A tale of two pathways: Review of immune checkpoint inhibitors in DNA mismatch repair-deficient and microsatellite instability-high endometrial cancers

Abstract

The DNA mismatch repair (MMR) pathway is critical for correcting DNA mismatches generated during DNA replication. MMR-deficiency (MMR-D) leads to microsatellite instability (MSI) associated with an increased mutation rate, driving cancer development. This is particularly relevant in endometrial cancer (EC) as 25%-30% of tumors are of MMR-D/MSI-high (MSI-H) phenotype. Comprehensive assessment using immunohistochemistry (IHC) and sequencing-based techniques are necessary to fully evaluate ECs given the importance of molecular subtyping in staging and prognosis. This also influences treatment selection as clinical trials have demonstrated survival benefits for immune checkpoint inhibitors (ICIs) alone and in combination with chemotherapy for MMR-D/MSI-H EC patients in various treatment settings. As a portion of MMR-D/MSI-H ECs are driven by Lynch syndrome, an inherited cancer predisposition syndrome that is also associated with colorectal cancer, this molecular subtype also prompts germline assessment that can affect at-risk family members. Additionally, heterogeneity in the tumor immune microenvironment and tumor mutation burden (TMB) have been described by MMR mechanism, meaning MLH1 promoter hypermethylation versus germline/somatic MMR gene mutation, and this may affect response to ICI therapies. Variations by ancestry in prevalence and mechanism of MMR-D/MSI-H tumors have also been reported and may influence health disparities given observed differences in tumors of Black compared to White patients which may affect ICI eligibility. These observations highlight the need for additional prospective studies to evaluate the nuances regarding MMR-D heterogeneity as well as markers of resistance to inform future trials of combination therapies to further improve outcomes for patients with EC.

Keywords: Lynch syndrome; MMR‐D mechanism; checkpoint inhibitors; endometrial cancer; genetic testing; microsatellite instability; mismatch repair‐deficiency.

Figure 1.. Mechanisms of mismatch-repair deficiency in cancer.

In endometrial cancer, mismatch-repair deficiency (MMR-D)/ microsatellite instability (MSI) is most commonly due to MLH1 promoter hypermethylation (epigenetic MMR-D; ~75%). Up to 10% are due to an underlying germline mutation (Lynch Syndrome) affecting MLH1, MSH2, MSH6 or PMS2, and biallelic somatic MMR gene mutations drive most of the remainder.

Figure 2.. Methods for MMR/ MSI detection in cancer.

The pros and cons of the different testing methods are shown. EC, endometrial cancer; MMR, mismatch-repair; MSI-H microsatellite instability-high, MSS – microsatellite stable.

Figure 3.. Endometrial cancer workflow and MMR/MSI testing algorithm for the identification of patients with Lynch Syndrome for referral to the clinical genetics service using clinical tumor-normal NGS sequencing.

Endometrial cancers undergo parallel IHC and MSI assessments with MLH1 promoter methylation testing as appropriate. Results of testing along with family history are used to triage referrals for additional genetic testing. Beginning in 2015, our institution also incorporated germline assessment of 76–90 genes using MSK-IMPACT for all patients independently of the IHC/MSI pathways (gray). gPV – germline pathogenic variant; NGS – next generation sequencing, FH – family history, CGS – clinical genetics service, IHC, immunohistochemistry, LS, Lynch Syndrome, MSI-I – MSI indeterminate, MSS – Microsatellite stable, MSK-IMPACT, Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets.