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Microsatellite Instability as a Biomarker for PD-1 Blockade
Jonathan C Dudley1, Ming-Tseh Lin2, Dung T Le3
1Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts.
Abstract:
Initial results by Le and colleagues, which were published in the June 25, 2015 issue of the New England Journal of Medicine, report significant responses of cancers with microsatellite instability (MSI) to anti-PD-1 inhibitors in patients who failed conventional therapy. This finding fits into a broader body of research associating somatic hypermutation and neoepitope formation with response to immunotherapy, with the added benefit of relying on a simple, widely used diagnostic test. This review surveys the pathogenesis and prognostic value of MSI, diagnostic guidelines for detecting it, and the frequency of MSI across tumors, with the goal of providing a reference for its use as a biomarker for PD-1 blockade. MSI usually arises from either germline mutations in components of the mismatch repair (MMR) machinery (MSH2, MSH6, MLH1, PMS2) in patients with Lynch syndrome or somatic hypermethylation of the MLH1 promoter. The result is a cancer with a 10- to 100-fold increase in mutations, associated in the colon with poor differentiation, an intense lymphocytic infiltrate, and a superior prognosis. Diagnostic approaches have evolved since the early 1990s, from relying exclusively on clinical criteria to incorporating pathologic features, PCR-based MSI testing, and immunohistochemistry for loss of MMR component expression. Tumor types can be grouped into categories based on the frequency of MSI, from colorectal (20%) and endometrial (22%-33%) to cervical (8%) and esophageal (7%) to skin and breast cancers (0%-2%). If initial results are validated, MSI testing could have an expanded role as a tool in the armamentarium of precision medicine.
Insights
Microsatellite instability (MSI) predicts positive responses to anti-PD-1 inhibitors in patients with advanced cancers. MSI testing offers a valuable biomarker for precision medicine, guiding immunotherapy selection for improved patient outcomes.
Area of Science:
- Oncology
- Immunology
- Genetics
Background:
- Microsatellite instability (MSI) is linked to increased mutations and neoepitope formation, potentially enhancing immunotherapy response.
- Previous research indicates MSI cancers show significant responses to anti-PD-1 inhibitors, especially in patients refractory to conventional treatments.
- MSI arises from DNA mismatch repair (MMR) gene defects (Lynch syndrome) or MLH1 promoter hypermethylation.
Purpose of the Study:
- To review the pathogenesis, prognostic significance, and diagnostic methods for MSI.
- To assess the frequency of MSI across various tumor types.
- To evaluate MSI as a predictive biomarker for anti-PD-1 blockade therapy.
Main Methods:
- Review of existing literature on MSI, immunotherapy, and diagnostic techniques.
- Analysis of MSI frequency data across different cancer types.
- Discussion of diagnostic guidelines including PCR and immunohistochemistry for MMR proteins.
Main Results:
- MSI cancers exhibit a 10- to 100-fold increase in mutation rates.
- Colorectal and endometrial cancers show higher MSI frequencies (20% and 22%-33%, respectively) compared to others.
- Diagnostic approaches have advanced from clinical criteria to molecular and protein-based tests.
Conclusions:
- MSI is a significant biomarker for predicting response to anti-PD-1 inhibitors.
- MSI testing can be integrated into precision medicine strategies.
- Further validation may expand the role of MSI testing in cancer treatment selection.
