Faculty Perspectives: Clinical Relevance and Rationale of Using MSI-H/dMMR Biomarkers in Immunotherapy of Colorectal Cancer and Other Solid Tumors | Part 3 of a 4-Part Series

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Clinical Relevance and Rationale of MSI-H/dMMR as a Biomarker in Patients with Cancer

Previously, testing for microsatellite instability (MSI) or mismatch repair deficiency (dMMR) has been performed as a screening test to identify patients with Lynch syndrome in colorectal and endometrial cancer, in addition to providing prognostic and predictive data in colo­rectal cancer (CRC).1-3 However, with the recent US Food and Drug Administration approval of pembrolizumab with MSI/dMMR as a companion biomarker, pathologists must re-evaluate their approach to MSI/dMMR testing. MSI has been characterized in at least 14 different tumor types, albeit at varying frequencies, and there is evidence to suggest that traditional polymerase chain reaction (PCR)-based MSI testing, which was optimized for colon cancer, may not be the best approach to identify MSI in other tumor types.4 Studies examining the landscape of MSI in various cancers have shown that different tumor types tend to exhibit instability at different microsatellite loci throughout the genome, and a PCR-based test that is limited to the evaluation of only 5 loci may not adequately capture this heterogeneity.4 These issues must be kept in mind when evaluating approaches to implement more universal MSI/dMMR testing to identify patients who may respond to immune checkpoint inhibitors.

Next-generation sequencing (NGS) offers many advantages, such as streamlining and integrating the growing number of tests and biomarkers that are required from a single pathology specimen. For example, MSI can be easily incorporated into a targeted cancer NGS panel, as it is currently being done in many molecular diagnostic laboratories, which offers the advantage of simultaneously detecting instability across tens to hundreds of microsatellite loci, potentially alleviating some of the limitations present in the PCR-based panels. This is a particularly attractive option for MSI/dMMR testing when other molecular alterations are already being investigated for clinical care and patient management, such as extended RAS mutation testing in CRC. Additionally, NGS has the advantage of being able to detect other emerging biomarkers for immunotherapy, including tumor mutational burden and POLE/POLD1 mutations that are associated with a high mutation rate and neoantigen load.5-7 However, limitations exist for this approach, such as the lack of universal reimbursement for NGS testing, and pathologists will likely still need to employ other methods of MSI/dMMR testing, such as immunohistochemistry and PCR. Because immunotherapy biomarkers are currently a dynamic area of active investigation, pathologists must be mindful of the most effective ways to implement these biomarkers in our laboratories to maximize utilization and improve patient care.

References

  1. Adar T, Rodgers LH, Shannon KM, et al. Universal screening of both endometrial and colon cancers increases the detection of Lynch syndrome. Cancer. 2018;124:3145-3153.
  2. Buza N, Ziai J, Hui P. Mismatch repair deficiency testing in clinical practice. Expert Rev Mol Diagn. 2016;16:591-604.
  3. Vilar E, Gruber SB. Microsatellite instability in colorectal cancer—the stable evidence. Nat Rev Clin Oncol. 2010;7:153-162.
  4. Hause RJ, Pritchard CC, Shendure J, Salipente SI. Classification and characterization of microsatellite instability across 18 cancer types [published corrections appear in Nat Med. 2017;23:1241 and Nat Med. 2018;24:525]. Nat Med. 2016;22:1342-1350.
  5. Hellmann MD, Ciuleanu T-E, Pluzanski A, et al. Nivolumab plus ipilimumab in lung cancer with a high tumor mutational burden. N Engl J Med. 2018;378:2093-2104.
  6. Howitt BE, Shukla SA, Sholl LM, et al. Association of polymerase e-mutated and microsatellite-instable endometrial cancers with neoantigen load, number of tumor-infiltrating lymphocytes, and expression of PD-1 and PD-L1. JAMA Oncol. 2015;1:1319-1323.
  7. Castellucci E, He T, Goldstein DY, et al. DNA polymerase deficiency leading to an ultramutator phenotype: a novel clinically relevant entity. Oncologist. 2017;22:497-502.
Uncategorized - October 29, 2018

Clinical Relevance and Rationale of Using MSI-H/dMMR Biomarkers in Immunotherapy of Colorectal Cancer and Other Solid Tumors

There is renewed interest in MSI analysis because the MSI-H/dMMR phenotype has emerged as an actionable predictive biomarker for immune checkpoint blockade therapy in different cancer types. This review presents available evidence supporting the clinical relevance and predictive value of MSI/dMMR in cancers, including those treated with immune checkpoint inhibitors (ICIs), and outlines the diagnostic approaches developed to assess MSI/dMMR in clinical practice.

Uncategorized - October 29, 2018

The Importance of MSI/dMMR as Biomarkers in Oncology

Genotyping tumors for microsatellite instability (MSI) has taken on new importance in the world of oncology. MSI screening has long been recognized as important in the care of patients with colorectal cancer (CRC) or endometrial cancer, and high-level MSI (MSI-H) is now being recognized as a potential marker for germline [ Read More ]