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Clinical Trial
. 2003 Jul 17;349(3):247-57.
doi: 10.1056/NEJMoa022289.

Tumor microsatellite-instability status as a predictor of benefit from fluorouracil-based adjuvant chemotherapy for colon cancer

Christine M Ribic  1 , Daniel J Sargent, Malcolm J Moore, Stephen N Thibodeau, Amy J French, Richard M Goldberg, Stanley R Hamilton, Pierre Laurent-Puig, Robert Gryfe, Lois E Shepherd, Dongsheng Tu, Mark Redston, Steven Gallinger
Affiliations
Clinical Trial

Tumor microsatellite-instability status as a predictor of benefit from fluorouracil-based adjuvant chemotherapy for colon cancer

Christine M Ribic et al. N Engl J Med. .

Abstract

Background: Colon cancers with high-frequency microsatellite instability have clinical and pathological features that distinguish them from microsatellite-stable tumors. We investigated the usefulness of microsatellite-instability status as a predictor of the benefit of adjuvant chemotherapy with fluorouracil in stage II and stage III colon cancer.

Methods: Tumor specimens were collected from patients with colon cancer who were enrolled in randomized trials of fluorouracil-based adjuvant chemotherapy. Microsatellite instability was assessed with the use of mononucleotide and dinucleotide markers.

Results: Of 570 tissue specimens, 95 (16.7 percent) exhibited high-frequency microsatellite instability. Among 287 patients who did not receive adjuvant therapy, those with tumors displaying high-frequency microsatellite instability had a better five-year rate of overall survival than patients with tumors exhibiting microsatellite stability or low-frequency instability (hazard ratio for death, 0.31 [95 percent confidence interval, 0.14 to 0.72]; P=0.004). Among patients who received adjuvant chemotherapy, high-frequency microsatellite instability was not correlated with increased overall survival (hazard ratio for death, 1.07 [95 percent confidence interval, 0.62 to 1.86]; P=0.80). The benefit of treatment differed significantly according to the microsatellite-instability status (P=0.01). Adjuvant chemotherapy improved overall survival among patients with microsatellite-stable tumors or tumors exhibiting low-frequency microsatellite instability, according to a multivariate analysis adjusted for stage and grade (hazard ratio for death, 0.72 [95 percent confidence interval, 0.53 to 0.99]; P=0.04). By contrast, there was no benefit of adjuvant chemotherapy in the group with high-frequency microsatellite instability.

Conclusions: Fluorouracil-based adjuvant chemotherapy benefited patients with stage II or stage III colon cancer with microsatellite-stable tumors or tumors exhibiting low-frequency microsatellite instability but not those with tumors exhibiting high-frequency microsatellite instability.

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Figures

Figure 1
Figure 1. Kaplan–Meier Estimates of Overall Survival among Patients with Stage II or Stage III Colon Cancer According to the Microsatellite-Instability Status of the Tumor
In the absence of adjuvant chemotherapy, the patients with tumors displaying high-frequency microsatellite instability had significantly longer overall survival than patients with tumors exhibiting microsatellite stability or low-frequency microsatellite instability (hazard ratio for death, 0.31 [95 percent confidence interval, 0.14 to 0.72]; P=0.004)(Panel A). When the analysis was limited to the group receiving adjuvant chemotherapy, patients with tumors exhibiting high-frequency microsatellite instability did not have a significant increase in overall survival as compared with patients with tumors exhibiting microsatellite stability or low-frequency microsatellite instability (hazard ratio for death, 1.07 [95 percent confidence interval, 0.62 to 1.86]; P=0.80)(Panel B). The analysis included data for eight years from the date of randomization.
Figure 2
Figure 2. Kaplan–Meier Estimates of Overall Survival among Patients with Stage II or Stage III Colon Cancer According to Treatment Status
Patients with tumors exhibiting microsatellite stability or low-frequency microsatellite instability who received adjuvant chemotherapy had a significant increase in overall survival as compared with patients who received no adjuvant chemotherapy (hazard ratio for death, 0.69 [95 percent confidence interval, 0.50 to 0.94]; P=0.02) (Panel A). Among patients with tumors exhibiting high-frequency microsatellite instability, there was no significant difference in the duration of overall survival between patients who received adjuvant chemotherapy and those who did not (hazard ratio for death, 2.17 [95 percent confidence interval, 0.84 to 5.55]; P=0.10) (Panel B). The analysis included data for eight years from the date of randomization.
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Comment in

  • Microsatellite instability.
    de la Chapelle A. de la Chapelle A. N Engl J Med. 2003 Jul 17;349(3):209-10. doi: 10.1056/NEJMp038099. N Engl J Med. 2003. PMID: 12867603 No abstract available.
  • Microsatellite instability in colon cancer.
    Allegra CJ, Kim G, Kirsch IR. Allegra CJ, et al. N Engl J Med. 2003 Oct 30;349(18):1774-6; author reply 1774-6. doi: 10.1056/NEJM200310303491818. N Engl J Med. 2003. PMID: 14585950 No abstract available.
  • Microsatellite instability in colon cancer.
    Iacopetta B, Elsaleh H, Zeps N. Iacopetta B, et al. N Engl J Med. 2003 Oct 30;349(18):1774-6; author reply 1774-6. N Engl J Med. 2003. PMID: 14593997 No abstract available.
  • Microsatellite instability in colon cancer.
    Jimenez JJ, Blanes A, Diaz-Cano SJ. Jimenez JJ, et al. N Engl J Med. 2003 Oct 30;349(18):1774-6; author reply 1774-6. N Engl J Med. 2003. PMID: 14593998 No abstract available.

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