3577: Thymidylate synthase (TS) expression as a prognostic molecular marker in stage II/III colon cancer.

Details

Serval ID
serval:BIB_FBAEACB696F1
Type
Inproceedings: an article in a conference proceedings.
Publication sub-type
Abstract (Abstract): shot summary in a article that contain essentials elements presented during a scientific conference, lecture or from a poster.
Collection
Publications
Institution
Title
3577: Thymidylate synthase (TS) expression as a prognostic molecular marker in stage II/III colon cancer.
Title of the conference
Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO)
Author(s)
Klingbiel D., Missiaglia E., Yan P., Tejpar S., Roth A., D'Ario G., Delorenzi M., Bosman F.
Address
Chicago, USA, May 31 - June 04, 2013
ISBN
0732-183X
ISSN-L
0732-183X
Publication state
Published
Issued date
2013
Volume
31
Series
Journal of Clinical Oncology
Pages
3577
Language
english
Abstract
Background: Studies on the association between colorectal cancer (CC) outcome and thymidylate synthase expression have provided inconsistent results. In this study we attempted to resolve the issue by assessing the associations between TS expression and outcome in a population of primary CC patients (pts), who after resection were randomized to 5-FU/FA vs. FOLFIRI adjuvant therapy. Methods: Immunohistochemical staining for TS protein was successfully performed for 1211 pts in the PETACC3 trial. TS immunoreactivity was scored as high expression (≥75% positive) and low expression (<75% positive). Gene expression respectively copy number data were available for 853 respectively 306 of these samples. Twelve single nucleotide polymorphisms (SNPs) close to the TYMS gene were assessed in 923 pts. Association of variables with relapse-free (RFS) and overall survival (OS) was assessed using Cox regression models. Results: High TS expression and RNA level were strongly associated (log fold change 0.65, p<0.001). Both were significantly higher in proximal CC. As expected, both were associated with other characteristics of proximal CC: MSI, BRAF mutation, high tumor grade. RNA was significantly correlated with gene copy number, distal CC showing more frequent allelic loss. Three SNPs were associated with gene expression which was validated in data from the 1000 genomes project, but none with survival. High TS expression was more strongly associated with better OS in pts receiving FOLFIRI (HR 0.4, 95% CI 0.3-0.6, p<0.001), than 5-FU/FA (HR 0.8, 95% CI 0.5-1.1, p=0.13), with a significant interaction (p=0.05). Similar results were observed for RFS (HR 0.5, p<0.001 vs. HR 0.7, p=0.07; interaction p=0.11). TS expression is still highly prognostic in multivariate models adjusting for factors associated with risk or proximal tumors in FOLFIRI treated pts (OS: HR 0.5, p=0.008; RFS: HR 0.6, p=0.02), but not in F-FU/FA treated pts (OS and RFS: HR=1, p=1). Conclusions: TS expression is lower in distal CC, partly due to deletion of the TYMS locus. Pts with high TS expression have longer RFS and OS, notably when treated with FOLFIRI. For these pts addition of irinotecan to 5-FU/FA adjuvant chemotherapy might be considered.
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Create date
10/08/2016 9:14
Last modification date
20/08/2019 16:26
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