Chemotherapeutic implications in microsatellite unstable colorectal cancer

Chemotherapy for colorectal cancer is currently offered to patients based on the stage of their cancer, and there is evidence to show an overall survival benefit with 5-fluorouracil-based (5-FU) therapy for patients with lymph node metastasis who receive it. The pathogenesis of colorectal cancer involves genomic instability, with about 15% of tumors demonstrating a form of genomic instability called high-frequency microsatellite instability (MSI-H) and due to loss of DNA mismatch repair function, and the remainder of colorectal tumors lacking MSI-H with retained DNA mismatch repair function and called microsatellite stable (MSS), with a large proportion of these tumors demonstrating another form of genomic instability called chromosomal instability. There is now evidence to show that the form of genomic instability that is present in a patient's colorectal cancer may predict a survival benefit from 5-FU. In particular, patients whose colorectal tumors have MSI-H do not gain a survival benefit with 5-FU as compared to patients with MSS tumors. In vitro evidence supports these findings, as MSI-H colon cancer cell lines are more resistant to 5-FU compared to MSS cell lines. More specifically, components of the DNA mismatch repair system have been shown to recognize and bind to 5-FU that becomes incorporated into DNA and which could be a trigger to induce cell death. The binding and subsequent cell death events would be absent in colorectal tumors with MSI-H, which have lost intact DNA mismatch repair function. These findings suggest that: (a) tumor cytotoxicity of 5-FU is mediated by DNA mechanisms in addition to well-known RNA mechanisms, and (b) patients whose tumors demonstrate MSI-H may not benefit from 5-FU therapy. Future studies should include a better understanding of the cellular mechanisms of the DNA recognition of 5-FU, multi-centered prospective trials investigating the survival benefit of 5-FU based on genomic instability, and the investigation of alternative chemotherapeutic regimens for patients with MSI-H tumors to improve survival.