Results from microsatellite instability (MSI) and mismatch repair (MMR) testing have implications in precision medicine beyond screening for Lynch syndrome.  The National Comprehensive Cancer Network (NCCN) recommends MSI or MMR testing for all colon and rectal cancers to identify patients to inform treatment decisions in patients with stage II colorectal disease and as of 2017, to identify patients who may benefit from immunotherapy.  In 2017, the FDA approved the first tumor agnostic yet genomically selected indication for the use of pembrolizumab in MSI high tumors¹.  Given this, the NCCN has expanded their recommendation for MSI or MMR testing to most advanced solid tumors (e.g. prostate, melanoma, endometrial, etc.).  For metastatic CRC, not only is pembrolizumab approved but nivolumab was also approved in 2017, and both are in the NCCN guidelines for treatment after initial chemotherapy.

Mechanism of action:

During tumorigenesis, acquired mutations in coding regions produce new proteins which act as neoantigens. The body recognizes these neoantigens as foreign and triggers immune response. Cancers can avoid T cell immune response and increase survival by upregulating immune checkpoint proteins (e.g. PD-L1, PD-L2). These immune checkpoint proteins bind with the PD-1 receptors on T cells and inactivate immune response, ensuring survival of the cancer cell.  Anti-PD-1 antibodies block the interaction between receptor on the T cells and ligand on the cancer cell which removes the inhibition of immune response, facilitating cancer cell death by the immune system.

MSI-high tumors, tumors with POLE mutations, and constitutional mismatch repair deficiency (CMMRD) syndrome-related tumors generally have a higher mutational burden and express more neoantigens than other cancer cell types which triggers a more robust immune response.  In earlier stage disease, MSI status is thought to be prognostic in such that these patients tend to have a better prognosis likely driven by an immune response.

Given the additional indications for MSI or MMR testing, many of these tests will be performed outside of the context of a universal Lynch syndrome screening program. In turn, a patient whose tumor is flagged as MSI-High or MMR deficient may not be identified as possibly having Lynch syndrome and/or be referred to a hereditary cancer specialist. Although the sensitivity and specificity of MSI/MMR testing has been reported for colon and endometrial tumors, it’s unclear if abnormal results in other tissue types would correlate as closely with an underlying diagnosis of Lynch syndrome. It would be important for medical oncologists, pathologists, genetic counselors and other stakeholders to create a system where all patients who have these tests receive appropriate follow-up for both treatment options and hereditary cancer risk assessment.

1. Le, D. T. et al. PD-1 blockade in tumors with mismatch-repair deficiency. N. Engl. J. Med.372, 2509–2520 (2015)