Microsatellite instability-high (MSI-H) and tumor mutational burden (TMB) are predictive biomarkers for immune-checkpoint inhibitors (ICIs). Still, the relationship between the underlying cause(s) of MSI and TMB in tumors remains poorly defined. We investigated associations of TMB to mismatch repair (MMR) protein expression patterns by immunohistochemistry (IHC) and MMR mutations in a diverse sample of tumors. Hypothesized differences were identified by the protein/gene affected/mutated and the tumor histology/primary site. Overall, 1057 MSI-H tumors were identified from the 32 932 tested. MSI was examined by NGS using 7000+ target microsatellite loci. TMB was calculated using only nonsynonymous missense mutations sequenced with a 592gene panel; a subset of MSI-H tumors also had MMR IHC performed. Analyses examined TMB by MMR protein heterodimer impacted (loss of MLH1/PMS2 vs. MSH2/ MSH6 expression) and gene-specific mutations. The sample was 54.6% female; mean age was 63.5 years. Among IHC tested tumors, loss of co-expression of MLH1/PMS2 was more common (n = 544/705, 77.2%) than loss of MSH2/MSH6 (n = 81/705, 11.5%; P < .0001), and was associated with lower mean TMB (MLH1/PMS2: 25.03 mut/Mb vs MSH2/MSH6 46.83 mut/Mb; P < .0001). TMB also varied by tumor histology: colorectal cancers demonstrating MLH1/PMS2 loss had higher TMBs (33.14 mut/ Mb) than endometrial cancers (20.60 mut/Mb) and other tumors (25.59 mut/Mb; P < .0001). MMR gene mutations were detected in 42.0% of tumors; among these, MSH6 mutations were most common (25.7%). MSH6 mutation patterns showed variability by tumor histology and TMB. TMB varies by underlying cause(s) of MSI and tumor histology; this heterogeneity may contribute to differences in response to ICI.

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13 Background: The incidence of colorectal cancer (CRC) in young adults (YA) is rising. Impact of sociodemographic status on YA with CRC is not well described. Methods: Data obtained from the NCDB were used to examine the impact of sociodemographic status on clinicopathological features and outcomes of YA with CRC. Patients (pts) were categorized based on whether they lived in areas of low or high income and education. Logistic regression and chi-square were used to examine the differences between the groups. Results: In total, 26,768 YA (≤40 yrs) pts diagnosed with CRC between 2004 and 2016 were retrospectively studied. The majority of pts were male (51.6%), and 78.7% were white, 14.6% black, and 6.6% of other races. Of the entire cohort, 32.3% pts resided in the highest income areas (median ≥$68,000), whereas 18.4% were in the lowest ( < $38,000); 23% lived in areas that had the highest high school graduation rate ( > 93%), while 20% lived in areas of the lowest graduation rate ( < 79%); and 32.3% came from metropolitan areas, while 18.4% came from urban areas. Pts in the lowest compared to highest income and education areas were more likely to be black (OR: 6.4, 5.6-7.4), not have private insurance (OR: 6.3, 5.6-7.0), have T3/T4 stage (OR: 1.4, 1.3-1.6), have positive nodes (OR: 1.2, 1.1-1.3), be rehospitalized within 30 days (OR: 1.3, 1.1-1.6), or have a Charlson-Deyo score ≥ 1 (OR: 1.6, 1.4-1.9), and were less likely to have surgery (OR: 0.63, 0.6-0.7). After adjusting for race, insurance status, T/N stage, and Charlson-Deyo comorbidity scores, pts from lowest vs. highest income and education areas had a 24% increased risk of death (HRadj: 1.24, CI 1.1-1.44, p = 0.004), and pts from urban vs. metropolitan areas had a 10% increased risk of death (HRadj = 1.10 (1.01-1.20), P = 0.02). Pts with stage IV disease in the lowest vs. highest income populations had worse mOS (1.72 vs. 2.17 years, p < 0.001). Conclusions: YA with CRC in the lowest income and education population were more likely to have worse OS. Furthermore, regardless of income, pts in metropolitan areas seemed to have a lower risk of death likely due to greater access to care. More efforts are needed to eliminate disparities and achieve health equity.

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