MSI screening has long been recognized as important in the care of patients with colorectal cancer (CRC) or endometrial cancer, and high-frequency MSI (MSI-H) is now recognized as a potential marker for germline mutations in certain DNA mismatch repair (MMR) genes associated with Lynch syndrome.
Tumors with defects in the expression of functional MMR (dMMR) proteins often have somatic mutations that produce novel or “foreign” proteins. These proteins can be immunogenic. As a result, these tumors are effective at priming an immune response and subsequently susceptible to immunotherapies. Because MSI can be the first evidence of an MMR deficiency, MSI-H status is predicative of a positive response to immunotherapies such as immune checkpoint blockade inhibitors.
Deficiencies in DNA mismatch repair (dMMR) can be caused by hereditary, germline mutations or epigenetic silencing by hypermethylation. Lynch syndrome, which is linked to hereditary mutations that cause dMMR, is the most common form of hereditary colorectal cancer. In addition to colorectal cancer, Lynch syndrome increases the lifetime risk of developing certain other cancers (1).
The NCCN® guidelines provide recommendations for MSI by PCR and/or MMR by IHC for fifteen different cancer types.
Genetic counselor Heather Hampel is an advocate for universal tumor screening. Screening all tumors and Lynch-associated cancers could help identify those who have an increased risk for colorectal and other cancers. As well as identifying tumors most likely to respond to immunotherapeutics.
The 2015 paper by Le et al. (3) reported the extended analysis on the efficacy of PD-1 blockade in patients with advanced mismatch repair-deficient cancers of both colorectal cancer and non-colorectal origins. Following 41 patients, the study found that patients with mismatch repair deficient tumors, experienced an objective response rate of 40% and a progression-free survival rate of 78%. In contrast, the objective response rate was 0% and the progression-free survival rate was 11% for mismatch repair-proficient patients (3).
Molecular Biomarkers for the Evaluation of Colorectal Cancer 2017
The American Society for Clinical Pathology, College of American Pathologists, Association for Molecular Pathology, and American Society of Clinical Oncology published guidelines for molecular biomarker testing for colorectal cancer tissues in 2017 (4).
This guideline validates immunohistochemical detection of MMR proteins as a trustworthy method for identification of loss of expression of individual MMR proteins in paraffin sections of colorectal cancer. At the same time, it recognizes that loss of MMR protein immunoreactivity is generally detected in dMMR colorectal cancer, but normal immunoreactivity can be seen in up to 10% of dMMR cases. As a result, the guidelines further recognize the value of MSI DNA testing either stepwise or as a concurrent test.
National Comprehensive Cancer Network (NCCN) Guidelines
The panel of twenty-eight leading cancer centers recommends tumor testing with MSI by PCR and/or IHC as the primary approach for universal screening and for guiding treatment decisions. It recommends all patients with colorectal cancer be screened by MSI by PCR and/or IHC. In addition to colorectal cancer, the panel recommends MSI screening for fourteen additional tumor types.
European Society for Medical Oncology (ESMO) recommendations
A recent report on immunotherapy in metastatic colorectal cancer showed an unacceptable percentage of patients (almost 10%) had been enrolled in immunotherapy trials and experienced failure due to false positive dMMR or MSI-PCR results assessed by local laboratories. Thus, the consensus panel recommends the use of both MSI by PCR and MMR by IHC to assess the eligibility to treatment with immune checkpoint inhibitors of metastatic colorectal cancer and other cancers of the Lynch syndrome spectrum (5).
- Latham, A. et al. (2018) Microsatellite Instability Is Associated With the Presence of Lynch Syndrome Pan-Cancer. J. Clin. Oncol. 36, 1–9.
- Hampel, H. and Chapelle, A. (2011) The Search for Unaffected Individuals with Lynch Syndrome: Do the Ends Justify the Means? Cancer Prev. Res. (Phila.) 4, 1–5.
- Le, D.T. et al. (2015) PD-1 Blockade in Tumors with Mismatch-Repair Deficiency. New Engl. J. Med. 372, 2509–20.
- Sepulveda, A.R. et al. (2017) 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. Diag. 19, 187–225.
- Luchini, C. et al. (2019) ESMO recommendations on microsatellite instability testing for immunotherapy in cancer, and its relationship with PD-1/PD-L1 expression and tumour mutational burden: a systematic review-based approach. Annals of Oncol Published online May 6, 2019.