Tumor Mutational Burden and Mismatch Repair Deficiency Discordance as a Mechanism of Immunotherapy Resistance

View More View Less
  • 1 Department of Medicine, Memorial Sloan Kettering Cancer Center;
  • 2 Tri-Institutional Program in Computational Biology and Medicine, Weill Cornell Medical College; and
  • 3 Marie-Josée and Henry R. Kravis Center for Molecular Oncology,
  • 4 Department of Epidemiology and Biostatistics,
  • 5 Human Oncology and Pathogenesis Program, and
  • 6 Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
Restricted access

Lynch syndrome is a heritable cancer syndrome caused by a heterozygous germline mutation in DNA mismatch repair (MMR) genes. MMR-deficient (dMMR) tumors are particularly sensitive to immune checkpoint inhibitors, an effect attributed to the higher mutation rate in these cancers. However, approximately 15% to 30% of patients with dMMR cancers do not respond to immunotherapy. This report describes 3 patients with Lynch syndrome who each had 2 primary malignancies: 1 with dMMR and a high tumor mutational burden (TMB), and 1 with dMMR but, unexpectedly, a low TMB. Two of these patients received immunotherapy for their TMB-low tumors but experienced no response. We have found that not all Lynch-associated dMMR tumors have a high TMB and propose that tumors with dMMR and TMB discordance may be resistant to immunotherapy. The possibility of dMMR/TMB discordance should be considered, particularly in less-typical Lynch cancers, in which TMB evaluation could guide the use of immune checkpoint inhibitors.

Submitted May 16, 2020; accepted for publication October 27, 2020.

Disclosures: The authors have not received any financial consideration from any person or organization to support the preparation, analysis, results, or discussion of this article.

Funding: Research reported in this article was supported by the NIH under award number P30 CA 008748. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. Work for this article was also supported by the American Cancer Society (134065-PF-19-125-01-CSM).

Correspondence: Rona Yaeger, MD, Department of Medicine, Memorial Sloan Kettering Cancer Center, 300 East 66th Street, 10th Floor, New York, NY 10065. Email: yaegerr@mskcc.org
  • 1.

    Sinicrope FA. Lynch syndrome–associated colorectal cancer. N Engl J Med 2018;379:764773.

  • 2.

    Watson P, Vasen HFA, Mecklin JP, . The risk of extra-colonic, extra-endometrial cancer in the Lynch syndrome. Int J Cancer 2008;123:444449.

  • 3.

    Latham A, Srinivasan P, Kemel Y, . Microsatellite instability is associated with the presence of Lynch syndrome pan-cancer. J Clin Oncol 2019;37:286295.

  • 4.

    Lynch HT, Snyder CL, Shaw TG, . Milestones of Lynch syndrome: 1895-2015. Nat Rev Cancer 2015;15:181194.

  • 5.

    Buckowitz A, Knaebel HP, Benner A, . Microsatellite instability in colorectal cancer is associated with local lymphocyte infiltration and low frequency of distant metastases. Br J Cancer 2005;92:17461753.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 6.

    Schwitalle Y, Kloor M, Eiermann S, . Immune response against frameshift-induced neopeptides in HNPCC patients and healthy HNPCC mutation carriers. Gastroenterology 2008;134:988997.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 7.

    Le DT, Uram JN, Wang H, . PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med 2015;372:25092520.

  • 8.

    Overman MJ, Lonardi S, Wong KYM, . Durable clinical benefit with nivolumab plus ipilimumab in DNA mismatch repair-deficient/microsatellite instability-high metastatic colorectal cancer. J Clin Oncol 2018;36:773779.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 9.

    Marabelle A, Le DT, Ascierto PA, . Efficacy of pembrolizumab in patients with noncolorectal high microsatellite instability/mismatch repair–deficient cancer: results from the phase II KEYNOTE-158 study. J Clin Oncol 2020;38:110.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 10.

    Le DT, Durham JN, Smith KN, . Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science 2017;357:409413.

  • 11.

    Cheng DT, Mitchell TN, Zehir A, . Memorial Sloan Kettering-integrated mutation profiling of actionable cancer targets (MSK-IMPACT): a hybridization capture-based next-generation sequencing clinical assay for solid tumor molecular oncology. J Mol Diagn 2015;17:251264.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 12.

    Middha S, Zhang L, Nafa K, . Reliable pan-cancer microsatellite instability assessment by using targeted next-generation sequencing data. JCO Precis Oncol 2017;2017:117.

    • Search Google Scholar
    • Export Citation
  • 13.

    Shen R, Seshan VE. FACETS—allele-specific copy number and clonal heterogeneity analysis tool for high-throughput DNA sequencing. Nucleic Acids Res 2016;44:16.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 14.

    Cerretelli G, Ager A, Arends MJ, . Molecular pathology of Lynch syndrome. J Pathol 2020;250:518531.

  • 15.

    Georgiadis A, Durham JN, Keefer LA, . Noninvasive detection of microsatellite instability and high tumor mutation burden in cancer patients treated with PD-1 blockade. Clin Cancer Res 2019;25:70247034.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 16.

    Schrock AB, Ouyang C, Sandhu J, . Tumor mutational burden is predictive of response to immune checkpoint inhibitors in MSI-high metastatic colorectal cancer. Ann Oncol 2019;30:10961103.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 17.

    Chang K, Taggart MW, Reyes-Uribe L, . Immune profiling of premalignant lesions in patients with Lynch syndrome. JAMA Oncol 2018;4:10851092.

All Time Past Year Past 30 Days
Abstract Views 0 0 0
Full Text Views 797 797 797
PDF Downloads 244 244 244
EPUB Downloads 0 0 0