Comprehensive genomic profiling of histologic subtypes of urethral carcinomas.

Abstract Background Carcinoma of the urethra (UrthCa) is an uncommon Genitourinary (GU) malignancy that can progress to advanced metastatic disease. Methods One hundred twenty-seven metastatic UrthCa underwent hybrid capture-based comprehensive genomic profiling to evaluate all classes of genomic alterations (GA). Tumor mutational burden was determined on up to 1.1 Mbp of sequenced DNA, and microsatellite instability was determined on 114 loci. PD-L1 expression was determined by IHC (Dako 22C3). Results Forty-nine (39%) urothelial (UrthUC), 31 (24%) squamous (UrthSCC), 24 (19%) adenocarcinomas NOS (UrthAC), and 12 (9%) clear cell (UrthCC) were evaluated. UrthUC and UrthSCC are more common in men; UrthAC and UrthCC are more common in women. Ages were similar in all 4 groups. GA in PIK3CA were the most frequent potentially targetable GA; mTOR pathway GA in PTEN were also identified. GA in other potentially targetable genes were also identified including ERBB2 (6% in UrthUC, 3% in UrthSCC, and 12% in UrthAC), FGFR1-3 (3% in UrthSCC), BRAF (3% in UrthAC), PTCH1 (8% in UrthCC), and MET (8% in UrthCC). Possibly reflecting their higher GA/tumor status, potential for immunotherapy benefit associated with higher tumor mutational burden and PD-L1 staining levels were seen in UrthUC and UrthSCC compared to UrthAC and UrthCC. Microsatellite instability high status was absent throughout. Conclusions Comprehensive genomic profiling reveals GA that may be predictive of both targeted and immunotherapy benefit in patients with advanced UrthCa and that could potentially be used in future adjuvant, neoadjuvant, and metastatic disease trials.