scholarly journals Combined analysis of genetic polymorphisms in thymidylate synthase, uridine diphosphate glucoronosyltransferase and X-ray cross complementing factor 1 genes as a prognostic factor in advanced colorectal cancer patients treated with 5-fluorouracil plus oxaliplatin or irinotecan

2007 ◽  
Author(s):  
Eva Martinez-Balibrea ◽  
Jose Manzano ◽  
Anna Martinez-Cardus ◽  
Teresa Moran ◽  
Beatriz Cirauqui ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Prognostic Factor ◽  
Cancer Patients ◽  
Genetic Polymorphisms ◽  
Thymidylate Synthase ◽  
Advanced Colorectal Cancer ◽  
Uridine Diphosphate ◽  
Combined Analysis ◽  
X Ray ◽  
Colorectal Cancer Patients

Tumor Thymidylate Synthase 1494del6 Genotype As a Prognostic Factor in Colorectal Cancer Patients Receiving Fluorouracil-Based Adjuvant Treatment

2006 ◽  
Vol 24 (10) ◽  
pp. 1603-1611 ◽  
Author(s):  
Emma Dotor ◽  
Miriam Cuatrecases ◽  
María Martínez-Iniesta ◽  
Matilde Navarro ◽  
Felip Vilardell ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Prognostic Factor ◽  
Cancer Patients ◽  
Adjuvant Treatment ◽  
Thymidylate Synthase ◽  
Allelic Loss ◽  
Strong Linkage Disequilibrium ◽  
Prognostic Information ◽  
Primary Tumors ◽  
Colorectal Cancer Patients

Purpose The purpose of this study was to analyze the value of germline and tumor thymidylate synthase (TS) genotyping as a prognostic marker in a series of colorectal cancer patients receiving adjuvant fluorouracil (FU) -based treatment. Patients and Methods One hundred twenty-nine colorectal cancer patients homogeneously treated with FU plus levamisole or leucovorin in the adjuvant setting were included. TS enhancer region, 3R G > C single nucleotide polymorphism (SNP), and TS 1494del6 polymorphisms were assessed in both fresh-frozen normal mucosa and tumor. Mutational analyses of TS and allelic imbalances were studied in all primary tumors and in 18 additional metachronic metastases. TS protein immunostaining was assessed in an expanded series of 214 tumors. Multivariate Cox models were adjusted for stage, differentiation, and location. Results Tumor genotyping (frequency of allelic loss, 26%) showed that the 3R/3R genotype was associated with a better outcome (hazard ratio [HR] = 0.38; 95% CI, 0.16 to 0.93; P = .020 for the recessive model). 3R G > C SNP genotyping did not add prognostic information. Tumor TS 1494del6 allele (frequency of allelic loss, 36%) was protective (for each allele with the deletion, based on an additive model, HR = 0.42; 95% CI, 0.22 to 0.82; P = .0034). Both polymorphisms were in strong linkage disequilibrium (D' = 0.71, P < .001), and the 3R/–6 base pair (bp) haplotype showed a significant overall survival benefit compared with the most prevalent haplotype 2R/+6bp (HR = 0.42; 95% CI, 0.20 to 0.85; P = .017). No TS point mutation was detected in primary tumors or metastases. TS protein immunostaining was not associated with survival or any of the genotypes analyzed. Conclusion Tumor TS 1494del6 genotype may be a prognostic factor in FU-based adjuvant treatment of colorectal cancer patients.

Prognostic value of ERCC1, thymidylate synthase and glutathione S-transferase π for 5-FU/oxaliplatin chemotherapy in advanced colorectal cancer

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 3607-3607 ◽  
Author(s):  
H. Kwon ◽  
M. S. Roh ◽  
S. Y. Oh ◽  
S. Kim ◽  
J. H. Lee ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Clinical Outcome ◽  
Cancer Patients ◽  
Thymidylate Synthase ◽  
Advanced Colorectal Cancer ◽  
Glutathione S Transferase ◽  
Primary Tumors ◽  
Ercc1 Expression ◽  
Immunohistochemical Studies ◽  
Colorectal Cancer Patients

3607 Background: The aim of this study was to determine whether expressions of the excision cross-complementing (ERCC1), thymidylate synthase (TS) and glutathione S-transferase π (GSTπ) predict clinical outcome in patients with advanced colorectal cancer treated with fluorouracil (5-FU)/oxaliplatin chemotherapy. Methods: The study population consisted of 70 advanced colorectal cancer patients (median age, 53 years). Patients were treated with oxaliplatin 85 mg/m2 as a 2-hour infusion at days 1 plus LV 20 mg/m2 over 10 minutes, followed by 5-FU bolus 400 mg/m2 and 22 hour continuous infusion of 600 mg/m2 at day 1–2. Treatment was repeated in 2 week intervals. The expressions of ERCC1, TS and GSTπ of primary tumors were examined by immunohistochemistry. Results: The positive rates of ERCC1, TS, and GSTπ were 55.7%, 68.6%, and 71.4%, respectively. The patients without TS expression were more likely to respond to chemotherapy (p=0.009). There were no significant differences between response and ERCC1 or GSTπ expression pattern (p=0.768, p=0.589, respectively). Median overall survival (OS) was significantly longer in patients without ERCC1 expression (p=0.0474). Patients with ERCC1 positive combined with TS positive, or those with ERCC1 positive combined with TS positive and GSTπ positive had poor OS (p=0.0017, p=0.0323, respectively). Multivariate analysis revealed that both ERCC1 and TS expression significantly impacted on OS (Hazard ratio 1.72, p=0.023). Conclusions: Immunohistochemical studies for ERCC1 and TS may be useful in prediction of the clinical outcome of advanced colorectal cancer patients treated with 5-FU and oxaliplatin. No significant financial relationships to disclose.

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