Evaluation of Microsatellite Instability Status, a Definitive Predictive Biomarker for Immune Checkpoint Inhibitors (ICI), in Underrepresented Minorities (URM) With Gastrointestinal (GI) Cancers

**Background:**Mismatch repair deficiency (dMMR) results in MSI-H state and is the first tumor type-agnostic biomarker predictive of ICI response. Among GI cancers, MSI-H is most frequent in colorectal cancer (CRC 15%), gastroesophageal (GEC, 5%) and other (small bowel, hepatopancreatobiliary; 1%). For CRC, MSI-H can be attributed to germline mutation (Lynch syndrome, 3%) or somatic inactivation (sporadic, 12%) of foundational MMR genes. Studies evaluating ICI efficacy in dMMR cancers focus primarily on non-Hispanic White (NHW) patients (pts). We present prevalence, tumor genomic features, and outcomes in pts from a large cohort at Memorial Sloan Kettering (MSK).

**Methods:**Retrospective analysis of MSI-H GI cancers from MSK-IMPACT database. Pts were grouped by self-reported race and ethnicity into 4 study arms: NHW, Asian, non-Hispanic Black (NHB), and Hispanic. Age, tumor type, tumor mutation burden (TMB), and MMR genes were analyzed. Overall survival (OS) estimated with Kaplan-Meier.

**Results:**Of 776 pts with MSI-H GI cancers: 623 (80.3 %) NHW, 60 (7.7 %) Hispanic, 50 Asian (6.5 %), and 43 (5.5 %) NHB. CRC (76%), GEC (14%), other cancers (10%). We present initial evaluation of CRC and GEC: Median age, TMB, and most frequently altered MMR genes (MMR gene FA) are in table. Median OS (mOS) in NHW/URM by receipt of ICI in MSI-H CRC were 38.5m/25.3m (p 0.07) in no-ICI group, 34.2m/28.7m (p 0.64) in +ICI group; MSI-H GEC 43.4m/30m (p 0.44) in no-ICI group, 28.8m/26.7m in +ICI group.

**Conclusions:**Number of URM MSI-H CRC/GEC pts is 7 to 15-fold less than NHW, with no such difference in % MSI-H/MSS between groups; reflecting significant undertesting in URM pts. In MSI-H CRC, median age (m-Age) at sequencing was younger in URM compared to NHW; pronounced in Asian and Hispanic patients, who were 10+ years younger than NHW. No such age difference seen in GEC. No difference in mOS detected between NHW and URM, however a non-significant trend towards worse mOS in URM was observed in the no-ICI group. Next steps include validation of clinico-genomics of MSI-H GI cancers in other large cohorts, including TEMPUS (N = 768) which is ongoing.

| | NHW | CRC | NHB | CRC | Asian | CRC | Hispanic | CRC |
| --- | --- | --- | --- | --- |
| MSI-H/MSS % (MSI-H, N) | 13% (3679) | 10% (349) | 8% (430) | 14% (331) |
| m-Age |range (p vs NHW) | 67 | 19-60 (1) | 61 | 28-78 (0.025) | 57 | 26-89 (0.023) | 55 | 25-87 (0.048) |
| m-TMB | range (p vs NHW) | 58 | 3-369 (1) | 54 | 21-201 (0.43) | 50 | 26-219 (0.06) | 61 | 32-400 (0.95) |
| MMR gene FA (% | N) | MSH6 (27% | 492) | MLH1 (26% | 34) | MSH2 (26% | 34) | MSH6 (36% | 45) |
| | NHW | GEC | NHB | GEC | Asian | GEC | Hispanic | GEC |
| MSI-H/MSS % (MSI-H, N) | 5% (1314) | 7% (83) | 5% (184) | 7% (124) |
| m-Age |range (p vs NHW) | 71 | 45-90 (1) | 70 | 55-81 (0.3) | 68 | 49-85 (0.55) | 68 | 35-88 (0.53) |
| m-TMB | range (p vs NHW) | 50 | 2-172 (1) | 75 | 30-87 (0.34) | 49 | 18-72 (0.59) | 44 | 31-62 (0.3) |
| MMR gene FA (% | N) | MSH6/MLH1 (13% | 76) | MLH1 (33% | 6) | MSH6 (30% | 10) | MSH2/MSH6 (11% | 9) |