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Benefits of Co-Testing

Co-Testing

MSI by PCR and dMMR by IHC provide fundamentally different information about tumor samples (1). Specifically, IHC provides information about the MMR proteins expressed in the sample, while MSI by PCR measures MMR function by detecting changes in DNA that results when major MMR function is lost. When used in parallel, these methods can increase the overall number of correctly characterized tumors to over 99%.

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Clinical Co-Testing Guidelines

“Although loss of MMR protein immunoreactivity is generally detected in dMMR colorectal cancer, normal immunoreactivity can be seen in up to 10% of dMMR cases; therefore, MSI DNA testing may be performed either stepwise or as a concurrent test”

–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 (5)

Recommendations for Co-Testing in Metastatic Colorectal Cancer

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 by 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 (6).

References:

  1. Zhang, et al. (2008) 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. Diagnostics 10, 301–7.
  2. Dudley, J.C. et al. (2016) Microsatellite Instability as a Biomarker for PD-1 Blockade. Clin. Cancer Res. 22, 813–820.
  3. Funkhouser et al. (2012) Relevance, pathogenesis, and testing algorithm for mismatch repair-defective colorectal carcinomas: a report of the association for molecular pathology. J. Mol. Diag. 14, 91–103
  4. Based on an internal analysis of publications comparing MSI-PCR v. IHC-dMMR in colorectal cancer from 2004–2018. Literature bundle available from Promega Medical Affairs upon request.
  5. 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.
  6. 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.