Defective mismatch repair as a predictive marker for lack of efficacy of fluorouracil-based adjuvant therapy in colon cancer.
OBJECTIVE
Prior reports have indicated that patients with colon cancer who demonstrate high-level microsatellite instability (MSI-H) or defective DNA mismatch repair (dMMR) have improved survival and receive no benefit from fluorouracil (FU) -based adjuvant therapy compared with patients who have microsatellite-stable or proficient mismatch repair (pMMR) tumors. We examined MMR status as a predictor of adjuvant therapy benefit in patients with stages II and III colon cancer.


METHODS
MSI assay or immunohistochemistry for MMR proteins were performed on 457 patients who were previously randomly assigned to FU-based therapy (either FU + levamisole or FU + leucovorin; n = 229) versus no postsurgical treatment (n = 228). Data were subsequently pooled with data from a previous analysis. The primary end point was disease-free survival (DFS).


RESULTS
Overall, 70 (15%) of 457 patients exhibited dMMR. Adjuvant therapy significantly improved DFS (hazard ratio [HR], 0.67; 95% CI, 0.48 to 0.93; P = .02) in patients with pMMR tumors. Patients with dMMR tumors receiving FU had no improvement in DFS (HR, 1.10; 95% CI, 0.42 to 2.91; P = .85) compared with those randomly assigned to surgery alone. In the pooled data set of 1,027 patients (n = 165 with dMMR), these findings were maintained; in patients with stage II disease and with dMMR tumors, treatment was associated with reduced overall survival (HR, 2.95; 95% CI, 1.02 to 8.54; P = .04).


CONCLUSIONS
Patient stratification by MMR status may provide a more tailored approach to colon cancer adjuvant therapy. These data support MMR status assessment for patients being considered for FU therapy alone and consideration of MMR status in treatment decision making.
Sargent
Daniel J
DJ
Division of Biomedical Statistics and Informatics, Department of Pathology, Mayo Clinic, Rochester, MN 55905, USA. sargent.daniel@mayo.edu
Marsoni
Silvia
S
Monges
Genevieve
G
Thibodeau
Stephen N
SN
Labianca
Roberto
R
Hamilton
Stanley R
SR
French
Amy J
AJ
Kabat
Brian
B
Foster
Nathan R
NR
Torri
Valter
V
Ribic
Christine
C
Grothey
Axel
A
Moore
Malcolm
M
Zaniboni
Alberto
A
Seitz
Jean-Francois
JF
Sinicrope
Frank
F
Gallinger
Steven
S
D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use; D015415:Biomarkers; D017024:Chemotherapy, Adjuvant; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality / Q000473:pathology; D003131:Combined Modality Therapy; D053843:DNA Mismatch Repair; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D016032:Randomized Controlled Trials as Topic
D000964:Antimetabolites, Antineoplastic; D015415:Biomarkers; D005472:Fluorouracil