The aim of this study is to evaluate if mismatch repair (MMR) defective colorectal cancer has a different response to adjuvant 5-fluorouracil (5-FU) chemotherapy in a cohort of patients prospectively followed during 5 years.
The cohort included 754 surgically treated patients with colorectal cancer. MMR status was diagnosed by MLH1 and MSH2 immunohistochemistry and microsatellite instability analysis. Median follow-up was 49.2 months (range 1–73). At inclusion, 505 patients were diagnosed as TNM II or III stage, analysis of the efficacy of adjuvant chemotherapy was made on this population. Adjuvant chemotherapy was applied to 248 patients (98.2% 5-FU based).
MMR deficiency was found in 76 patients (10.1%). No differences were found in overall survival (log-rank p = 0.3) or disease-free survival (log-rank p = 0.3) regarding MMR status. Adjuvant chemotherapy improves survival in patients in the II or III stage, but this improvement is only evident in patients with MMR-competent tumours (log-rank p = 0.00001). Survival of patients with MMR-defective tumours does not improve with adjuvant chemotherapy (log-rank p = 0.7). A multivariate analysis showed an independent effect of the interaction between MMR status and adjuvant chemotherapy (Hazard ratio 2.04; 95% confidence interval: 1.42–2.93).
In a cohort of colorectal cancer patients, those with MMR-deficient tumours seem not to benefit from 5-FU-based chemotherapy.
To read this article in full you will need to make a payment
Purchase one-time access:Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
One-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:Subscribe to European Journal of Cancer
Already a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
- Chemotherapy and radiation therapy of colorectal cancer.in: Rustgi A.K. Gastrointestinal cancers. 1st ed. Saunders, Philadelphia2003: 453-472
- Microsatellite instability in cancer of the proximal colon.Science. 1993; 260: 816-819
- DNA mismatch repair genes and colorectal cancer.Gut. 2000; 47: 148-153
- Systematic review of microsatellite instability and colorectal cancer prognosis.J Clin Oncol. 2005; 23: 609-618
- Association of tumour site and sex with survival benefit from adjuvant chemotherapy in colorectal cancer.Lancet. 2000; 355: 1745-1750
- Microsatellite instability is a favorable prognostic indicator in patients with colorectal cancer receiving chemotherapy.Gastroenterology. 2000; 119: 921-928
- DNA markers predicting benefit from adjuvant fluorouracil in patients with colon cancer: a molecular study.Lancet. 2002; 360: 1381-1391
- Use of 5-fluorouracil and survival in patients with microsatellite-unstable colorectal cancer.Gastroenterology. 2004; 126: 394-401
- Immunohistochemical test for MLH1 and MSH2 expression predicts clinical outcome in stage II and III colorectal cancer patients.J Clin Oncol. 2006; 24: 2359-2367
- Tumor microsatellite-instability status as a predictor of benefit from fluorouracil-based adjuvant chemotherapy for colon cancer.New Engl J Med. 2003; 349: 247-257
- Mismatch repair status in the prediction of benefit from adjuvant fluorouracil chemotherapy in colorectal cancer.Gut. 2006; 55: 848-855
- Frequency of hereditary non-polyposis colorectal cancer and other colorectal cancer familial forms in Spain: a multicentre, prospective, nationwide study.Eur J Gastroenterol Hepatol. 2004; 16: 39-45
- Accuracy of revised Bethesda guidelines, microsatellite instability, and immunohistochemistry for the identification of patients with hereditary nonpolyposis colorectal cancer.JAMA. 2005; 293: 1986-1994
- Levamisole and fluorouracil for adjuvant therapy of resected colon carcinoma.New Engl J Med. 1990; 322: 352-358
- Fluorouracil plus levamisole as effective adjuvant therapy after resection of stage III colon carcinoma: a final report.Ann Intern Med. 1995; 122: 321-326
- The benefit of leucovorin-modulated fluorouracil as postoperative adjuvant therapy for primary colon cancer: results from National Surgical Adjuvant Breast and Bowel Project protocol C-03.J Clin Oncol. 1993; 11: 1879-1887
- Clinical trial to assess the relative efficacy of fluorouracil and leucovorin, fluorouracil and levamisole, and fluorouracil, leucovorin, and levamisole in patients with Dukes’ B and C carcinoma of the colon: results from National Surgical Adjuvant Breast and Bowel Project C-04.J Clin Oncol. 1999; 17: 3553-3559
- A National Cancer Institute Workshop on Microsatellite Instability for cancer detection and familial predisposition: development of international criteria for the determination of microsatellite instability in colorectal cancer.Cancer Res. 1998; 58: 5248-5257
- Performance of different microsatellite marker panels for detection of mismatch repair-deficient colorectal tumors.J Natl Cancer Inst. 2007; 99: 244-252
- P53 alteration and microsatellite instability have predictive value for survival benefit from chemotherapy in stage III colorectal carcinoma.Clin Cancer Res. 2001; 7: 1343-1349
- Microsatellite instability and colorectal cancer prognosis.Clin Cancer Res. 2005; 11: 8332-8340
- Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer.New Engl J Med. 2004; 350: 2343-2351
- Role of hMLH1 promoter hypermethylation in drug resistance to 5-fluorouracil in colorectal cancer cell lines.Int J Cancer. 2003; 106: 66-73
- Mismatch repair proficiency and in vitro response to 5-fluorouracil.Gastroenterology. 1999; 117: 123-131
- Role of the hMLH1 DNA mismatch repair protein in fluoropyrimidine-mediated cell death and cell cycle responses.Cancer Res. 2001; 61: 5193-5201
- Influence of target gene mutations on survival, stage and histology in sporadic microsatellite unstable colon cancers.Int J Cancer. 2006; 118: 2509-2513
- Molecular predictors of survival after adjuvant chemotherapy for colon cancer.New Engl J Med. 2001; 344: 1196-1206
- 5-Fluorouracil incorporated into DNA is excised by the Smug1 DNA glycosylase to reduce drug cytotoxicity.Cancer Res. 2007; 67: 940-945
- 5-Fluorouracil is efficiently removed from DNA by the base excision and mismatch repair systems.Gastroenterology. 2007; 133: 1858-1868
- The role of DNA mismatch repair in platinum drug resistance.Cancer Res. 1996; 56: 4881-4886
- The role of hMLH1, hMSH3, and hMSH6 defects in cisplatin and oxaliplatin resistance. Correlation with replicative bypass of platinum-DNA adducts.Cancer Res. 1998; 58: 3579-3585
- Sensitivity to CPT-11 of xenografted human colorectal cancers as a function of microsatellite instability and p53 status.Br J Cancer. 2000; 82: 913-923
- Microsatellite instability is a predictive factor of the tumor response to irinotecan in patients with advanced colorectal cancer.Cancer Res. 2003; 63: 5738-5744
- Choice of management strategy for colorectal cancer based on a diagnostic immunohistochemical test for defective mismatch repair.Gut. 1999; 45: 409-415
- Screening for the Lynch syndrome (hereditary nonpolyposis colorectal cancer).New Engl J Med. 2005; 352: 1851-1860
- Defective mismatch-repair colorectal cancer: clinicopathologic characteristics and usefulness of immunohistochemical analysis for diagnosis.Am J Clin Pathol. 2004; 122: 389-394
Published online: August 26, 2008
Accepted: July 1, 2008
Received in revised form: June 30, 2008
Received: May 8, 2008
© 2008 Elsevier Ltd. Published by Elsevier Inc. All rights reserved.