A tale of two pathways: Review of immune checkpoint inhibitors in DNA mismatch repair-deficient and microsatellite instability-high endometrial cancers Review
| Authors: | Liu, Y. L.; Weigelt, B. |
| Review Title: | 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. © 2024 American Cancer Society. |
| Keywords: | immunohistochemistry; signal transduction; protein expression; gene mutation; overall survival; promoter region; somatic mutation; genetics; review; outcome assessment; endometrial cancer; endometrial neoplasms; endometrium cancer; polymerase chain reaction; tumor associated leukocyte; phenotype; gene; cancer susceptibility; carboplatin; cell infiltration; prevalence; dna methylation; immunology; immune response; mismatch repair; microsatellite instability; dna mismatch repair; immunogenicity; natural killer cell; tumor immunity; mutation rate; immunosuppressive treatment; disease predisposition; genetic screening; fluoxetine; lynch syndrome; endometrium tumor; colorectal neoplasms, hereditary nonpolyposis; turcot syndrome; mlh1 gene; genetic testing; health disparity; olaparib; hereditary nonpolyposis colorectal cancer; personalized medicine; recurrence free survival; tumor microenvironment; germline mutation; mmr gene; tumor immunogenicity; immune checkpoint inhibitor; high throughput sequencing; nivolumab; humans; human; female; pembrolizumab; social determinants of health; durvalumab; hereditary tumor syndrome; whole exome sequencing; immune checkpoint inhibitors; checkpoint inhibitors; avelumab; tumor mutational burden; mismatch repair-deficiency; dostarlimab; mmr-d mechanism |
| Journal Title: | Cancer |
| Volume: | 130 |
| Issue: | 10 |
| ISSN: | 0008-543X |
| Publisher: | Wiley Blackwell |
| Date Published: | 2024-05-15 |
| Start Page: | 1733 |
| End Page: | 1746 |
| Language: | English |
| DOI: | 10.1002/cncr.35267 |
| PUBMED: | 38422006 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | The MSK Cancer Center Support Grant (P30 CA008748) is acknowledged in the PDF -- Corresponding author is MSK author: Britta Weigelt -- Source: Scopus |
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