About 15 percent of colon cancers develop when damaged DNA is not repaired and mutated cells grow into malignant tumors.  So-called deficient mismatch repair (dMMR) tumors have features different from most colorectal cancer, including a better prognosis.  They also have a very poor response to 5-FU-based chemotherapy.

However, researchers studying tumor tissue from patients enrolled in a clinical trial comparing 5-FU and leucovorin alone to 5-FU, leucovorin, and irinotecan found that those with deficient mismatch repair tumors who received irinotecan had better disease-free survival and overall survival at five years than patients whose mismatch repair genes were working.  Those with dMMR on the 5-FU-only arm of the trial had no similar benefit.

Deficient mismatch repair can be identified by measuring  mutated microsatellites — short lengths of DNA that are abnormally shorter or longer because they were not caught and corrected during cell division.  This is known as microsatellite instability or MSI. dMMR can also be diagnosed by looking for missing mismatch repair gene expression in tumor tissue.

To find out if there was any benefit for irinotecan in deficient mismatch repair tumors, researchers tested tissue saved after surgery for both MSI and loss of MLH1 and MSH2 gene expression from patients enrolled in the CALGB-89803 clinical trial.

CALGB-89803 randomly assigned stage III colon cancer patients after surgery to chemotherapy to an IV shot of 5-FU plus intravenous leucovorin (FU/LV) or the same 5-FU and leucovorin treatment plus irinotecan (IFL).   Chemotherapy was given every week.

For all of the nearly 1,300 people enrolled in the trial, there was no significant difference in overall survival after 5 years (70 percent for IFL and 72 percent for FU/LV).  There was a significant increase in toxic side effects in the IFL arm and some unexpected deaths.

However, when tumors were analyzed by deficient mismatch repair status (dMMR), as evidenced by high microsatellite instability (MSI-H) compared to intact mismatch repair (iMMR) or low or stable microsatellite stability (MSI-L/S), adding irinotecan did make a difference in disease free survival and overall survival five years after surgery:

Five year disease free survival

• All patients:  61 percent
• FU/LV and MMR-D (MSI-high): 57 percent
• FU/LV and MMR-I (MSI low or stable): 51 percent   (no significant difference)
• IFL and MMR-I: 59 percent
• IFL and MMR-D: 76 percent  (significant difference in this group)

Overall survival at five years

• All patients:  67 percent
• FU/LV MMR-D:  67 percent
• FU/LV MMR-I:   72 percent
• IFL  MMR-I:   70 percent
• IFL MMR-D: 78 percent  (significant difference in this group of patients)

Some, but not all, dMMR tumors are caused by inherited genetic mutations in mismatch repair genes.  Lynch syndrome or hereditary non-polyposis colon cancer (HNPCC) leads to colorectal, uterine, and other cancers through such inherited mutations.

Since colon cancer caused by deficient mismatch repair does not benefit from 5-FU chemotherapy, it is common to test for MSI or missing MLH1 or MSH2 gene expression in tissue removed during surgery before prescribing chemotherapy.  Testing tissue also screens for Lynch syndrome.

Monica M. Bertagnolli, M.D. and her colleague in the Cancer and Leukemia Group B (CALGB) concluded,

Loss of tumor MMR function may predict improved outcome in patients treated with the IFL regimen as compared with those receiving FU/LV.

SOURCE:  Bertagnolli et al., Journal of Clinical Oncology, Volume 17, Number 11, April 10, 2009.