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DNA Mismatch Repair and 5-FU: What's the Connection?

Some colon cancer patients don’t benefit from treatment with 5-FU based chemotherapy and may even have worse outcomes than if they no chemo at all.

Of every 100 people with colon cancer, about 15 will have cancers that arise when mistakes in DNA during cell division are not caught and fixed.  Scientists call this defective mismatch repair or dMMR.

More often, colon cancer occurs when mutations in chromosomes accumulate but DNA repair pathways remain intact and mismatch repair is proficient (pMMR). This is true for about 85 percent of colon cancer.

Both prognosis and the potential benefit from FU-based chemotherapy appear to be very different for these two types of colon cancer. Knowing mismatch repair status of colon tumors can help patients and their doctors make better treatment decisions.

Patients with defective mismatch repair have better disease-free and overall survival and don’t seem to benefit from 5-FU at either stage II or stage III.  Stage II patients with dMMR have significantly poorer overall survival if they get chemo after surgery.

Caution:  These results come from studies of 5-FU plus levamisole or 5-FU plus leucovorin.  They don’t include any information from the current standard treatments of FOLFOX or FLOX which contain oxaliplatin in addition to 5-FU and leucovorin.

Defective mismatch repair is uncovered when either tumors have microsatellite instability (MSI) or immunohistochemical tests can’t find the proteins that are expressed by genes that control mismatch repair — MLH1, MSH2, MSH6, and PMS2.  Measuring either MSI or lack of MLH1 or MSH2 expression gives similar results in deciding whether a tumor is mismatch defective or proficient.

Almost all defective mismatch repair tumors are located in the right side of the colon.  They are poorly differentiated, often have lots of mucus, and tend to be infiltrated with immune-system cells (lymphocytes). Some scientists speculate that it is this improved immune-response that gives them their survival advantage.

Daniel Sargent, Ph.D., and his team analyzed mismatch repair status in the tumors of 457 patients in five different clinical trials with stage II or III colon cancer who had received either FU-based chemotherapy after surgery to remove their cancer or surgery alone.  They then pooled their information with a group of 570 patients who had been analyzed earlier.  The entire set included 1,027 patients, including 165 (16 percent) with defective mismatch repair.

They analyzed the impact of either proficient or defective mismatch repair as both a prognosis marker (its effect on survival despite treatment) and predictive marker (if chemotherapy treatment changes outcomes).

Pooled Results

Mismatch Repair Status as a Prognostic Marker

  • Patients with defective mismatch repair (dMMR) who didn’t get 5-FU had significantly better disease-free and overall survival than patients with proficient mismatch repair (pMMR).
  • When patients got chemotherapy, mismatch repair status had no impact on survival.

Mismatch Repair Status as a Predictive Marker for FU- based chemotherapy

  • There was no benefit of FU-based chemotherapy for either stage II or stage III colon cancer patients with defective mismatch repair.
  • There was no benefit of FU chemo for stage II patients with proficient mismatch repair.
  • Stage III patients with pMMR did benefit from chemotherapy with 5-FU.
  • Stage II patients with dMMR had worse overall survival when they got 5-FU than when they had surgery alone.

Graph of Predictive Value of dMMR in Adjuvant Colon Cancer

Line graphs comparing progression-free survival for dMMR and pMMR tumors treated with either surgery or surgery plus chemotherapy

A — Stage II, dMMR
B–  StageIII dMMR
C — Stage II pMMR
D — Stage III pMMR

Click on graph to enlarge it.

Dr. Sargent’s analysis confirmed an earlier study reported in 2003 in the New England Journal of Medicine by Christine Ribic that found no benefit to treatment with 5-FU for patients with stage II or III colon cancer with high microsatellite stability, who may possibly be harmed by  5-FU-based chemotherapy and have a better overall prognosis after diagnosis.

His team concluded,

In conclusion, this prospectively specified analysis of data from randomized, clinical trials provides independent, supportive evidence of the following: dMMR colon cancers have a favorable stage adjusted prognosis compared with the majority of colon cancers; and patients with dMMR colon cancers do not benefit from FU based adjuvant therapy.

Further, they point out,

These findings support the conclusion that average-risk patients with colon cancer who are considered for FU based adjuvant therapy should have the tumor MMR status assessed to inform the likelihood of patient benefit of chemotherapy. Our conclusions are restricted to patients being considered for single agent, fluoropyrimidine-based therapy (ie, patients with stage II disease), and the conclusions provide guidance as to who should not be treated (ie, the dMMR subset). We believe that dMMR status in the setting of stage II disease should be considered a clinically useful marker of tumor biology and represents an additional step in individualized cancer therapy.

SOURCE: Sargent et al.,  Defective Mismatch Repair As a Predictive Marker for Lack of Efficacy of Fluorouracil-Based Adjuvant Therapy in Colon Cancer. Journal of Clinical Oncology, Volume 28, Number 20, pages 3219-3226,July 10, 2010.

Image:  Figure #2, Sargent et al., JCO

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3 Comments

  1. E Dalbec said:

    I would appreciate clarification on the term colon cancer as used in this study. . The term colon cancer not colorectal cancer is used throughout this article. Does this study only pertain to colon cancer diagnosis or does the term colon cancer include colorectal cancer as well? Thank you for your answer.

  2. Karen Lehman said:

    Please advise if you know of any trial treatment for a recuring colorectal cancer size 5X5X8.5cm not metastasized but attached to rectum,vaginal wall,uterus,tail bone. I have had surgery of colon 2years ago, recured almost immediately,had radiation and chemo a year ago and no further surgey. Tumor is growing slowly and starting to come out of rectum. Is there any laser or other means to localy prevent the growth of the tumor by ciiking the cancer cells or preventing blood flow to feed tumor? I am otherwise in good health.
    Thank you for your response,
    Karen Lehman

  3. Kate Murphy said:

    We know of no laser treatments that are used to treat rectal cancer.

    If your surgery was not done by a colorectal surgeon,we suggest you get a second opinion from one to see if further surgery might help now.

    You can find a colorectal surgeon in your area here.

    Also, an opinion from a large cancer center with a team of doctors including surgeons, medical oncologists, and radiologists might help you make a plan to deal with your tumors.

    You can find an NCI-designated cancer center in your state here.

    Further surgery or chemotherapy might be able to shrink your rectal tumor.

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