Thymidylate synthase expression in gastroenteropancreatic and pulmonary neuroendocrine tumors

Paolo Ceppi*, Marco Volante, Anna Ferrero, Luisella Righi, Ida Rapa, Rosj Rosas, Alfredo Berruti, Luigi Dogliotti, Giorgio V. Scagliotti, Mauro Papotti

*Kontaktforfatter for dette arbejde

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

Resumé

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.

OriginalsprogEngelsk
TidsskriftClinical Cancer Research
Vol/bind14
Udgave nummer4
Sider (fra-til)1059-1064
Antal sider6
ISSN1078-0432
DOI
StatusUdgivet - 15. feb. 2008

Fingeraftryk

Lung
Fluorouracil
Folic Acid Antagonists
Neoplasms
Messenger RNA
Real-Time Polymerase Chain Reaction
Neuroendocrine Tumors
Paraffin
Research Design
Multivariate Analysis
RNA
Pharmaceutical Preparations
Proteins

Citer dette

Ceppi, Paolo ; Volante, Marco ; Ferrero, Anna ; Righi, Luisella ; Rapa, Ida ; Rosas, Rosj ; Berruti, Alfredo ; Dogliotti, Luigi ; Scagliotti, Giorgio V. ; Papotti, Mauro. / Thymidylate synthase expression in gastroenteropancreatic and pulmonary neuroendocrine tumors. I: Clinical Cancer Research. 2008 ; Bind 14, Nr. 4. s. 1059-1064.
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title = "Thymidylate synthase expression in gastroenteropancreatic and pulmonary neuroendocrine tumors",
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.",
author = "Paolo Ceppi and Marco Volante and Anna Ferrero and Luisella Righi and Ida Rapa and Rosj Rosas and Alfredo Berruti and Luigi Dogliotti and Scagliotti, {Giorgio V.} and Mauro Papotti",
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doi = "10.1158/1078-0432.CCR-07-1513",
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Ceppi, P, Volante, M, Ferrero, A, Righi, L, Rapa, I, Rosas, R, Berruti, A, Dogliotti, L, Scagliotti, GV & Papotti, M 2008, 'Thymidylate synthase expression in gastroenteropancreatic and pulmonary neuroendocrine tumors', Clinical Cancer Research, bind 14, nr. 4, s. 1059-1064. https://doi.org/10.1158/1078-0432.CCR-07-1513

Thymidylate synthase expression in gastroenteropancreatic and pulmonary neuroendocrine tumors. / Ceppi, Paolo; Volante, Marco; Ferrero, Anna; Righi, Luisella; Rapa, Ida; Rosas, Rosj; Berruti, Alfredo; Dogliotti, Luigi; Scagliotti, Giorgio V.; Papotti, Mauro.

I: Clinical Cancer Research, Bind 14, Nr. 4, 15.02.2008, s. 1059-1064.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

TY - JOUR

T1 - Thymidylate synthase expression in gastroenteropancreatic and pulmonary neuroendocrine tumors

AU - Ceppi, Paolo

AU - Volante, Marco

AU - Ferrero, Anna

AU - Righi, Luisella

AU - Rapa, Ida

AU - Rosas, Rosj

AU - Berruti, Alfredo

AU - Dogliotti, Luigi

AU - Scagliotti, Giorgio V.

AU - Papotti, Mauro

PY - 2008/2/15

Y1 - 2008/2/15

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=39749121476&partnerID=8YFLogxK

U2 - 10.1158/1078-0432.CCR-07-1513

DO - 10.1158/1078-0432.CCR-07-1513

M3 - Journal article

VL - 14

SP - 1059

EP - 1064

JO - Clinical Cancer Research

JF - Clinical Cancer Research

SN - 1078-0432

IS - 4

ER -