05/26/2023

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

ASCO 2023 PRESENTATION
Authors Fiyinfolu Balogun, Mirella Altoe, Catherine O'Connor, Nobel Chowdhury, Andrea Cercek, Choong-kun Lee, Michael Bonner Foote, Daehee Kim, Steven Brad Maron, Dae Won Kim, Karyn Ronski, Joon Oh Park, Calvin Y. Chao, Yelena Y. Janjigian, Ghassan K. Abou-Alfa, Luis A. Diaz, Eileen Mary O'Reilly, Francisco Sanchez-Vega, Debyani Chakravarty, Wungki Park

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)

 

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