Microsatellites are repeated sequences that are distributed throughout the genome. When microsatellites are copied incorrectly, the Mismatch Repair (MMR) system ensures surveillance and correction of these errors and ensures microsatellite stability. Defects in the MMR system lead to microsatellite instability (MSI) and are present in about 15% of all colon cancers. Tumors displaying a lack of one of the four MMR proteins, MLH-1, MSH-2, MSH-6 and PMS-2, are considered to have high frequency MSI (MSI-H) or deficient MMR (dMMR). When all 4 proteins are present and functioning in tumors, they are considered to be microsatellite stable (MSS) or proficient MMR (pMMR). MSI can be sporadic, specific to the tumor, or hereditary as in Hereditary Non-Polyposis Colon Cancer (HPNCC), also called Lynch Syndrome.
Current data for chemotherapy selection in Stage II colon cancer suggests that patients with MSI, or dMMR are less likely to respond to 5-Fluorouracil (5-FU) therapy. In fact, 5-FU may even be harmful to these patients. Patients that are MSS or pMMR, respond better to 5-FU and better tolerate the therapies side effects. The opposite is nearly true for irinotecan (Camptosar), where studies suggest that MSI, or dMMR patients may be more responsive to treatment than patients identified as MSS or pMMR. Oxaliplatin when combined with 5-FU and leucovorin (FOLFOX) also seems to have a better effect in MSI or dMMR patients, compared to those of MSS or pMMR patients. This was shown in a retrospective study analysis of Stage III CRC patients where the 3-year disease free survival (DFS) rate was 91% versus 74%, respectively. In short, there is mounting evidence to support the use of MSI testing, through the MMR system, to predict a patient’s personalized response to adjuvant therapy drugs in colorectal cancer.
