5-Fluorouracil Adjuvant Chemotherapy Does Not Increase Survival in Patients With CpG Island Methylator Phenotype Colorectal Cancer

Jover, Rodrigo; Nguyen, Thuy–Phuong; Pérez–Carbonell, Lucía; Zapater, Pedro; Payá, Artemio; Alenda, Cristina; Rojas, Estefanía; Cubiella, Joaquín; Balaguer, Francesc; Morillas, Juan Diego; Clofent, Juan; Bujanda, Luís; Reñé, Josep Maria; Bessa, Xavier; Xicola, Rosa M.; Nicolás–Pérez, David; Castells, Antoni; Andreu, Montserrat; Llor, Xavier; Boland, C. Richard; Goel, Ajay

doi:10.1053/j.gastro.2010.12.035

Cited by 180 publications

(160 citation statements)

References 29 publications

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“…6 However, prognostic features and chemotherapy responses according to CIMP status in colorectal cancer were controversial. 1,7,9,[38][39][40][41][42] More importantly, although HSP110wt expression was an independent prognostic factor in the present analysis, CIMP status was not ( Table 2). In addition, it is difficult to find a molecular mechanistic connection between the HSP110wt expression level and the CIMP status because HSP110 mutation is a genetic alteration, whereas CIMP is an epigenetic change.…”

Section: Discussionmentioning

confidence: 53%

Expression status of wild-type HSP110 correlates with HSP110 T17 deletion size and patient prognosis in microsatellite-unstable colorectal cancer

Kim

Rhee

et al. 2014

Modern Pathology

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It has been recently suggested that the expression levels of mutant HSP110 could be a prognostic marker in colorectal cancer with a high level of microsatellite instability (MSI-H). The aim of our study was to validate the prognostic significance of HSP110 mutation using immunohistochemistry and DNA testing in MSI-H colorectal cancer. Wild-type HSP110 (HSP110wt)-specific immunohistochemistry was performed in 168 MSI-H colorectal cancer tissues, and their expression levels were evaluated using a four-tier scoring system (0/1 þ /2 þ /3 þ ). Of these tissues, 167 cases were analyzed for HSP110 T 17 deletion. Associations with clinicopathological, molecular and survival parameters were statistically analyzed. The low-level expression of HSP110wt (0/1 þ ) was observed in 40 MSI-H colorectal cancers (24%) and was significantly related to large HSP110 T 17 deletions (Z 4 bp, Po0.001). In survival analysis, patients with low HSP110wt expression (0/1 þ ) showed better diseasefree survival compared with those with high expression (2 þ /3 þ ; P ¼ 0.005). This significance in survival difference was maintained in patients with 5-fluorouracil-based chemotherapy-treated tumors (P ¼ 0.024) and in those with stage III/IV tumors (P ¼ 0.032). Multivariate analysis confirmed the role of HSP110wt expression as an independent prognostic factor (P ¼ 0.016, hazard ratio ¼ 4.32). In MSI-H colorectal cancer, a low expression of HSP110wt is associated with large HSP110 T 17 deletions and better clinical outcome. Immunohistochemistry of HSP110wt can be a simple and valuable tool for the prognostic and therapeutic stratification of patients with MSI-H colorectal cancer.

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Section: Discussionmentioning

confidence: 53%

Expression status of wild-type HSP110 correlates with HSP110 T17 deletion size and patient prognosis in microsatellite-unstable colorectal cancer

Kim

Rhee

et al. 2014

Modern Pathology

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“…CIMP may confer resistance to adjuvant 5-flurouracil, which might provide an explanation for the observed inferior survival in mucinous histology [28,29]. …”

Section: Discussionmentioning

confidence: 99%

Factors associated with short recurrence-free survival in completely resected colon cancer

