Microsatellite Instability: Response to Immunotherapy

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Caris Molecular Intelligence tumour profiling includes Microsatellite Instability (MSI) testing via Next-Generation sequencing (NGS). MSI is caused by failure of the DNA mismatch repair (MMR) system. High levels of MSI correlate to an increased neoantigen burden, which may indicate the tumour is more sensitive to immunotherapy.

MSI-High status across Caris Molecular Intelligence cases

Earlier studies have associated MSI-High status with benefit to immunotherapy in metastatic colorectal cancer. Recent data, however, show that MSI is a useful indicator for predicting response to pembrolizumab in any solid tumour type.1

MSI expression across tumour types1

Traditionally, MSI is detected through polymerase chain reaction (PCR) by fragment analysis (FA) of five conserved satellite regions and comparing cancer tissue to normal tissue to identify differences in tandem repeats.3-4 To validate MSI testing via NGS, Caris evaluated more than 7,000 target microsatellite loci and compared the results from PCR for 2,189 cases across 26 different tumour types. These data were published in Cancer Medicine and demonstrated that MSI testing with Caris’ NGS platform is highly concordant with the traditional standard method of PCR-FA and is a more efficient and cost-effective approach to identifying patient candidates for immunotherapy.2

Concordance data: PCR vs NGS2

Lineage Sensitivity Specificity PPV NPV
All 95.8% 99.4% 94.5% 99.2%
CRC 100.0% 99.9% 98.7% 98.7%

 

 

Unlock the power of immunotherapies

By harnessing the body’s immune system to detect and destroy tumour cells, immune checkpoint inhibitors are rapidly ushering in a new era of precision medicine.5-8 Although immune checkpoint inhibitors have demonstrated durable clinical responses across several tumour types, these therapies are costly and may present toxic side effects.5,7-10

Understanding the relationships between TMB, MSI and PD-L1 can help oncologists make more informed immunotherapy decisions.2

TMB (tumour mutational burden) measures the total number of non-synonymous somatic mutations identified per megabase of the genome coding area. Tumours with high TMB likely harbour neoantigens and may respond more favourably to immunotherapies.8-9,11

Caris Experience data across all lineages: 33,000+


MSI (microsatellite instability)
is caused by failure of the DNA mismatch repair (MMR) system.7 MSI-High correlates to an increased neoantigen burden, which may indicate the tumour is more likely to respond favourably to immunotherapies.

Caris Experience data across all lineages: 24,000+


PD-L1 (programmed death ligand-1)
is among the most important checkpoint proteins that mediate tumour-induced immune suppression through T-cell downregulation.9,12 PD-L1 expression may indicate a more likely response to immunotherapies.6,13-15

Caris Experience data across all lineages: 64,000+

Identify patients more likely to respond to immunotherapies through Comprehensive Genomic Profiling PLUS (CGP+) with Caris Molecular Intelligence.

 

References

  1. Le DT, Durham JN, Smith KN, et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science. 2017;357(6349):409-413. [Abstract]
  2. Vanderwalde A, Spetzler D, Xiao N, et al. Microsatellite instability status determined by next-generation sequencing and compared with PD-L1 and tumor mutational burden in 11,348 patients. Cancer Med. 2018. doi:10.1002/cam4.1372. [Abstract]
  3. de la Chapelle A, Hampel H. Clinical relevance of microsatellite instability in colorectal cancer. J Clin Oncol. 2010;28(20):3380-7. [Abstract]
  4. Zhang L. Immunohistochemistry versus microsatellite instability testing for screening colorectal cancer patients at risk for hereditary nonpolyposis colorectal cancer syndrome. Part II. The utility of microsatellite instability testing. J Mol Diagn. 2008;10(4):301-7. [Abstract]
  5. Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012;366(26):2443-54. [Abstract]
  6. Patel SP, Kurzrock R. PD-L1 expression as a predictive biomarker in cancer immunotherapy. Mol Cancer Ther. 2015;14(4):847-56. [Abstract]
  7. Le DT, Uram JN, Wang H, et al. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med. 2015;372(26):2509-20. [Abstract]
  8. Rizvi NA, Hellmann MD, Snyder A, et al. Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science. 2015; 384(6230):124-8. [Abstract]
  9. Rosenberg JE, Hoffman-Censits J, Powles T, et al. Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial. Lancet. 2016; 387(10031):1909-20. [Abstract]
  10. Motzer RJ, Escudier B, McDermott DF, et al. Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015; 373(19):1803-13. [Abstract]
  11. Snyder A, Makarov V, Merghoub T, et al. Genetic basis for clinical response to CTLA-4 blockade in melanoma. N Engl J Med. 2014; 371(23):2189-99. [Abstract]
  12. Mellman I, Coukos G, Dranoff G. Cancer immunotherapy comes of age. Nature. 2011;480(7378):480-9. [Abstract]
  13. Borghaei H, Paz-Ares L, Horn L, et al. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med. 2015;373(17):1627-39. [Abstract]
  14. Garon EB, Rizvi NA, Hui R, et al. Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med. 2015;372(21):2018-28. [Abstract]
  15. Taube JM, Klein A, Brahmer JR, et al. Association of PD-1, PD-1 ligands, and other features of the tumor immune microenvironment with response to anti-PD-1 therapy. Clin Cancer Res. 2014;20(19):5064-74. [Abstract]

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