Microsatellite instability-high status as a pan-cancer biomarker for immunotherapy efficacy.

Abstract

Background: Microsatellite instability-high (MSI-H) cancers are linked to exceptional benefit from immune checkpoint inhibitors (ICIs), but studies on their efficacy across various MSI-H cancer types are limited.

Methods: Randomized clinical trials (RCTs) comparing ICIs to chemotherapy in advanced MSI-H/dMMR cancers were systematically reviewed. Eligible studies included 13 RCTs with 1633 MSI-H patients across colorectal, gastric, and endometrial cancers. Data were analyzed using hazard ratios for progression-free survival (PFS) and overall survival (OS), with subgroup analyses by tumor type. Statistical heterogeneity was assessed using Cochrane's Q and I².

Results: Immunotherapy significantly improved PFS and OS in MSI-H patients, with an HR for OS of 0.35 (95% CI 0.27-0.46; p < 0.00001) versus 0.81 for MSS patients. PFS showed a 64% reduced risk of progression (HR = 0.36, 95% CI 0.28-0.46; p < 0.0001). Subgroup analyses highlighted PFS benefits across tumor types: colorectal (HR = 0.28, 95% CI 0.11-0.73), gastric (HR = 0.43, 95% CI 0.27-0.68), and endometrial cancers (HR = 0.34, 95% CI 0.27-0.42).

Conclusions: This meta-analysis establishes MSI-H as a predictive biomarker for ICIs, supporting its role in therapy selection and underscoring the need for MSI-H/dMMR-focused clinical trials.