Defective Mismatch Repair As a Predictive Marker for Lack of Efficacy of Fluorouracil-Based Adjuvant Therapy in Colon Cancer
Open accessAbstract
Purpose: 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). Conclusion: 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.
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SFM-C's better survival is probably because of enrichment of MSI phenotype.
“Moreover, although SFM-C displayed nonresponsive to FOLFIRI and FOLFOX, which was also consistent with previous studies suggesting MSI tumors barely responded to fluorouracil-based therapy42, it had better survival in this combined dataset probably because of the enrichment of MSI phenotype, which has been proofed to have relative better survival43.”
From A tumor microenvironment-specific gene expression signature predicts chemotherapy resistance in colorectal cancer patients (2021) · cites this paper as [42]
MSI tumors barely responded to fluorouracil-based therapy.
“which was also consistent with previous studies suggesting MSI tumors barely responded to fluorouracil-based therapy42”
From A tumor microenvironment-specific gene expression signature predicts chemotherapy resistance in colorectal cancer patients (2021) · cites this paper as [42]
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- Authors
- Sargent, D. J., Marsoni, S., Monges, G., Thibodeau, S. N., Labianca, R., Hamilton, S. R., French, A. J., Kabat, B., Foster, N. R., Torri, V., Ribic, C., Grothey, A., Moore, M., Zaniboni, A., Seitz, J.-F., Sinicrope, F., & Gallinger, S.
- Affiliations
- Mayo Clinic (US)
- Division of Biomedical Statistics and Informatics; Laboratory Medicine/Pathology; and Departments of Pathology, Medical Oncology, and Gastroenterology, Mayo Clinic, Rochester, MN; University of the Mediterranean; Department of Biopathology, Paoli Calmettes Institute, Marseilles, France; Department of Pathology and Laboratory Medicine, The University of Texas M. D. Anderson Cancer Center, Houston, TX; SENDO Foundation; Mario Negri Institute, Milan; Ospedali Riuniti, Bergamo; Fondazione Poliambulanza,...
- ORCID
- Venue
- Journal of Clinical Oncology
- Published
- 2010-07-10
- Volume
- 28
- Issue
- 20
- Pages
- 3219-3226
- ISSN
- 0732-183X (ISSN-L)
- 1527-7755
- PMC
- PMC2903323
- OpenAlex
- W2168680994
- Cited by
- 1,623
- References
- 0
- Citations by year
- 2026: 55 · 2025: 70 · 2024: 107 · 2023: 105 · 2022: 109 · 2021: 144 · 2020: 138 · 2019: 101 · 2018: 108 · 2017: 92 · 2016: 99 · 2015: 105 · 2014: 85 · 2013: 106 · 2012: 81
- FWCI
- 65.78
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Oncology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- U.S. Public Health Service (C25224)
- National Cancer Institute (K05CA142885)
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK084567)
- Topics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Genetic factors in colorectal cancer
- Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
- Health Sciences › Medicine › Oncology › Colorectal Cancer Surgical Treatments
- Keywords
- colon cancer, microsatellite instability, 5-fluorouracil, adjuvant chemotherapy, predictive biomarkers, disease-free survival, stage II colon cancer, stage III colon cancer, levamisole, leucovorin, patient stratification, overall survival
- MeSH terms
- Aged, Antimetabolites, Antineoplastic, Colonic Neoplasms, Combined Modality Therapy, Female, Fluorouracil, Humans, Male, Middle Aged, Prognosis, Biomarkers, Randomized Controlled Trials as Topic, Chemotherapy, Adjuvant, Disease-Free Survival, Drug Resistance, Neoplasm, DNA Mismatch Repair
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