FOLFOX Effectiveness Not Related to DNA Mismatch Repair or MSI

Colon cancers that are caused by defects in genes that repair damaged DNA don’t respond well to 5-FU treatment after surgery.

However, a new analysis of patients treated with FOLFOX (oxaliplatin, leucovorin, and 5-FU) found no differences between patients with deficient mismatch repair tumors and those with normal gene expression.

In this small study of 135 patients, the research team concluded that adding oxaliplatin to 5-FU and leucovorin may overcome resistance to chemotherapy in mismatch repair deficient and microsatellite instable (MSI) colon cancer.

South Korean researchers analyzed tumors from patients with stage II, III, or IV colorectal cancer, all of whom had surgery that completely removed all visible signs of cancer.  The 14 patients with stage IV cancer had liver metastases only, which were successfully removed.

They studied two genes related to deficient DNA repair — MLH1 and MSH2.  They also used genotyping to determine microsatellite instability (MSI), and stained tumors for the expression of p53 protein.

They found that:

  • About 1 in 10  tumors were MSI-high (MSI-H); 9 out of 10 were MSI-low or microsatellite stable (MSI-L/S).
  • Similarly, almost 10 percent showed deficient mismatch repair gene expression (MMR-D).
  • There was almost complete agreement (94.7 percent) between the MSI-high and deficient mismatch repair specimens.

Comparing results to disease-free and overall survival, the study showed:

  • There was no difference between patients with deficient and intact DNA mismatch repair for either disease-free or overall survival.
  • p53 expression made no difference in either disease-free or overall survival.
  • For patients with agreement between genotyping and immunohistochemical tests, microsatellite instability — either high or low/stable — also made no difference in disease-free or overall survival.

Seung Tae Kim and the team in Seoul concluded,

The MMR status or p53 positivity was not significantly associated with outcomes to FOLFOX as adjuvant chemotherapy in colon cancer patients with R0 resection. Adding oxaliplatin in adjuvant chemotherapy may overcome negative impact of 5-FU on colon cancers with MSI-H/MMR-D.

SOURCE: Kim et al., Cancer Chemotherapy and Pharmacology,Online First, December 24, 2009.

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Comments

  1. Northern California supporters of C3 says

    Could you please elaborate on the concluding sentence: “Adding oxaliplatin in adjuvant chemotherapy may overcome negative impact of 5-FU on colon cancers with MSI-H/MMR-D.”

    I am unclear what that means in terms of whether adding oxaliplatin does increase effectiveness for treatment for colorectal (colon and rectal) cancers?

    Thank you!

  2. Kate Murphy says

    First, realize that the phrase “Adding oxaliplatin in adjuvant chemotherapy may overcome negative impact of 5-FU on colon cancers with MSI-H/MMR-D” was the conclusion reached by the authors of the South Korean study.

    It was not a conclusion that C3 drew.

    This study was looking at the possibility that oxaliplatin might overcome the resistance to 5-FU treatment in a small group of people with colon cancer whose cancer comes from changes in the genes that repair damaged DNA (about 15 percent of colorectal cancers.)

    The researchers found no difference in survival benefits between groups of patients who had these gene changes (deficient mismatch repair) or those who did not. That led them to believe that adding oxaliplatin to 5-FU might be a better treatment for those patients than 5-FU alone.

    We do know from other research that adding oxaliplatin to 5-FU reduces recurrences and increases overall survival for stage III and stage IV colon cancer and high-risk stage II colon cancer.

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