Cure Alveolar Soft Part Sarcoma International (iCureASPS)

“Where We Stand With Immunotherapy in Colorectal Cancer: Deficient Mismatch Repair, Proficient Mismatch Repair, and Toxicity Management”

dMMR CRC and pMMR CRC


ABSTRACT
With the recent U.S. Food and Drug Administration approvals of pembrolizumab and nivolumab for refractory deficient mismatch repair metastatic colorectal cancer, immune checkpoint inhibitors have now entered into clinical care for gastrointestinal cancers. Extensive ongoing efforts are exploring additional combinations of therapy in both deficient and proficient mismatch repair colorectal cancer. This review will outline the current status of such efforts and discuss the critical aspects of recognition and management of immune-related toxicities from checkpoint inhibitors.

PRACTICAL APPLICATIONS

All patients with colorectal cancer should undergo testing for microsatellite instability (mismatch repair) status.

Checkpoint blockade therapy shows dramatic response rates and durability of response in MSI-H (dMMR) colorectal cancer and is currently approved by the FDA for MSI-H (dMMR) after fluoropyrimidine, oxaliplatin, and irinotecan.

Because microsatellite‐stable (proficient mismatch repair) colorectal cancer does not respond to single-agent checkpoint blockade, new strategies are evaluating combinations with chemotherapy, vaccines, depletion of myeloid-derived suppressor cells, and depletion of regulatory T cells.

A high index of suspicion should be maintained for immune-related adverse events caused by checkpoint blockade, which can affect any organ system.

Treatment of suspected severe immune-related adverse events is generally 1 mg/kg of prednisone or equivalent. Refractory autoimmunity may require additional immune modulators.




https://ascopubs.org/doi/full/10.1200/EDBK_200821

UNDERSTANDING MISMATCH REPAIR AND MICROSATELLITE INSTABILITY


MMR is one of the many mechanisms that cells use to repair damaged DNA. In particular, MMR recognizes and repairs insertions, deletions, and mis-incorporations of DNA bases during DNA replication. As expected, deficiency in the MMR system leads to the accumulation of mutations. Thus, CRCs with dMMR have a markedly elevated tumor mutation rate, with one study demonstrating a mean mutation rate of 1,782 for dMMR CRC compared with 73 for pMMR CRC.1 These types of DNA errors, which are recognized and repaired by MMR, preferentially occur at areas of DNA repeats, termed microsatellites. Because of this association, patients with dMMR will demonstrate variation in the length of various microsatellites when comparing normal and tumor sequences and this is termed MSI-H. Deficiency or dysfunction of MMR proteins such as MLH1, MSH2, MSH6, PMS2, and TACSTD1/EPCAM will result in dMMR.

Identification of dMMR can be accomplished by immunohistochemical staining for the complete loss of one of the four most common MMR proteins: MLH1, MSH2, MSH6, and PMS2. In addition, testing for variation in length of microsatellites can be used to diagnosis dMMR. The classic testing for MSI-H is based on consensus guidelines that recommend the testing of five specific microsatellites (BAT25, BAT26, D2S123, D5S346, and D17S250) via polymerase chain reaction with the determination of MSI-H based on instability (length variation between tumor and normal) at greater than 30% of tested microsatellites. More recently, large-coverage next-generation sequencing panels have demonstrated the ability to identify patients with dMMR by evaluating variation at a large number of microsatellites across the genome. In one recent report evaluating the next-generation sequencing MSI identification algorithm termed “MSIsensor”, the specificity and sensitivity were 100% and 99.3%, respectively, for 178 patients with CRC and endometrial cancer compared with MSI by polymerase chain reaction or immunohistochemistry.2 Given the strong concordance across the various dMMR/MSI-H methodologies, the FDA approvals for dMMR CRC, discussed below, were not based on a specific testing methodology.

Approximately 15% of CRCs have dMMR; however, this rate decreases by stage, with approximately 4% of patients with stage IV disease demonstrating dMMR. Of patients with dMMR, Lynch syndrome or hereditary nonpolyposis CRC will be present in about one-third of patients. The remainder of patients will have dMMR from sporadic acquisition, most commonly from methylation of MLH1, resulting in loss of MLH1 protein expression, or from biallelic mismatch repair somatic mutations. At present, it is recommended that all patients with metastatic CRC undergo testing for dMMR to identify not only patients with Lynch syndrome but also patients who could be treated with anti–PD-1 therapy.