Tumor Microsatellite-Instability Status as a Predictor of Benefit from Fluorouracil-Based Adjuvant Chemotherapy for Colon Cancer

Ribic, Christine; Sargent, Daniel J.; Moore, Malcolm J.; Thibodeau, Stephen N.; French, Amy J.; Goldberg, Richard M.; Hamilton, Stanley R.; Laurent‐Puig, Pierre; Gryfe, Robert; Shepherd, Lois E.; Tu, Dongsheng; Redston, Mark; Gallinger, Steven

doi:10.1056/nejmoa022289

Cited by 1,969 publications

(1,455 citation statements)

References 45 publications

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“…The relationship between TANs and chemotherapy efficacy needs further study. Although the use of MMR status to predict the outcomes of adjuvant chemotherapy is still controversial, the results from previous trials are very promising and indicate that 5‐FU is beneficial for treating dMMR CRC 28, 32, 33. A large multicenter AGEO study indicated that high‐risk stage II dMMR colon cancer tended to have better outcomes with oxaliplatin‐based adjuvant chemotherapy than with surgery alone 34.…”

Section: Discussionmentioning

confidence: 99%

“…dMMR CRCs are notable for greater survivability, particularly in Stage II/III CRC 28, 30, 31. Retrospective studies have demonstrated improved survival in patients with MMR‐competent tumors after receiving 5‐FU‐based chemotherapy 32, 33. A large multicenter study supports the use of adjuvant chemotherapy with fluoropyrimidine plus oxaliplatin for stage III‐dMMR colon cancer 34.…”

Section: Introductionmentioning

confidence: 99%

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Prognostic significance of nomograms integrating IL‐37 expression, neutrophil level, and MMR status in patients with colorectal cancer

et al. 2018

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Interleukin (IL)‐37 and neutrophils are considered to be involved in human cancer, but their prognostic significance in colorectal cancer (CRC) has not been elucidated. The aim of this study was to evaluate the prognostic value of IL‐37 expression and neutrophil levels in CRC. We retrospectively analyzed IL‐37 expression, CD66b+ neutrophil levels, and mismatch repair (MMR) status in 337 paraffin‐embedded CRC specimens from the training cohort by immunohistochemistry. Their prognostic values were assessed using Kaplan‐Meier curves and multivariate Cox regression models. Moreover, several risk factors were used to form nomograms to evaluate survival, and the performance of the nomograms was assessed with respect to calibration, discrimination, and clinical usefulness. Further validation was performed in an independent cohort of 245 cases. Low IL‐37 expression and high CD66b+ neutrophil levels were significantly associated with diminished disease‐free survival (DFS) and overall survival (OS), and patients with MMR‐deficient CRC had better clinical outcomes. Furthermore, multivariate Cox analysis identified IL‐37, CD66b+ neutrophils, and MMR status as independent prognostic factors for DFS and OS. Two nomograms integrating the three markers with four clinicopathological risk factors were developed and validated for predicting DFS and OS with good calibration and discrimination (C‐index: training cohort, 0.798 (95% confidence interval:0.764‐0.832) and 0.828 (0.796‐0.860), respectively; validation cohort, 0.739 (0.696‐0.783) and 0.761 (0.715‐0.808), respectively). Decision curve analysis demonstrated that the nomograms were clinically useful. Intratumoral IL‐37, CD66b+ neutrophils, and MMR status were independent prognostic factors for CRC patients. Nomograms incorporating these biomarkers and clinicopathological features could be conveniently used to facilitate the individualized prediction of DFS and OS.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Prognostic significance of nomograms integrating IL‐37 expression, neutrophil level, and MMR status in patients with colorectal cancer

et al. 2018

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“…3. Chemotherapy response -Although with conflicting results, a large amount of preclinical and clinical evidence suggests a possible reduced response to 5-FU based chemotherapy in dMMR tumours (Benatti et al, 2005;Hutchins et al, 2011;Ribic et al, 2003;Sargent et al, 2010) According to the National Comprehensive Cancer Network (NCCN), MMR testing should be considered for all patients with stage-II disease, as stage-II MSI tumours have a good prognosis and may not benefit from chemotherapy (NCCN, 2015). 4.…”

Section: Introductionmentioning

confidence: 99%

The current value of determining the mismatch repair status of colorectal cancer: A rationale for routine testing

Ryan

Sheahan

Creavin

et al. 2017

Critical Reviews in Oncology/Hematology

100

118

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“…MSI has been reported by several studies to be a marker of good prognosis in CRC and a meta-analysis of 2,935 stage II or III CRCs found better overall survival for MSI or defective DNA mismatch repair (hazard ratio (HR) = 0.67, 95 % CI 0.58 -0.78) ( 8 ). In addition, it has been suggested that MSI predicts absence of benefi t from 5-fl uorouracil--based adjuvant chemotherapy ( 9,10 ).…”

Section: Introductionmentioning

confidence: 99%

Survival in stage II/III colorectal cancer is independently predicted by chromosomal and microsatellite instability, but not by specific driver mutations

Mouradov

Domingo

Gibbs

et al. 2013

American Journal of Gastroenterology

128

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Microsatellite instability (MSI) is an established marker of good prognosis in colorectal cancer (CRC).Chromosomal instability (CIN) is strongly negatively associated with MSI and has been shown to be a marker of poor prognosis in a small number of studies. However, a substantial group of " doublenegative " (MSI − / CIN − ) CRCs exists. The prognosis of these patients is unclear. Furthermore, MSI and CIN are each associated with specifi c molecular changes, such as mutations in KRAS and BRAF , that have been associated with prognosis. It is not known which of MSI, CIN, and the specifi c gene mutations are primary predictors of survival. METHODS:We evaluated the prognostic value (disease-free survival, DFS) of CIN, MSI, mutations in KRAS , NRAS , BRAF , PIK3CA , FBXW7 , and TP53 , and chromosome 18q loss-of-heterozygosity (LOH) in 822 patients from the VICTOR trial of stage II / III CRC. We followed up promising associations in an Australian community-based cohort ( N = 375). RESULTS:In the VICTOR patients, no specifi c mutation was associated with DFS, but individually MSI and CIN showed signifi cant associations after adjusting for stage, age, gender, tumor location, and therapy. A combined analysis of the VICTOR and community-based cohorts showed that MSI and CIN were independent predictors of DFS (for MSI, hazard ratio (HR) = 0.58, 95 % confi dence interval (CI) 0.36 -0.93, and P = 0.021; for CIN, HR = 1.54, 95 % CI 1.14 -2.08, and P = 0.005), and joint CIN / MSI testing signifi cantly improved the prognostic prediction of MSI alone ( P = 0.028). Higher levels of CIN were monotonically associated with progressively poorer DFS, and a semi-quantitative measure of CIN was a better predictor of outcome than a simple CIN + / − variable . All measures of CIN predicted DFS better than the recently described Watanabe LOH ratio. SUPPLEMENTARY MATERIAL is linked to the online version of the paper at

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Tumor Microsatellite-Instability Status as a Predictor of Benefit from Fluorouracil-Based Adjuvant Chemotherapy for Colon Cancer

Cited by 1,969 publications

References 45 publications

Prognostic significance of nomograms integrating IL‐37 expression, neutrophil level, and MMR status in patients with colorectal cancer

Prognostic significance of nomograms integrating IL‐37 expression, neutrophil level, and MMR status in patients with colorectal cancer

The current value of determining the mismatch repair status of colorectal cancer: A rationale for routine testing

Survival in stage II/III colorectal cancer is independently predicted by chromosomal and microsatellite instability, but not by specific driver mutations

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