MMR/MSI

  • DNA mismatch repair/microsatellite instability

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

Testing Guideline Recommendations:

  • 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

Targeted Therapies

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