Colorectal cancers with microsatellite instability: Treatment advances and questions

Résumé 0

The Microsatellite Instability (MSI) phenotype is related to a deficiency in the DNA mismatch repair system (dMMR) and is observed in 5% of metastatic colorectal cancers (mCRC). The dMMR/MSI phenotype should be routinely tested for in all CRCs regardless of stage. Two complementary techniques with a high concordance (90–97%) are used to determine the dMMR/MSI status of a tumor: immunohistochemistry (IHC) and Polymerase Chain Reaction (PCR). Since 2020 and the presentation of the results of the phase III KEYNOTE-177 study, pembrolizumab has become the new first-line standard of care for patients with dMMR/MSI mCRC. Currently, there is no validated combination of chemotherapy ± targeted therapy with immune checkpoint inhibitors (ICIs) in the management of dMMR/MSI mCRC, and it is not known whether the combination of chemotherapy with ICIs is beneficial. It is also not known whether a combination of two ICIs is more effective than monotherapy. Several phase III trials are underway to answer these questions. Despite the high response rate and durable efficacy of first-line anti-PD1 therapy, 30–50% of patients with dMMR/MSI mCRC progress either immediately or secondarily. There is currently no clinically validated predictive biomarker of resistance to anti-PD1 anti-CTLA4 in these patients. In the event of early progression when ICIs are used, the possibility of pseudoprogression or misdiagnosis of dMMR/MSI status should be assessed. To date, there is no data on the use of ICIs in the adjuvant setting for resected dMMR/MSI CRC. However, an increasing amount of data is being produced on the efficacy of neoadjuvant ICIs in CRC, with studies showing that two-thirds of patients have a pathologic complete response (pCR), which could lead to the development of “Watch-and-Wait” strategies in the future.