Chao, Calvin Y.

260 Background: NGS to identify HRR mutations (mut) is indicated in advanced prostate cancer (aPC); samples for testing may be tissue or plasma. In a large real-world (RW) database, we determined concordance between plasma ctDNA and primary tumor tissue (PT) and/or metastatic tissue (MT) for BRCA1, BRCA2, and ATM mut in PC patients (pts) who received both LB and tissue NGS any time during standard of care (SOC) management. The study objective was to assess the utility of LB to detect actionable mut in these HRR genes and demonstrate the utility of combined LB and tissue testing. Methods: We examined de-identified data from pts who had NGS using both Tempus xF (105 genes-LB) and Tempus xT (648 genes-tissue) during SOC for aPC. Analyses included 1) PT and LB and 2) MT and LB. The results from the pts’ earliest PT or MT and earliest LB were used for paired analyses. The prevalence of a pathogenic/likely pathogenic germline and/or somatic mut in BRCA1, BRCA2, or ATM was reported as N (%), 95% CI. The sensitivity of the LB to identify observed HRR mut in tissue was also reported as N (%), 95% CI. Concordance between pairs was evaluated by Cohen’s kappa statistic with 95% CI. Results: HRR results are show for 1074 PC pts who had NGS performed on PT and LB and 451 PC pts with NGS on both MT and LB. In the PT and LB analysis, HRR mut were found in 6.2% (95% CI: 4.9%-7.9%) of LB and 8.8% (95% CI: 7.2%-11%) of PT. The sensitivity of LB to detect HRR mut in the PT was 53% (95% CI: 43%-64%). Cohen’s kappa statistic was 0.59, 95% CI=0.50-0.68, between PT and LB. In the MT and LB analysis, HRR mut were found in 10% (95% CI 7.8%-14%) of LB and 10% (7.6%-13%) of MT. The sensitivity of LB to detect HRR mut in the MT was 70% (95% CI: 54%-82%). Cohen’s kappa statistic was 0.65, 95% CI=0.54-0.77, between MT and LB. Conclusions: In this large RW dataset, plasma ctDNA-based analysis of BRCA1, BRCA2, and ATM mut showed greater concordance between LB and MT than LB and PT, and may be used as an initial tool for HRR mut detection. When LB results are negative, further exploration with tissue-based testing may identify HRR mut to guide clinical decisions. [Table: see text]

231 Background: The recent development of KRAS G12C inhibitors underscores the potential to target KRAS mutations. Right-sided and left-sided colon tumors (RT and LT) exhibit different molecular features. We characterize the prevalence of KRAS-variants, interrelation with primary tumor location, and association with immune biomarkers in CRC. Methods: We retrospectively reviewed CRC tumors of all stages (with known sidedness) that underwent NGS with the Tempus xT assay (DNA-seq of 648 genes at 500x coverage, full transcriptome RNA-seq). Bivariate analyses were performed to compare KRAS alterations, immune biomarkers, and co-mutations by tumor location. P-values comparing individual co-mutations between groups were adjusted for false discovery (FDR). Results: A total of 3,391 CRC were analyzed (RT: n = 442 [13%], transverse: n = 116 [3%], LT; n = 2,833 [84%]) of which 1486 (44%) tumors harbored KRAS mutations. Overall, KRAS mutations were more frequent in RT compared to transverse tumors and LT (52% vs 41% vs 43%, p<0.001, respectively). The most frequent KRAS mutation variants observed were G12D (29 %), G12V (22%), G13D (16%), and G12C (5.7%). There was no significant difference in the prevalence of KRAS variant types between LT and RT (p=0.5). Significant differences in genomic co-mutations with various KRAS variants were observed in the following genes: TP53, FBXW7, and NF1 (FDR- P<0.05). RT and transverse tumors were more likely have MSI-H and TMB-H (>10 mut/mb) status than LT (MSI-H: 18% vs 22% vs 2.2% and TMB-H (20% vs 22% vs 3%, P<0.001), respectively. CRC tumors harboring G13D variants were more likely to be associated with and MSI-H and TMB-H status (and 7.7% and 8.5%) compared to G12D (2.8 % and 3.9 %), G12V (1.8 % and 2.1%), and G12C (0% and 2.4%); P = 0.003 and 0.001. Conclusions: The most frequent KRAS mutation variants observed in CRC tumors were G12D, G12V, G13D, and G12C. There was no significant difference in the prevalence of KRAS variant types between tumors of the left vs right colon. CRC tumors that harbored G13D variants were significantly more likely to be associated with MSI-H and TMB-H status. [Table: see text]