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Clin Cancer Res. 2008 Feb 15;14(4):1059-64. doi: 10.1158/1078-0432.CCR-07-1513.

Thymidylate synthase expression in gastroenteropancreatic and pulmonary neuroendocrine tumors.

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1
Thoracic Oncology Unit, Pathology Division, Department of Clinical and Biological Sciences, University of Torino, San Luigi Hospital, Torino, Italy. paolo.ceppi@unito.it

Abstract

PURPOSE:

The predictive role of the quantification of thymidylate synthase (TS) in tumors treated with antifolate drugs, such as 5-fluorouracil (5-FU), has been extensively reported in a variety of human tumors. Neuroendocrine tumors (NET) represent potential targets of antifolate agents, but no data on TS expression level in these tumors are currently available.

EXPERIMENTAL DESIGN:

A series of 116 NETs were collected, including 58 gastroenteropancreatic (GEP) and 58 lung NETs. In 24 well-differentiated GEP neuroendocrine carcinomas (WD-NEC), a 5-FU-based treatment was given. Total RNA was extracted from microdissected paraffin blocks. TS mRNA quantification was done by real-time PCR, whereas protein expression was evaluated by immunohistochemistry.

RESULTS:

By means of both quantification by real-time PCR and immunohistochemistry, a higher TS expression in pulmonary small cell lung cancer and large cell NEC compared with typical and atypical carcinoids was observed (P < 0.01). Similarly, in GEP tumors, a higher TS expression in poorly differentiated carcinomas than both WD-NEC and benign tumors (P < 0.01) was found. In patients with WD-NEC treated with 5-FU, high TS mRNA levels were associated with shorter time to progression (P = 0.002) and overall survival (P = 0.04). This negative prognostic role was confirmed in multivariate analysis adjusting for major prognostic variables (P = 0.01). No association between TS mRNA and survival was observed in WD-NEC patients not receiving 5-FU.

CONCLUSIONS:

This study, for the first time, (a) reports the differential TS expression in the spectrum of NETs and (b) indicates TS as a possible predictive marker of treatment efficacy in WD-NEC patients treated with 5-FU.

PMID:
18281538
DOI:
10.1158/1078-0432.CCR-07-1513
[Indexed for MEDLINE]
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