Alnimer

Ghamrawi

Aburahma

et al. 2017

Journal of Community Hospital Internal Medicine Perspectives

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Background: Several factors could affect disease recurrence in surgically resected colon cancer. While the role of certain factors such as cancer stage and grade is well established, the role of other factors (e.g., histological subtypes) is yet to be determined. Objective:Therefore, we conducted a study to evaluate the impact of several factors in recurrence-free survival (RFS) in patients who were disease free following surgical resection of the colon cancer. Design/Methods: Data were collected for patients with Stage I–III colon cancer who underwent complete surgical resection of the tumor between January 2010 and December 2015 in our institution. A total of 90 subjects met the inclusion criteria and were included in the study. The following factors were collected at the time of surgical resection of the colonic tumor: patient’s age, gender, colon cancer stage, grade and histological subtype, body mass index, hemoglobin A1c, and smoking history. Results: A total of 28 patients (31%) developed recurrence and had a mean follow-up time of 19.8 months (range: 2–54.4 months). Median RFS was 54.4 months with a 5-year RFS of 49%. Advanced colonic cancer stage and mucinous histological subtype were associated with shorter RFS with an HR of 2.37, 95% CI = 1.38–4.06, and 95% CI = 1.02–5.90, respectively. Current smokers or those who quit less than 15 years earlier tended to have worse RFS with an HR of 2.47, 95% CI = 0.98–6.27. Conclusion: Advanced colon cancer stage and mucinous histological subtype are independent risk factors for cancer recurrence and shorter RFS in completely resected colonic tumor.

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“…No significant deleterious effect of overdosing is found in obese cancer patients using the dose based on real body weight. Nevertheless, 5-FU-based adjuvant chemotherapy may not increase survival in the tumors with defective DNA mismatch repair and the CpG island methylator phenotype (Sargent et al, 2010;Jover et al, 2011). 5-FU principally works as a TS inhibitor to block the synthesis of the thymidine, and direct incorporation of 5-FU metabolites into DNA and RNA may cause strand breaks and apoptosis (Xu et al, 2002;Longley et al, 2003).…”

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confidence: 99%

High Glucose Modulates Antiproliferative Effect and Cytotoxicity of 5-Fluorouracil in Human Colon Cancer Cells

Yang

Tsai

et al. 2014

DNA and Cell Biology

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5-Fluorouracil (5-FU)-based chemotherapy is widely used for the treatment of colorectal cancer (CRC). While optimal doses of 5-FU are generally established based on a patient's estimated body surface area, the plasma concentrations of 5-FU vary among patients. In addition, hyperglycemia in patients with CRC has been reported as a risk factor in poor prognosis. The aim of the present study was to investigate whether hyperglycemia affects antiproliferative effect of 5-FU on the human colon cancer cells (SW480, SW620, LoVo, and HCT116). Growth inhibition of 5-FU was accessed by WST-8 assay. The effect of high glucose (HG, 15 mM) and 5-FU on the cellular proliferation was evaluated by flow cytometry analysis using 5-ethynyl-2¢-deoxy-uridine (EdU) incorporation plus 7-AAD. Cell death was determined by flow cytometry using Annexin V-FITC and PI. The results showed that HG, compared to physiological normal glucose (NG) concentration (5 mM), leads to increased cell proliferation and increased GI50 of 5-FU in the four colon cancer cell lines. When the cells were pretreated with a low-dose 5-FU in NG condition, subsequent HG treatment eliminated inhibitory effect of 5-FU in cancer cell growth. In the presence of 5-FU (0.5 mg/mL for LoVo and HCT116; 1 mg/mL for SW480 and SW620), culture with HG for 72 h does not significantly altered cell cycle profile in the four cell lines but significantly increased DNA replication in SW620 (21%) and LoVo (17%). Flow cytometric analysis showed that HG protects cells against 5-FU-induced cell death in SW480. Finally, HG did not alter intracellular level of reactive oxygen species (ROS), although 5-FU indeed induced higher intracellular level of ROS. In conclusion, HG attenuates growth inhibition of 5-FU and our results indicate that decreased cell death and increased DNA replication may account for the attenuating effect of a HG environment on 5-FU-induced tumor growth inhibition.

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5-Fluorouracil Adjuvant Chemotherapy Does Not Increase Survival in Patients With CpG Island Methylator Phenotype Colorectal Cancer

Abstract: Background & Aims-5-FU-based adjuvant chemotherapy does not increase survival times of patients with colorectal tumors with microsatellite instability. We determined the response of patients with colorectal tumors with the CpG island methylator phenotype (CIMP) to 5-FU-based therapy.

Cited by 180 publications

References 29 publications

Expression status of wild-type HSP110 correlates with HSP110 T17 deletion size and patient prognosis in microsatellite-unstable colorectal cancer

Expression status of wild-type HSP110 correlates with HSP110 T17 deletion size and patient prognosis in microsatellite-unstable colorectal cancer

Factors associated with short recurrence-free survival in completely resected colon cancer

High Glucose Modulates Antiproliferative Effect and Cytotoxicity of 5-Fluorouracil in Human Colon Cancer Cells

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