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

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

Research output: Contribution to journalArticle

282 Scopus citations

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 immunohisto- chemistry (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.

Original languageEnglish (US)
Pages (from-to)1814-1821
Number of pages8
JournalJournal of Clinical Oncology
Volume27
Issue number11
DOIs
StatePublished - Apr 10 2009
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Fingerprint Dive into the research topics of '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'. Together they form a unique fingerprint.

  • Cite this

    Bertagnolli, M. M., Niedzwiecki, D., Compton, C. C., Hahn, H. P., Hall, M., Damas, B., Jewell, S. D., Mayer, R. J., Goldberg, R. M., Saltz, L. B., Warren, R. S., & Redston, M. (2009). 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. Journal of Clinical Oncology, 27(11), 1814-1821. https://doi.org/10.1200/JCO.2008.18.2071