MMR/MSI

  • DNA mismatch repair/microsatellite instability

MMR and MSI Biology

  • DNA MMR is involved in preserving genomic fidelity by repairing DNA after mismatching errors after replication or recombination.1,2
  • MMR is also involved in cell cycle regulation and apoptosis in response to DNA damage.3,4
  • Four genes regulate MMR mechanisms, and the dimer proteins they form are responsible for mismatch recognition, insertion-deletion loops, base excision, and other functions. Biallelic inactivation of 1 or more MMR genes can result from either somatic or germline mutations as well as from epigenetic silencing.5,6
  • Germline mutations in MMR genes are frequently associated with Lynch syndrome, which is known to increase the risk of several types of cancers.7-10

Etiology and Epidemiology

  • Microsatellites are short tandem nucleotide repeats (1-6 nucleotides) scattered throughout the genome and prone to high rates of mutation.11,12
  • MSI refers to a hypermutable phenotype that results when MMR genes are inactive or faulty.
  • MSI status is generally categorized into 3 types: high MSI (MSI-H), low MSI (MSI-L), and microsatellite stability (MSS).
  • The incidence of advanced biliary tract cancers (BTCs) with MMR-deficiency (dMMR)/MSI-H is approximately 1% to 3%.13

Testing for MMR/MSI Status

  • When to Test: All patients with unresectable or metastatic gallbladder cancer, intrahepatic CCA, or extrahepatic CCA should receive MSI or MMR testing at diagnosis.13
  • Available Testing Methods: Several techniques are used to test for the presence of dMMR in colorectal cancer, including immunohistochemistry (IHC) or polymerase chain reaction (PCR)–based assays as well as next-generation sequencing (NGS) testing. IHC assays assess expression of MMR proteins, PCR evaluates tumor DNA for microsatellite repeats, and NGS identifies inactivating mutations in MMR genes. MSI-H status correlates with the loss expression in 2 of 4 MMR proteins and abnormal microsatellites in 2 or more regions.13
  • Guideline Recommendations for Testing: The National Comprehensive Cancer Network guidelines recommended MMR and MSI testing in patients with unresectable or metastatic BTCs including intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, and gallbladder cancer.13

Treatment

  • Approved Agents: The FDA has approved several immunotherapy agents for the treatment of patients with dMMR/MSI-H solid tumors.14,15 In 2023, pembrolizumab received approval for the treatment of adult and pediatric patients who have unresectable or metastatic MSI-H or dMMR solid tumors as determined by an FDA-approved test, who have progressed following prior treatment, and who have no satisfactory alternative treatment options.16 Subsequently, based on KEYNOTE-966 study (NCT04003636) findings, pembrolizumab was approved as a first-line therapy option to be used in combination with gemcitabine and cisplatin for locally advanced unresectable or metastatic BTC.17 Dostarlimab has also received accelerated approval for dMMR recurrent or advanced solid tumors with no satisfactory alternative treatment options based on findings from the GARNET trial (NCT02715284).18
  • Mechanism of Action: Dostarlimab and pembrolizumab act by inhibiting the programmed death ligand 1 (PD-L1) receptor found on T cells, thereby restoring the antitumor immune response.14,15

Learn more about Dostarlimab >

Learn more about Pembrolizumab >

References

  1. Modrich P, Lahue R. Mismatch repair in replication fidelity, genetic recombination, and cancer biology. Annu Rev Biochem. 1996; 65:101-33. doi:10.1146/annurev.bi.65.070196.000533
  2. Marti TM, Kunz C, Fleck O. DNA mismatch repair and mutation avoidance pathways. J Cell Physiol. 2002; 191:28-41. doi:10.1002/jcp.1007
  3. Bellacosa A. Functional interactions and signaling properties of mammalian DNA mismatch repair proteins. Cell Death Differ. 2001; 8:1076-1092. doi:10.1038/sj.cdd.4400948
  4. Peters AC, Young LC, Maeda T, Tron VA, Andrew SE. Mammalian DNA mismatch repair protects cells from UVB-induced DNA damage by facilitating apoptosis and p53 activation. DNA Repair (Amst) 2003; 2:427-435. doi:10.1016/s1568-7864(03)00003-x
  5. Modrich P, Lahue R. Mismatch repair in replication fidelity, genetic recombination, and cancer biology. Annu Rev Biochem 1996; 65:101-133. doi:10.1146/annurev.bi.65.070196.000533
  6. Herman JG, Umar A, Polyak K, et al. Incidence and functional consequences of hMLH1 promoter hypermethylation in colorectal carcinoma. Proc Natl Acad Sci USA. 1998;95:6870-6875. doi:10.1073/pnas.95.12.6870
  7. Hampel H, Frankel WL, Martin E, et al. Feasibility of screening for Lynch syndrome among patients with colorectal cancer. J Clin Oncol. 2008;26:5783-5788. doi:10.1200/JCO.2008.17.5950
  8. Lynch HT, de la Chapelle A. Hereditary colorectal cancer. N Engl J Med. 2003;348:919-932. doi:10.1056/NEJMra012242
  9. Aaltonen LA, Salovaara R, Kristo P, et al. Incidence of hereditary nonpolyposis colorectal cancer and the feasibility of molecular screening for the disease. N Engl J Med. 1998;338:1481-1487. doi:10.1056/NEJM199805213382101
  10. Hampel H, Frankel WL, Martin E, et al. Screening for the Lynch syndrome (hereditary nonpolyposis colorectal cancer). N Engl J Med. 2005;352:1851-1860. doi:10.1056/NEJMoa043146
  11. Bonneville R, Krook MA, Chen HZ, et al. Detection of microsatellite instability biomarkers via next-generation sequencing. Methods Mol Biol. 2020;2055:11-32. doi:10.1007/978-1-4939-9773-2_5
  12. Li K, Luo H, Huang L, Luo H, Zhu X. Microsatellite instability: a review of what the oncologist should know. Cancer Cell Int. 2020;20:16. doi:10.1186/s12935-019-1091-8
  13. NCCN. Clinical Practice Guidelines in Oncology. Biliary tract cancers, version 1.2024. Accessed April 10, 2024. https://www.nccn.org/professionals/physician_gls/pdf/btc.pdf
  14. KEYTRUDA (pembrolizumab). Prescribing information. Merck & Co; 12018. Accessed April 10, 2024. https://www.merck.com/product/usa/pi_circulars/k/keytruda/keytruda_pi.pdf
  15. JEMPERLI (dostarlimab). Prescribing information. GlaxoSmithKline; 2024. Accessed April 10, 2024. https://gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Jemperli/pdf/JEMPERLI-PI-MG.PDF
  16. FDA converts to full approval indication for KETRUDA (pembrolizumab) for certain adult and pediatric patients with advanced microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) solid tumors. Press release. Merck. March 29, 2023. Accessed April 10, 2024. https://www.merck.com/news/fda-converts-to-full-approval-indication-for-keytruda-pembrolizumab-for-certain-adult-and-pediatric-patients-with-advanced-microsatellite-instability-high-msi-h-or-mismatch-repair-deficient/
  17. FDA approves pembrolizumab with chemotherapy for biliary tract cancer. FDA. November 1, 2023. Accessed April 10, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pembrolizumab-chemotherapy-biliary-tract-cancer
  18. FDA grants accelerated approval to dostarlimab-gxly for dMMR advanced solid tumors. FDA. Updated July 18, 2023. Accessed April 10, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-dostarlimab-gxly-dmmr-advanced-solid-tumors