Originally published as JCO Early Release 10.1200/JCO.2008.18.2071 on March 9 2009

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Microsatellite Instability Predicts Improved Response to Adjuvant Therapy With Irinotecan, Fluorouracil, and Leucovorin in Stage III Colon Cancer: Cancer and Leukemia Group B Protocol 89803

From the Brigham and Women's Hospital; Dana-Farber Cancer Institute, Boston, MA; Cancer and Leukemia Group B Statistical Center, Duke University Medical Center, Durham; University of North Carolina at Chapel Hill, Chapel Hill, NC; National Cancer Institute, Bethesda, MD; Ohio State University, Columbus, OH; Memorial Sloan-Kettering Cancer Center, New York, NY; and the University of California at San Francisco, San Francisco, CA.

Corresponding author: Monica M. Bertagnolli, MD, Brigham and Women's Hospital, 75 Francis St, Boston, MA 02115; e-mail: mbertagnolli{at}partners.org.

Purpose Colon cancers exhibiting DNA mismatch repair (MMR) defects demonstrate distinct clinical and pathologic features, including better prognosis and reduced response to fluorouracil (FU) –based chemotherapy. This prospective study investigated adjuvant chemotherapy containing FU and irinotecan in patients with MMR deficient (MMR-D) colon cancers.

Patients and Methods Cancer and Leukemia Group B 89803 randomly assigned 1,264 patients with stage III colon cancer to postoperative weekly bolus FU/leucovorin (LV) or weekly bolus irinotecan, FU, and LV (IFL). The primary end point was overall survival; disease-free survival (DFS) was a secondary end point. Tumor expression of the MMR proteins, MLH1 and MSH2, was determined by immunohistochemistry (IHC). DNA microsatellite instability was also assessed using a panel of mono- and dinucleotide markers. Tumors with MMR defects were those demonstrating loss of MMR protein expression (MMR-D) and/or microsatellite instability high (MSI-H) genotype.

Results Of 723 tumor cases examined by genotyping and IHC, 96 (13.3%) were MMR-D/MSI-H. Genotyping results were consistent with IHC in 702 cases (97.1%). IFL-treated patients with MMR-D/MSI-H tumors showed improved 5-year DFS as compared with those with mismatch repair intact tumors (0.76; 95% CI, 0.64 to 0.88 v 0.59; 95% CI, 0.53 to 0.64; P = .03). This relationship was not observed among patients treated with FU/LV. A trend toward longer DFS was observed in IFL-treated patients with MMR-D/MSI-H tumors as compared with those receiving FU/LV (0.57; 95% CI, 0.42 to 0.71 v 0.76; 95% CI, 0.64 to 0.88; P = .07; hazard ratio interaction between tumor status and treatment, 0.51; likelihood ratio P = .117).

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

Supported in part by Grant No. CA31946 (to the Cancer and Leukemia Group B; Richard L. Schilsky, MD, Chair) and Grant No. CA33601 (to the Cancer and Leukemia Group B Statistical Center; Stephen George, PhD) from the National Cancer Institute.

The content of this article is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

Clinical Trials repository link available on JCO.org.

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