Defective mismatch repair as a predictive marker for lack of efficacy of fluorouracil-based adjuvant therapy in colon cancer - PubMed (original) (raw)
. 2010 Jul 10;28(20):3219-26.
doi: 10.1200/JCO.2009.27.1825. Epub 2010 May 24.
Silvia Marsoni, Genevieve Monges, Stephen N Thibodeau, Roberto Labianca, Stanley R Hamilton, Amy J French, Brian Kabat, Nathan R Foster, Valter Torri, Christine Ribic, Axel Grothey, Malcolm Moore, Alberto Zaniboni, Jean-Francois Seitz, Frank Sinicrope, Steven Gallinger
Affiliations
- PMID: 20498393
- PMCID: PMC2903323
- DOI: 10.1200/JCO.2009.27.1825
Defective mismatch repair as a predictive marker for lack of efficacy of fluorouracil-based adjuvant therapy in colon cancer
Daniel J Sargent et al. J Clin Oncol. 2010.
Erratum in
- J Clin Oncol. 2010 Oct 20;28(30):4664
Abstract
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.
Conflict of interest statement
Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
Figures
Fig 1.
(A) Disease-free survival (DFS) in untreated patients by DNA mismatch repair (MMR) status. (B) DFS in treated patients by MMR. dMMR, defective DNA mismatch repair; pMMR, proficient DNA mismatch repair.
Fig 2.
(A) Disease-free survival (DFS) in patients with stage II disease and defective DNA mismatch repair (dMMR) by treatment status. (B) DFS in patients with stage III disease and dMMR by treatment status. (C) DFS in patients with stage II disease and proficient MMR (pMMR) by treatment status. (D) DFS in patients with stage III disease and pMMR by treatment status. HR, hazard ratio; FU, fluorouracil.
Comment in
- Microsatellite instability and adjuvant fluorouracil chemotherapy: a mismatch?
Ng K, Schrag D. Ng K, et al. J Clin Oncol. 2010 Jul 10;28(20):3207-10. doi: 10.1200/JCO.2010.28.9314. Epub 2010 May 24. J Clin Oncol. 2010. PMID: 20498398 No abstract available. - Defective mismatch repair in colon cancer: a prognostic or predictive biomarker?
Kerr DJ, Midgley R. Kerr DJ, et al. J Clin Oncol. 2010 Jul 10;28(20):3210-2. doi: 10.1200/JCO.2010.28.9322. Epub 2010 May 24. J Clin Oncol. 2010. PMID: 20498404 No abstract available. - Predictive value of defective mismatch repair in adjuvant colon cancer.
Atkins CD. Atkins CD. J Clin Oncol. 2010 Dec 10;28(35):e746; author reply e747. doi: 10.1200/JCO.2010.31.8824. Epub 2010 Nov 1. J Clin Oncol. 2010. PMID: 21041713 No abstract available.
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