DNA repair system affects colon cancer recurrence and survival

About 15% of colorectal cancers are associated with mismatch repair defects. Some defects are caused by the inherited gene mutations found in Lynch syndrome and others occur by chance, or "sporadically." But it has never been clear whether mismatch repair defects are linked to cancer recurrence rates, time-to-recurrence and site of recurrence and whether such defects influence response to chemotherapy.

To explore these questions, Frank A. Sinicrope, M.D., of the Mayo Clinic in Rochester, Minn., and colleagues analyzed data from more than 2,000 clinical trial patients who had been treated after surgery with chemotherapy that included 5-fluorouracil (5-FU), a standard drug used in colorectal cancer. All patients had stage II or III colon cancer.

The patients with defective mismatch repair had lower rates of tumor recurrence, longer remissions, fewer metastases, and better survival rates compared to those without the defects. Both overall survival and disease-free survival were improved.

Whether mismatch repair status influences response to 5-FU therapy has been a subject of some debate. In this study treatment with 5-FU reduced recurrence rates in stage III, regardless of mismatch repair status, but not stage II patients.

The researchers also compared the effects of 5-FU-based therapy in patients thought to have inherited mismatch repair defects versus those whose defects occurred sporadically. They suggest that 5-FU appeared to reduce recurrences only in those with inherited defects.

"In conclusion," they write, "our data demonstrate that patients with defective mismatch repair colon cancers have a statistically significant reduction in their rates of tumor recurrence, a delayed time to recurrence, and better survival rates" than those without the defects. They note that the difference between inherited and sporadic tumors, though a preliminary finding, warrants further study.

In an accompanying editorial, Sabine Tejpar,M.D., Ph.D., of University Hospital Gasthuisberg, Leuven, Belgium, and colleagues note that the influence of mismatch repair defects on patients' prognosis and response to 5-FU has long been a contentious issue. They say that this study, with its large number of samples, provides "valuable information about the prognostic and certainly the predictive role" of mismatch repair defects. The editorialists conclude that it will be important to validate whether patients should have their mismatch repair defects identified as hereditary or sporadic before deciding on chemotherapy with 5-FU.

Provided by Journal of the National Cancer Institute