Introduction:

Mutation of the Kirsten rat sarcoma (KRAS) gene is a common oncogenic driver in many cancers. Recently, due to the capability of wide genomic screens, KRAS mutations have been identified in various genitourinary (GU) malignancies. Additionally, KRAS has recently emerged as a potential therapeutic target with the development of novel small molecule agents specifically targeting the KRAS G12C genomic alteration (GA). The objective of the present study was to perform comprehensive genomic analysis to identify opportunities for KRAS targeting in advanced GU malignancies. 

Methods:

The total cohort for the study consisted of over 12,000 patient samples of advanced GU cancers. 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) using standard methodology previously described by Foundation Medicine, Inc. Tumor mutational burden (TMB) was determined on 0.8 to 1.2 Mbp of sequenced DNA and microsatellite instability (MSI) was determined on 114 loci. PD-L1 expression (Dako 22C3) was measured by IHC.

Results:

Among study samples, urothelial bladder carcinomas had the highest frequency of GA in the KRAS gene with 5.2% showing alterations, followed by prostate cancer samples (1.9%), and RCC (<1%). Similar trends were observed when KRAS G12C was specifically examined; G12C mutations were observed in 2% of urothelial bladder carcinomas, <1% of prostate carcinoma, and none in RCC. There were no differences in age of the patients evaluated. Additionally, 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. 

Conclusion:

While KRAS G12C mutations are very rare in the major GU malignancies, a small proportion of such patients may benefit from emerging specific anti-KRAS G12C targeted therapies. Additionally, given the low prevalence of KRAS G12C mutations among major GU malignancies, investigation may be best approached in basket-type clinical trials using novel anti-KRAS G12C targeted therapies.

Funding: N/A