Tumor microsatellite-instability status as a predictor of benefit from fluorouracil-based adjuvant chemotherapy for colon cancer.
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.
Ribic
Christine M
CM
Centre for Cancer Genetics, Samuel Lunenfeld Research Institute, Toronto.
Sargent
Daniel J
DJ
Moore
Malcolm J
MJ
Thibodeau
Stephen N
SN
French
Amy J
AJ
Goldberg
Richard M
RM
Hamilton
Stanley R
SR
Laurent-Puig
Pierre
P
Gryfe
Robert
R
Shepherd
Lois E
LE
Tu
Dongsheng
D
Redston
Mark
M
Gallinger
Steven
S
D000704:Analysis of Variance; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use*; D020137:Base Pair Mismatch; D017024:Chemotherapy, Adjuvant; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality / Q000601:surgery; D004260:DNA Repair; D004273:DNA, Neoplasm / Q000032:analysis*; D005472:Fluorouracil / Q000627:therapeutic use*; D005500:Follow-Up Studies; D006801:Humans; D018895:Microsatellite Repeats / Q000235:genetics*; D009367:Neoplasm Staging; D011379:Prognosis; D016019:Survival Analysis
D000964:Antimetabolites, Antineoplastic; D004273:DNA, Neoplasm; D005472:Fluorouracil