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.

Abstract

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.

• Authors: Monica M Bertagnolli, Donna Niedzwiecki, Carolyn C Compton, Hejin P Hahn, Margaret Hall, Beatrice Damas, Scott D Jewell, Robert J Mayer, Richard M Goldberg, Leonard B Saltz, Robert S Warren, Mark Redston
• Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology (J Clin Oncol) Vol. 27 Issue 11 Pg. 1814-21 (Apr 10 2009) ISSN: 1527-7755 [Electronic] United States
• PMID: 19273709 (Publication Type: Clinical Trial, Phase III, Journal Article, Randomized Controlled Trial, Research Support, N.I.H., Extramural)

Chemical References

• Irinotecan
• Leucovorin
• Fluorouracil
• Camptothecin

Topics

• Adult
• Aged
• Aged, 80 and over
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Camptothecin (administration & dosage, analogs & derivatives)
• Chemotherapy, Adjuvant
• Colonic Neoplasms (drug therapy, genetics)
• Female
• Fluorouracil (administration & dosage)
• Humans
• Irinotecan
• Leucovorin (administration & dosage)
• Male
• Microsatellite Instability
• Middle Aged
• Neoplasm Staging
• Prognosis
• Prospective Studies
• Survival Analysis
• Young Adult