Genomic landscape of KRAS mutations: A retrospective clinico-genomic database analysis.

e15085 Background: Since the approval of KRAS G12C inhibitors, there is ongoing interest in trials for combination treatments with these agents beyond lung cancer, KRAS G12D and pan-RAS inhibitors. In this context, we present the genomic landscape of KRAS mutations to inform future clinical studies. Methods: We searched the American Association for cancer research project genomics evidence neoplasia information exchange (AACR GENIE) version 19.0, for distribution of KRAS mutations across tumor types, race and sex; as well as mutation subtypes, copy number alterations (CNA), and co-mutations. For patients with multiple samples, only one was retained. The data was filtered for p-value 2 or 99%). 52.1% of these were females, 63.1% white and 6.6% were black. 54% of mutated samples were from primary tumors and 31% from metastatic sites. The most common cancers with KRAS alterations were colorectal cancer (CRC) (26.8%), pancreatic cancer (PAC) (24.7%), non-small cell lung cancer (NSCLC) (23.3%), endometrial cancer (4.6%) and cancer of unknown primary (3.9%). 584 different KRAS variants were identified. The most common alterations were G12D, G12V, and G12C in both sexes, with females harboring more G12C and males more G12D. Similarly, Asians were ore enriched in G12D and G13D compared to black and white patients but the p values were not statistically significant due to smaller representation of minority races in the data. Most common KRAS mutations in NSCLC were G12C, G12V, G12D and G12F. Most common KRAS mutations in pancreatic cancer were G12D, G12V, G12R and Q61H. The frequencies of relevant co-mutations in CRC, PAC and NSCLC are described in the table. Relevant CNA observed were FLT1/3, MYC, BRCA2 amplifications and SMAD4 deletions for CRC; CDKN2A/B, MTAP and SMAD4 deletions and GATA6 amplifications for PAC. These patterns were similar for both sexes and races with slightly higher prevalence of TP53 mutations in Asians. PTEN, EGFR, ERBB2, MET and BRAF were mutually exclusive with KRAS. Conclusions: The distribution of KRAS mutations in our study is consistent with known literature. We found higher prevalence of KRAS G12D mutations in Asians, which is informative for future clinical trial designs. With KRAS G12D inhibitors on the horizon, and ongoing research for pan-RAs inhibitors and combination therapies, it is important to review the current genomic landscape of KRAS mutations in diverse cohorts of patients to address any disparities, and ideally lead to better insight into the reasons for these differences. Relevant Co-mutations with KRAS in major solid tumors. Tumor Type Gene Frequency (%) Colorectal cancer APC 73.1 TP53 63.6 NDRG1 33.3 PIK3CA 26.3 Pancreatic cancer SET 89.5 NDRG1 84.2 STIL 84.2 TP53 77.1 FGFR1 73.7 Non-small cell lung cancer TP53 40.9 FGFR1 21.8 STK11 21.4 KEAP1 19.5