ASCO GU 2020: Comprehensive Genomic Profiling of Histologic Subtypes of Urethral Carcinomas

San Francisco, California ( Urethral carcinomas are rare amongst genitourinary cancers, with limited systemic treatment options. Metastatic disease, in general, responds poorly to therapy, but responses are seen with certain chemotherapy combinations such as cisplatin and fluorouracil, MVAC, or paclitaxel and ifosfamide. Limited prospective studies have been done in the space, and genomic analysis to understand putative drivers has so far been lacking. In this study, the authors undertook genomic profiling of 127 metastatic urethral carcinomas using a hybrid-capture based assay. In addition to searching for oncogenic driver mutations, they analyzed tumor mutations burden, microsatellite instability, and also performed immunohistochemistry for PD-L1 tumor expression.

Multiple urethral carcinoma histologies were captured in this study, with 49 urothelial carcinomas, 31 squamous carcinomas, 34 adenocarcinoma, and 13 clear cell samples. Men tended to have urothelial and squamous carcinomas, women tended to have adenocarcinoma or clear cell carcinomas. Patient age was balanced amongst histology.

Numerous alterations in both targetable and non-targetable oncogenic drivers were discovered, some in common across histological subtype. The most common potentially targetable alteration were mutations in PIK3CA. FGFR3 alterations were seen in multiple histologic subtypes as well.


A subset of urothelial and squamous carcinomas showed high levels of tumor mutational burden. Only urothelial and squamous carcinomas had evidence of HPV16/18 involvement.


While an important first step in understanding genomic drivers and potential targeted therapies in this uncommon and difficult to treat cancer, genomic alterations were not called using patient normal tissue as a comparator. It is therefore not possible to know if these alterations are germline and somatic, and further analysis is required before exploring targeted therapies as part of clinical trials in this disease. 

Presented by: Joseph Jacob, MD, Assistant Professor of Urology, Upstate Medical University, Syracuse, New York

Written by: Alok Tewari, MD, PhD, Medical Oncology Fellow at the Dana-Farber Cancer Institute, at the 2020 Genitourinary Cancers Symposium, ASCO GU #GU20, February 13-15, 2020, San Francisco, California

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