The Emerging Target Kras G12c In Genitourinary Malignancies

434 Background: KRAS has recently emerged as a druggable driver with novel agents targeting G12C genomic alteration (GA). Methods: FFPE tissue from 1453 renal clear cell carcinomas (RCCC), 3879 urothelial bladder carcinomas (UBC) and 8322 prostate acinar adenocarcinomas (PAAC) underwent comprehensive genomic profiling (CGP). Tumor mutational burden (TMB) was determined on 0.8 to 1.2 Mbp of sequenced DNA and MSI was determined on 114 loci. PD-L1 expression (Dako 22C3) was measured by IHC. Results: KRAS GA were identified in 7 RCCC (<1%), 202 UBC (5.2%), and 158 PAAC (1.9%). KRAS G12C mutations were observed in 0 RCCC, 24 (2%) of UBC, and 1 (<1%) PAAC. Age/gender distributions were similar. VHL, SETD2, and PBRM1 mutations were the most frequent concurrent GA in the 7 RCCC with KRAS G12C GA. In KRAS G12C mutated UBC, co-mutations in TERT were significantly reduced and in KDM6A were significantly increased (both p<0.05) in cases with KRAS G12C GA versus KRAS G12C negative tumors. Conclusions: KRAS G12C mutations are extremely rare in the major genitourinary malignancies. However, given the emerging interest in identifying KRAS G12C for potential basket-type clinical trials using novel anti-KRAS G12C targeted therapies, further study of these alterations in genitourinary malignancies, especially bladder and prostatic carcinomas, appears warranted.[Table: see text]