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Clinical Cancer Research 14, 1059, February 15, 2008. doi: 10.1158/1078-0432.CCR-07-1513
© 2008 American Association for Cancer Research

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Imaging, Diagnosis, Prognosis

Thymidylate Synthase Expression in Gastroenteropancreatic and Pulmonary Neuroendocrine Tumors

Paolo Ceppi1, Marco Volante2, Anna Ferrero3, Luisella Righi2, Ida Rapa2, Rosj Rosas2, Alfredo Berruti3, Luigi Dogliotti3, Giorgio V. Scagliotti1 and Mauro Papotti2

Authors' Affiliations: 1 Thoracic Oncology Unit, 2 Pathology Division, and 3 Division of Medical Oncology, Department of Clinical and Biological Sciences, University of Torino, San Luigi Hospital, Torino, Italy

Requests for reprints: Paolo Ceppi, Department of Clinical and Biological Sciences, University of Turin, San Luigi Hospital Regione Gonzole 10, 10043 Orbassano, Torino, Italy. Phone: 39-011-9026644; Fax: 39-011-9026753; E-mail: paolo.ceppi{at}unito.it.

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.




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Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
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Annual Meeting Education Book Meeting Abstracts Online
Copyright © 2008 by the American Association for Cancer Research.