
CiteScore
9.10
自引率
4.30%
发文量
363
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