Mismatch Repair Deficiency in Colorectal Cancer

The prognostic impact of mismatch repair (MMR) deficiency in stage III colorectal cancer (CRC) remains unclear, as clinical trials continue to assess this genetic defect. In a retrospective study of patients treated with FOLFOX with or without cetuximab, MMR status was not prognostic, nor was there any difference in outcome, explains John Marshall, MD.

Some of the variation in outcomes that have been observed could be a result of chromosomal aberrations that differ between stage II and III CRC, suggests Richard L. Goldberg, MD. Approximately 15% of stage II disease is MMR enzyme deficient, which is significantly more than for stage III or IV tumors, notes Howard S. Hochster, MD.

At this point, treatment should not be withheld for patients with stage III disease based on microsatellite stability-high (MSI-H) or MMR deficiency, suggests Fadi Braiteh, MD. However, individuals with stage II CRC and MMR deficiency do not seem to benefit from chemotherapy. Data have suggested that patients with MSI-H tumors may be harmed by 5-fluorouracil chemotherapy, comments Goldberg. It is challenging to determine whether chemotherapy is potentially harmful in this setting because prospective data in this field are lacking, states Hochster.

Outside of prognostic qualities, the panelists recommend universal staining for MMR deficiency for patients with CRC, given the connection to hereditary syndromes. Furthermore, as more research uncovers the importance of immune checkpoint inhibitors, the role of MMR deficiency could rapidly change.

In a study presented at the ASCO Annual Meeting, treatment with pembrolizumab demonstrated an objective response rate of 62% in patients with CRC who had MMR deficiencies. This was compared with 0% in patients with MMR-proficient tumors. Median progression-free survival and overall survival were not reached, with many patients responding to treatment for longer than 12 months in the MMR-deficient arm. The main toxicities with pembrolizumab are primarily due to the activation of the immune system, resulting in immune endocrine deficiencies and immune lung disease, explains Goldberg.

One explanation for the lack of prognostic ability for MMR is that current chemotherapy may be destroying lymphocytes that are helping to contain micrometastatic disease, explains Goldberg. PD-1 inhibition could be effective, since it activates stimulatory molecules in the immune system.