MSI-MMR testing

When assessing MSI/MMR status

Quality testing is critical¹

Validation of MSI/MMR testing assays can be important for the accuracy of the results and proper patient care¹

Pre-analytics¹

• If available and adequate, metastatic or recurrent CRC tissues should be used for MSI/MMR testing.^a
• Formalin-fixed, paraffin-embedded samples are acceptable for MSI/MMR testing.^a

Follow good clinical practice and available guidelines for MSI/MMR sample acquisition, preparation, and processing.

Analytics¹

• Laboratories must use validated biomarker testing methods to assess MSI/MMR status.^b
• Laboratories should verify assay accuracy using validated methods or interlaboratory comparisons.^b
• Laboratories should establish policies to ensure efficient tissue utilization and timeliness of testing.^a

Use testing protocols validated in accordance with best laboratory practices to ensure accurate results.

Post-analytics¹

• Laboratories should validate software used to analyze tissue samples for MSI status, with verification of updates.
• Patient reports should include specimen adequacy findings, a results and interpretation section, and considerations for treatment.

Consult available guidelines and resources to develop accurate and timely reporting protocols.

Monitoring quality¹

• Laboratories should implement quality improvement programs and participate in formal proficiency testing programs.^b
• Laboratories should take steps to ensure consistency throughout the testing and reporting process.^b
• MSI/MMR testing validation protocols should be informed by evidence-based guidelines and other published clinical literature.

Participate in formal proficiency testing programs to assess the reliability and accuracy of MSI/MMR testing.

^aExpert consensus opinion with serious limitations in strength or quality of evidence.^1
bStrong recommendation supported by convincing or adequate strength or quality of evidence.¹

CRC = colorectal cancer; MMR = deficient mismatch repair; MSI = microsatellite instability

Reference:

1. Sepulveda AR, Hamilton SR, Allegra CJ, et al. Molecular biomarkers for the evaluation of colorectal cancer: guideline from the American Society for Clinical Pathology, College of American Pathologists, Association for Molecular Pathology, and American Society of Clinical Oncology. J Mol Diagn. 2017;19(2):187–225.

Testing expression of all MMR proteins may help identify patients who are eligible for KEYTRUDA^®1,2

The determination of MMR status and/or MSI status is recommended by ComPerMed³

IHC Detects the Presence or Absence of MMR Protein Expression^2,4,5,6,7
Examples of MMR Test Results

ComPerMed = Personalised Medicine Commission; dMMR = Mismatch repair deficient;IHC = immunohistochemistry; MLH1 = MutL homolog 1; MMR = mismatch repair; MSH2 = MutS homolog 2; MSH6 = MutS homolog 6; MSI = microsatellite instability; MSI-H = Microsatellite Instability High; PMS2 = Postmeiotic Segregation 1 homolog 2

Reference:

1. SmPC KEYTRUDA^® 03/2021
2. Chen W, et al. practical guide to biomarkers for the evaluation of colorectal cancer. Mod Pathol. 2019;32(Suppl 1): S1-S15. doi:10.1038/s41379-018-0136-1.
3. ComPerMed workflow on colorectal cancer – October 2020
4. Zhang X, et al. Era of universal testing of microsatellite instability in colorectal cancer. World J Gastrointest Oncol. 2013;5(2):12–19
5. Genoptix, Inc. Stain images. Used with permission. 2016.
6. Lin C-H, et al. Molecular profile and copy number analysis of sporadic colorectal cancer in Taiwan. J Biomed Sci. 2011;18(1):36. doi:10.1186/1423-0127-18-36.
7. Gibson J, et al. Microsatellite instability testing in colorectal carcinoma: a practical guide. Clin Gastroenterol Hepatol. 2014;12(2):171–176.

Test for MSI/MMR status at the time of diagnosis for appropriate patients with CRC

ComPerMed recommends to test MMR proteins (MLH1, MSH2, MSH6, PMS2) and/or MSI for all CRC patients.¹

Approximately 15% of patients with CRC are MSI-H/dMMR.¹

MSI/MMR Status Should Be Clearly Reported to Help Identify metastatic colorectal Patients Appropriate for Treatment With KEYTRUDA^{® 2,3,4}

For treatment with KEYTRUDA® as monotherapy in first line, testing for MSI-H/dMMR tumour status using a validated test is recommended to select patients with CRC

ComPerMed = Personalised Medicine Commission; CRC = colorectal cancer; dMMR = mismatch repair deficient; IHC = immunohistochemistry; MLH1 = MutL homologue 1; MMR = mismatch repair;MSH2 = MutS homologue 2; MSH6 = MutS homologue 6; MSI = microsatellite instability; MSI-H = microsatellite instabilityhigh; MSI-L = microsatellite instability-low; MSS = microsatellite stable; PCR = polymerase chain reaction; PMS2 = postmeiotic segregation increased 2

Reference:

1. ComPerMed workflow on colorectal cancer – October 2020.
2. SmPC Keytruda 03/2021
3. Bartley AN, Hamilton SR, Alsabeh R, et al. Template for reporting results of biomarker testing of specimens from patients with carcinoma of the colon and rectum. Arch Pathol Lab Med. 2014;138(2):166–170.
4. Vilar E, Gruber SB. Microsatellite instability in colorectalcancer—the stable evidence. Nat Rev Clin Oncol. 2010;7(3):153–162.