How is MSI/dMMR status determined, and how does it influence immunotherapy decisions?

How is MSI/dMMR status determined, and how does it influence immunotherapy decisions?

• A. MSI/dMMR is assessed by PCR-based microsatellite instability testing or by immunohistochemistry for MMR proteins; MSI-H/dMMR tumors are more likely to respond to immune checkpoint inhibitors.
• B. MSI/dMMR status is determined by BRCA sequencing; it guides PARP inhibitor therapy.
• C. MSI/dMMR status is determined only by germline testing for MMR genes; has no therapy implications.
• D. MSI/dMMR status is not clinically useful.

Answer: (A)

Determining MSI/dMMR status identifies tumors that are more likely to respond to immune-based therapies. Mismatch repair deficiency is detected either by immunohistochemistry, which shows loss of one or more MMR proteins (such as MLH1, MSH2, MSH6, or PMS2), or by PCR-based microsatellite instability testing, which compares tumor DNA to normal tissue to see if microsatellite repeats are unstable. If instability is found at multiple markers, the tumor is classified as MSI-H; if MMR proteins are absent on IHC, it is dMMR. Why this matters for immunotherapy is that MSI-H/dMMR tumors tend to have a higher mutational burden, producing more neoantigens that can be recognized by the immune system. This makes them more responsive to immune checkpoint inhibitors that unleash T cells against cancer cells. Clinically, checkpoint inhibitors like pembrolizumab (and other PD-1/PD-L1 inhibitors) are approved for MSI-H/dMMR tumors across various cancer types, guiding treatment decisions beyond where the cancer originated. Other ideas, such as using BRCA sequencing for PARP inhibitors or relying solely on germline testing without therapy implications, don’t capture the primary method or the therapeutic consequence of MSI/dMMR status. And saying MSI/dMMR status isn’t clinically useful is incorrect given its predictive value for immunotherapy response.

Determining MSI/dMMR status identifies tumors that are more likely to respond to immune-based therapies. Mismatch repair deficiency is detected either by immunohistochemistry, which shows loss of one or more MMR proteins (such as MLH1, MSH2, MSH6, or PMS2), or by PCR-based microsatellite instability testing, which compares tumor DNA to normal tissue to see if microsatellite repeats are unstable. If instability is found at multiple markers, the tumor is classified as MSI-H; if MMR proteins are absent on IHC, it is dMMR.

Why this matters for immunotherapy is that MSI-H/dMMR tumors tend to have a higher mutational burden, producing more neoantigens that can be recognized by the immune system. This makes them more responsive to immune checkpoint inhibitors that unleash T cells against cancer cells. Clinically, checkpoint inhibitors like pembrolizumab (and other PD-1/PD-L1 inhibitors) are approved for MSI-H/dMMR tumors across various cancer types, guiding treatment decisions beyond where the cancer originated.

Other ideas, such as using BRCA sequencing for PARP inhibitors or relying solely on germline testing without therapy implications, don’t capture the primary method or the therapeutic consequence of MSI/dMMR status. And saying MSI/dMMR status isn’t clinically useful is incorrect given its predictive value for immunotherapy response.