The European Society of Medical Oncology (ESMO) has released a series of best practice recommendations on the implementation of detection of DNA mismatch repair in tumors.1 Because these mutations typically occur in monomorphic microsatellites, they are usually labeled as having microsatellite instability (MSI).

The expert panel said that with its article, it provided expert consensus-based recommendations for MSI definition and testing. “Furthermore,” the authors of the panel wrote, “studying the relationships among TMD [tumor mutational burden], MSI, and PD-1/PD-L1 expression, we highlight that their prevalence and role may differ based on tumour type and can be affected by several factors.”

The panel’s first recommendation was to use immunohistochemistry to test for MSI, using antibodies recognizing the 4 MMR proteins: MLH1, MSH2, MSH6, and PMS2. These proteins are codified by genes — and if these specific genes become inactivated, a defective MMR (dMMR) mechanism results.

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“MMR proteins form heterodimers; for a correct IHC interpretation, the consensus panel highlights that mutations in MLH1 are associated with IHC loss of both MLH1 and PMS2, while mutations in MSH2 are associated with IHC loss of both MSH2 and MSH6,” the panelists wrote. “There exist isolated losses of PMS2, MSH2 or MSH6 … strengthening the recommendation to use all 4 antibodies.”

Secondly, the recommendations said that if immunohistochemistry was in doubt, confirmatory analysis is mandatory using polymerase chain reaction (PCR). The 2 recommended PCR panels included a panel with 2 mononucleotide and 3 dinucleotide repeats, or a panel with 5 poly-A mononucleotide repeats. “Both the suggested panels have been and are being used to assess MSI in clinical trials,” the panelists wrote. “Molecular tests guarantee the highest values of specificity and sensitivity in MSI testing.”

The final recommendations discussed next-generation sequencing (NGS), another type of molecular test used to assess MSI. The main advantages of NGS is the possibility to couple MSI analysis with the determination of tumor mutational burden. However, the panel noted that NGS “should be carried out only in selected centers devoted to these techniques.”

The recommendations also detailed the use of MSI testing in different cancer types.

Disclosure: Some of the authors of the Annals of Oncology study disclosed ties to the pharmaceutical industry. For a full list of disclosures, please refer to the original study.

Reference

Luchini C, Bibeau F, Ligtenberg MJL, et al. ESMO recommendations on microsatellite instability testing for immunotherapy in cancer, and its relationship with PD-1/PD-L1 expression and tumor mutation burden: a systematic review-based approach [published online May 6, 2019]. Ann Oncol. doi: 10.1093/annonc/mdz116