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Microsatellite instability-high status as a pan-cancer biomarker for immunotherapy efficacy
Thierry Landre1, Gaëtan Des Guetz2
1Assistance Publique Hôpitaux de Paris (AP-HP), Hôpital René Muret, Hôpitaux Universitaires de Paris Seine-St-Denis, Avenue du Dr Schaeffner, 93270, Sevran, France. thierry.landre@aphp.fr.
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.
Insights
Microsatellite instability-high (MSI-H) cancers show significant survival benefits with immune checkpoint inhibitors (ICIs). This meta-analysis confirms MSI-H as a key biomarker for predicting ICI response across various cancer types.
Area of Science:
- Oncology
- Immunotherapy
- Cancer Genomics
Background:
- Microsatellite instability-high (MSI-H) cancers are known to respond exceptionally well to immune checkpoint inhibitors (ICIs).
- However, comprehensive data on ICI efficacy across different MSI-H cancer types have been limited.
- This study addresses this gap by analyzing existing clinical trial data.
Purpose of the Study:
- To systematically review and meta-analyze randomized clinical trials (RCTs) comparing ICIs with chemotherapy in advanced MSI-H/dMMR cancers.
- To evaluate the efficacy of ICIs in terms of progression-free survival (PFS) and overall survival (OS) across various tumor types.
- To establish MSI-H as a predictive biomarker for ICI therapy.
Main Methods:
- A systematic review of RCTs comparing ICIs to chemotherapy in advanced MSI-H/dMMR cancers.
- Inclusion of 13 RCTs with 1633 MSI-H patients across colorectal, gastric, and endometrial cancers.
- Analysis of hazard ratios (HRs) for PFS and OS, with subgroup analyses by tumor type and assessment of statistical heterogeneity.
Main Results:
- Immunotherapy significantly improved PFS and OS in MSI-H patients compared to MSS patients (OS HR=0.35).
- A 64% reduced risk of progression was observed with immunotherapy (PFS HR=0.36).
- Significant PFS benefits were noted across colorectal (HR=0.28), gastric (HR=0.43), and endometrial cancers (HR=0.34).
Conclusions:
- This meta-analysis confirms that MSI-H is a robust predictive biomarker for immune checkpoint inhibitor therapy.
- The findings support the use of MSI-H status in guiding treatment selection for advanced cancers.
- There is a clear need for further clinical trials specifically focusing on MSI-H/dMMR populations.
