Carissa E. Chu, Ziyu Chen, Karissa Whiting, Irina Ostrovnaya, Andrew T. Lenis, Timothy N. Clinton, Rayan Rammal, Gamze Gokturk Ozcan, Dilara Akbulut, Merve Basar, Jie-Fu Chen, Ying-Bei Chen, Anuradha Gopalan, Samson W. Fine, Satish K. Tickoo, Maria Arcila, A. Rose Brannon, Michael F. Berger, Eugene K. Cha, Alvin C. Goh, Hikmat Al-Ahmadie
{"title":"Clinical Outcomes, Genomic Heterogeneity, and Therapeutic Considerations Across Histologic Subtypes of Urothelial Carcinoma","authors":"Carissa E. Chu, Ziyu Chen, Karissa Whiting, Irina Ostrovnaya, Andrew T. Lenis, Timothy N. Clinton, Rayan Rammal, Gamze Gokturk Ozcan, Dilara Akbulut, Merve Basar, Jie-Fu Chen, Ying-Bei Chen, Anuradha Gopalan, Samson W. Fine, Satish K. Tickoo, Maria Arcila, A. Rose Brannon, Michael F. Berger, Eugene K. Cha, Alvin C. Goh, Hikmat Al-Ahmadie","doi":"10.1016/j.eururo.2025.04.008","DOIUrl":null,"url":null,"abstract":"<h3>Background and objective</h3>Divergent differentiation and histologic subtypes are common findings in urothelial carcinoma (UC). Clinically relevant genomic alterations and oncogenic drivers of individual subtypes remain poorly defined. We characterized surgical outcomes and the genomic landscape of UC with aberrant histology (UCAH), with a focus on biomarkers and targetable alterations.<h3>Methods</h3>The clinical cohort comprised 3052 patients who underwent radical cystectomy (RC) with or without neoadjuvant chemotherapy. Targeted exon sequencing was performed for a genomic cohort of 1060 bladder tumors from RC or transurethral resection specimens. We characterized the frequency of oncogenic mutations and targetable alterations, and the tumor mutational burden (TMB) of each subtype. We defined the clonal relatedness of morphologically distinct regions of tumors with mixed histology.<h3>Key findings and limitations</h3>Patients with plasmacytoid, micropapillary, sarcomatoid, or mixed-histology tumors had worse cancer-specific survival than patients with pure urothelial histology. <em>ERBB2, FGFR3,</em> and <em>PTEN</em> alterations were most frequent in micropapillary, nested/squamous, and sarcomatoid UC, respectively. TMB was highest in plasmacytoid, neuroendocrine, and micropapillary tumors. Regions of mixed histology had shared clonal origins, but exceptions were observed. The retrospective design and potential for selection bias are limitations of our study.<h3>Conclusions and clinical implications</h3>UCAH tumors have distinct patterns of genomic alterations, which may be targetable via novel therapies and have implications for clinical trial inclusion. Biomarker-driven systemic therapy should be explored in patients with histologic subtypes that are associated with worse clinical outcomes.","PeriodicalId":12223,"journal":{"name":"European urology","volume":"55 1","pages":""},"PeriodicalIF":25.3000,"publicationDate":"2025-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"European urology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.eururo.2025.04.008","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"UROLOGY & NEPHROLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Background and objective
Divergent differentiation and histologic subtypes are common findings in urothelial carcinoma (UC). Clinically relevant genomic alterations and oncogenic drivers of individual subtypes remain poorly defined. We characterized surgical outcomes and the genomic landscape of UC with aberrant histology (UCAH), with a focus on biomarkers and targetable alterations.
Methods
The clinical cohort comprised 3052 patients who underwent radical cystectomy (RC) with or without neoadjuvant chemotherapy. Targeted exon sequencing was performed for a genomic cohort of 1060 bladder tumors from RC or transurethral resection specimens. We characterized the frequency of oncogenic mutations and targetable alterations, and the tumor mutational burden (TMB) of each subtype. We defined the clonal relatedness of morphologically distinct regions of tumors with mixed histology.
Key findings and limitations
Patients with plasmacytoid, micropapillary, sarcomatoid, or mixed-histology tumors had worse cancer-specific survival than patients with pure urothelial histology. ERBB2, FGFR3, and PTEN alterations were most frequent in micropapillary, nested/squamous, and sarcomatoid UC, respectively. TMB was highest in plasmacytoid, neuroendocrine, and micropapillary tumors. Regions of mixed histology had shared clonal origins, but exceptions were observed. The retrospective design and potential for selection bias are limitations of our study.
Conclusions and clinical implications
UCAH tumors have distinct patterns of genomic alterations, which may be targetable via novel therapies and have implications for clinical trial inclusion. Biomarker-driven systemic therapy should be explored in patients with histologic subtypes that are associated with worse clinical outcomes.
期刊介绍:
European Urology is a peer-reviewed journal that publishes original articles and reviews on a broad spectrum of urological issues. Covering topics such as oncology, impotence, infertility, pediatrics, lithiasis and endourology, the journal also highlights recent advances in techniques, instrumentation, surgery, and pediatric urology. This comprehensive approach provides readers with an in-depth guide to international developments in urology.