Aldo Scarpa, MD, PhD
Since the first tumor-agnostic immunotherapy was approved in 2017, questions about optimal procedures for biomarker testing have become more pressing. A Working Group of the European Society for Medical Oncology (ESMO) has determined that a decision tree on the sequential use of different tests in immunotherapy decision-making cannot be a general one for all cancers but should be designed on the basis of the specific tumor type.
To better understand the rationale behind testing methodologies, the collaborative group examined the mechanisms underlying DNA mismatch repair (MMR) across different solid tumors.
Table 1. Definitions of MSI and MSI-Related Terms1,4 (Click to Enlarge)
The MMR proteins form heterodimers consisting of MLH1 and PMS2 or MSH2 and MSH6. MLH1 and MSH2 are considered the “obligatory partners” in these protein pairs; alterations in them interfere with dimerization and result in proteolytic degradation of both proteins in the heterodimer. However, the same is not necessarily true of the “secondary partners,” PMS2 and MSH6, because other proteins may substitute for them in the heterodimer. Therefore, functional heterodimers may be present despite PMS2
For the spectrum of cancers associated with Lynch syndrome, immunohistochemistry (IHC) of all 4 MMR proteins is the first line of testing. Subsequently, MSI–polymerase chain reaction (PCR) molecular testing of specific microsatellite loci is indicated for cases in which IHC results are indeterminate, such as the loss of only 1 heterodimer subunit.
“When you have an alteration of a secondary partner, you may have an immunohistochemistry [result that] is not informative because you do not have the loss of both partners,” Scarpa said. “This is because PMS2 may be substituted for PMS1 or MLH3, and MSH6 may be substituted for MSH3. Alterations of secondary proteins may be compensated by other partners, and so the machinery is working.”
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