Thymidilate synthase expression predicts longer survival in patients with stage II colon cancer treated with 5-flurouracil independently of microsatellite instability

Donada, Marisa; Bonin, Serena; Nardon, Ermanno; Pellegrin, Alessandro De; Decorti, Giuliana; Stanta, Giorgio

doi:10.1007/s00432-010-0872-1

Cited by 22 publications

(18 citation statements)

References 37 publications

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“…This finding is of particular interest as it again supports the concept that mixed carcinomas have a distinct molecular profile and possibly clinical behavior, and that molecular biomarkers might be predictive of the response to chemotherapy also in this group of neoplasms. In fact, referring to the knowledge available about colorectal cancer (which was the most prevalent location in our series), our data are in line with some previous studies on the unfavorable prognostic role of low TS gene expression in colon cancer patients, with special reference to those treated with antifolate drugs [24,25], even though at the same time our results are in sharp contrast to recent data on the adverse prognostic role of high TS protein expression in gastroenteropancreatic neuroendocrine neoplasms [16]. However, due to the limited number of cases, it was not possible to analyze the impact of TS gene expression levels on survival in a homogeneous group of chemotherapy-treated patients.…”

Section: Discussionsupporting

confidence: 79%

Expression Analysis of Genes Involved in DNA Repair or Synthesis in Mixed Neuroendocrine/Nonneuroendocrine Carcinomas

Volante

Monica

Birocco³

et al. 2015

Neuroendocrinology

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Background: Mixed neuroendocrine/nonneuroendocrine carcinomas are heterogeneous tumors with poorly defined diagnostic and clinical features and without pathological or molecular markers of prognosis or markers predicting their response to therapy. We aimed at analyzing the pathological features and the expression of genes involved in DNA repair or synthesis in a cohort of patients with mixed carcinomas from different sites as compared to the patients' outcome. Methods: Relative cDNA quantification of ribonucleotide reductase, large subunit 1, excision repair cross-complementation group 1, thymidylate synthase and topoisomerase IIa genes was tested using real-time PCR on microdissected neuroendocrine and nonneuroendocrine tumor components of 42 mixed cases (from the lung as well as the gastrointestinal and genitourinary tracts) and on 45 control cases of pure neuroendocrine and nonneuroendocrine carcinomas. Results: The expression levels of all genes were stable comparing nonneuroendocrine and neuroendocrine components of mixed cases (except for topoisomerase IIa in lung samples) but significantly different as compared to control nonneuroendocrine and neuroendocrine tumors. In the multivariate analysis including all clinical and pathological parameters and gene expression levels available, a predominant nonneuroendocrine component, the administration of additional therapy other than surgery and a high thymidylate synthase expression in nonneuroendocrine tumor tissue were significantly associated with a lower risk of a patient's death. Conclusions: Our data show that mixed neuroendocrine/nonneuroendocrine carcinomas are different at the molecular level from their pure neuroendocrine and nonneuroendocrine counterparts, and detailed analyses of their clinical, pathological and molecular features may improve the clinical strategies for the treatment of these rare and underestimated tumors.

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Section: Discussionsupporting

confidence: 79%

Expression Analysis of Genes Involved in DNA Repair or Synthesis in Mixed Neuroendocrine/Nonneuroendocrine Carcinomas

Volante

Monica

Birocco³

et al. 2015

Neuroendocrinology

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“…In this study, the Cox hazard regression model revealed that only TP mRNA expression could predict the efficacy This finding is consistent with earlier findings that TP may be a prognostic marker in the adjuvant setting [29,34,35]. However, OPRT was not a prognostic factor in our study; this finding was inconsistent with previous findings [20].…”

Section: Discussionsupporting

confidence: 70%

Evaluation of 5‐Fluorouracil Metabolic Enzymes as Predictors of Response to Adjuvant Chemotherapy Outcomes in Patients with Stage II/III Colorectal Cancer: A Decision‐Curve Analysis

et al. 2014

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“…For our study we selected as candidate molecular markers the colorectal cancer classifiers MMR system and CIMP, as well as the following single molecular markers: TP53 (p53), β-catenin (CTNNB1), BRAF c.1799 T > A (V600E) mutation and TYMS. The first three markers were chosen because they are involved in CRC tumorigenesis [30], whereas TYMS was analysed because it could be used to identify a subgroup of stage II colon cancer patients who better benefit from the use of adjuvant chemotherapy, as we pointed out in a previous study [31]. …”

Section: Introductionmentioning

confidence: 99%

Management of stage II colon cancer - the use of molecular biomarkers for adjuvant therapy decision

et al. 2013

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BackgroundThere is uncertainty on the benefit of adjuvant chemotherapy in patients with stage II colorectal cancers. The aim of this study is to investigate the combined role of clinical, pathological and molecular parameters to identify those stage II patients who better benefit from adjuvant therapy.MethodsWe examined 120 stage II colon cancer patients. Of these, 60 patients received adjuvant 5-FU chemotherapy after surgery and the other 60 did not receive therapy. Immunohistochemical (IHC) analyses were performed to evaluate the expressions of Thymidylate synthetase (TYMS), TP53 (p53), β-catenin (CTNNB1) and CD8. For TYMS, its mRNA expression levels were also investigated by real time qRT-PCR. The entire case study was characterized by the presence of a defect in the MMR (mismatch repair) system, the presence of the CpG island methylator phenotype (CIMP or CIMP-High) and for the V600E mutation in the BRAF gene. At the histo-pathological level, the depth of tumour invasion, lymphovascular invasion, invasion of large veins, host lymphocytic response and tumour border configuration were recorded.ResultsThe presence of the V600E mutation in the BRAF gene was a poor prognostic factor for disease free and overall survival (DFS; hazard ratio [HR], 2.57; 95% CI: 1.03 -6.37; p = 0.04 and OS; HR, 3.68; 95% CI: 1.43-9.47; p < 0.01 respectively), independently of 5-FU treatment. Adjuvant therapy significantly improved survival in patients with high TYMS levels (p = 0.04), while patients with low TYMS had a better outcome if treated by surgery alone (DFS; HR, 6.07; 95% CI, 0.82 to 44.89; p = 0.04). In patients with a defect in the MMR system (dMMR), 5-FU therapy was associated to reduced survival (DFS; HR, 37.98; 95% CI, 1.04 to 1381.31; p = 0.04), while it was beneficial for CIMP-High associated tumours (DFS; HR, 0.17; 95% CI, 0.02 to 1.13; p = 0.05).ConclusionsPatients’ characterization according to MMR status, CIMP phenotype and TYMS mRNA expression may provide a more tailored approach for adjuvant therapy in stage II colon cancer.

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Thymidilate synthase expression predicts longer survival in patients with stage II colon cancer treated with 5-flurouracil independently of microsatellite instability

Abstract: This retrospective investigation suggests that TS gene expression at mRNA level can be a useful marker of better survival in patients (especially of those with cancers of stage II) receiving 5-FU adjuvant chemotherapy, independently of the MSI status.

Cited by 22 publications

References 37 publications

Expression Analysis of Genes Involved in DNA Repair or Synthesis in Mixed Neuroendocrine/Nonneuroendocrine Carcinomas

Expression Analysis of Genes Involved in DNA Repair or Synthesis in Mixed Neuroendocrine/Nonneuroendocrine Carcinomas

Evaluation of 5‐Fluorouracil Metabolic Enzymes as Predictors of Response to Adjuvant Chemotherapy Outcomes in Patients with Stage II/III Colorectal Cancer: A Decision‐Curve Analysis

Management of stage II colon cancer - the use of molecular biomarkers for adjuvant therapy decision

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