Comprehensive Genomic Profiling of Upper-tract and Bladder Urothelial Carcinoma.

Characterization of the different genomic alterations (GAs) in urothelial carcinoma (UC), by site of origin, may identify contrasting therapeutic opportunities and inform distinct putative pathogenetic mechanisms.

To describe the genomic landscape of UC based on the anatomic site of the primary tumor.

In total, 479 upper tract UC (UTUC) and 1984 bladder UC (BUC) patients underwent comprehensive genomic profiling (CGP) to evaluate all classes of GAs, tumor mutational burden (TMB), and microsatellite instability (MSI) status. Targetable GAs and signatures were assessed according to the European Society for Medical Oncology Scale for Clinical Actionability of molecular Targets (ESCAT).

Hybrid-capture-based CGP.

Descriptive analyses and differences between anatomic subgroups were reported.

In total, 39% of patients with UC harbored one or more tier 1-2 GAs, suggesting potential benefit from approved or investigational therapies. UTUC cases were enriched in FGFR3 short variant (SV) GA (20% vs 13%) and HRAS SV GA (7.3% vs 3%), the latter attributed specifically to enrichment in renal pelvis UC (9.5%) versus ureteral UC (1.8%, p=0.002). RB1 GAs were more frequent in BUC than in UTUC (21% vs 7.8% p<0.001). Non-FGFR3 kinase fusions were observed in 1% of patients, including BRAF/RAF1 fusions in 0.5%. BRAF mutations/fusions were observed in 2% of cases and were mutually exclusive with FGFR3 GA (p=0.002). There were no differences of TMB high/MSI high for primary tumor and metastatic sites, but UTUC was enriched for MSI high (3.4%) relative to BUC (0.8%, p<0.001).

Differences in the genomic landscapes of UTUC and BUC were modest; however, patients with UTUC were enriched for FGFR3 and HRAS SV relative to BUC. Further investigation on UC, stratified by the site of origin, is warranted. In addition, these results suggest an opportunity for the routine incorporation of CGP prior to systemic therapy initiation in metastatic UC.

Genomic profiling of advanced urothelial carcinoma can inform several therapeutic opportunities for patients, particularly those with upper tract urothelial carcinoma, an infrequent and generally aggressive tumor entity with nonoverlapping clinical features compared with its bladder counterpart, which is often treated based on the data extrapolated from bladder cancer.

European urology focus. 2020 Aug 26 [Epub ahead of print]

Andrea Necchi, Russell Madison, Sumanta K Pal, Jeffrey S Ross, Neeraj Agarwal, Guru Sonpavde, Monika Joshi, Ming Yin, Vincent A Miller, Petros Grivas, Jon H Chung, Siraj M Ali

Fondazione IRCCS-Istituto Nazionale dei Tumori, Milan, Italy. Electronic address: ., Foundation Medicine, Inc., Cambridge, MA, USA., City of Hope Comprehensive Cancer Center, Duarte, CA, USA., Foundation Medicine, Inc., Cambridge, MA, USA; Upstate Medical University, Syracuse, NY, USA., Huntsman Cancer Institute and University of Utah, Salt Lake City, UT, USA., Dana Farber Cancer Institute, Boston, MA, USA., Penn State Cancer Institute, Hershey, PA, USA., The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA., University of Washington, Seattle Cancer Care Alliance, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.