Background
MMRd/Microsatellite instability (MSI) High tumors represent the first tumor-agnostic indication for ICB. Emerging data suggest that the specific MMR protein lost and the mechanism of loss (genetic vs epigenetic) drive distinct genotypic patterns, which may modulate immunosensitivity. We assessed how the specific MMR protein lost affects survival outcomes after ICB across two large pan-cancer cohorts.
Methods
All patients (pts) had MMRd confirmed by immunohistochemistry (IHC) for MLH1, PMS2, MSH2, and MSH6. Complex (>2 protein lost) and Normal IHC were excluded. Both discovery cohort (MSK: 2014–2025, MSK-IMPACT) and validation cohort (Caris) included pts with IHC-defined MMRd and tumor sequencing. MSI status was determined by NGS. MLH1 loss was classified as epigenetic or genetic based on sequencing. OS was defined from ICB initiation to death or last follow-up.
Results
The MSK cohort (n=2,001; 779 received ICB) was: 63% MLH1/PMS2 (82% epigenetic), 21% MSH2/MSH6, 6% MSH6, and 5% PMS2. Median OS was 110 months (95% CI: 81.7–NR). OS differed by MMR subtype (P=0.0011): PMS2 and MLH1-epigenetic losses had worse OS vs MLH1-genetic loss (HR=3.5 [1.7–7.0] and HR=2.0 [1.2–3.4], respectively). MSI-H prevalence was lowest in MSH6 (46%) and PMS2 (62%), with MSS tumors in these subgroups associated with inferior survival (P=0.02 and P=0.0017, respectively). The Caris cohort (n=13,043; 4,070 received ICB) was: 75% MLH1/PMS2 (85% epigenetic), 11% MSH2/MSH6, 5% MSH6, and 7% PMS2. The shortest mOS was in PMS2 loss (22.4 months; 95% CI: 18.6–25.7). The prognosis impact of the MMR subtype was consistent across cancers, particularly for PMS2 and MLH1-epigenetic losses in endometrial and non-colorectal gastrointestinal tumors. PMS2 and MSH6 losses had lower MSI-H prevalence (67% and 72%; P<0.0001) and poorer outcomes in MSS cases (P=0.0421 and P=0.0074, respectively). In pts not receiving ICB, MMR subtype had minimal prognostic value.
Conclusions
Across two independent cohorts, the mechanism of MMR deficiency informs ICB outcomes. Attenuated MSI, often observed with PMS2 and MSH6 single losses, confers worse prognosis, highlighting the need to jointly assess MMR IHC and MSI status in clinical practice.