Alberola, Vicente

Blasco, Ana

Brea, Marta L.

de las Peñas, Ramon

González-Larriba, José-Luis

López-Vivanco, Guillermo

Molina, Miguel A.

Ramírez, José L.

Rosell, Rafael

Salazar, Fernanda

Elsevier - Publisher Connector 

Copyright © 2007 by the International Association for the Study of Lung Cancer S525
Journal of Thoracic Oncology • Volume 2, Number 8, Supplement 4, August 2007  12th World Conference on Lung Cancer
P2-086 BSTB: Prognostic Factors Posters, Tue, Sept 4 
Predictive value of thymidylate synthase, dihydropyrimidine 
dehydrogenase, thymidine phosphorylase and orotate 
phosphoribosyl transferase expression in tumor tissue, regarding 
the efficacy of postoperatively administered UFT (Tegafur + 
Uracil) in patients with non-small cell lung cancer
Miyoshi, Takanori1 Kondo, Kazuya1 Toba, Hiroaki1 Nagao, Taeko1 
Yoshida, Mitsuteru1 Hirose, Yukiko1 Kenzaki, Koichiro1 Sakiyama, 
Shoji1 Takehisa, Masatsugu2 Tangoku, Akira1 
1 Department of Oncological and Regenerative Surgery, Institute of 
Health Bioscience, University of Tokushima Graduate School, Tokushi-
ma, Japan 2 Department of Surgery, Tokushima Hospital, Tokushima, 
Japan 
Introduction: UFT (Tegafur + Uracil) has been reported to be effective 
for postoperative adjuvant chemotherapy of non-small cell lung cancer 
(NSCLC) in randomized prospective study. Recently, many clinical 
studies have revealed that the effect of UFT was effective for cancer 
with a low activity of Thymidylate Synthase (TS) and Dihydropyrimi-
dine Dehydrogenase (DPD). Firstly, we studied the correlation between 
the activity and the mRNA expression of TS and DPD in NSCLC. 
Secondly, we also examined the relationship between TS and DPD 
protein expression and several data including prognosis in NSCLC 
patients. In this study, we examined the mRNA expression of TS, DPD, 
thymidine phosphorylase (TP) and orotate phosphoribosyl transferase 
(OPRT) from the parafﬁn-embedded tissue samples.[Patient] Eighty 
patients underwent complete surgical resection and administered UFT 
after operation in NSCLC from 1993 to 2001 at the University of 
Tokushima-afﬁliated hospital for the ﬁrst and second studies. Sixty-ﬁve 
patients underwent same as above in NSCLC from 1988 to 2004 for 
this third study.
Method: Firstly, the activity of TS was determined by the FdUMP 
binding assay combined with gel ﬁltration. The activity of DPD was 
determined by the radio-enzymatic assay. And the mRNA expression 
of TS and DPD was examined by real time RT-PCR method. Secondly, 
TS and DPD protein expression in tumor tissues was evaluated by 
immunohistochemical staining (IHC) by LSAB method. For this study, 
mRNA was isolated from parafﬁn-embedded specimens. A quantita-
tive real-time reverse transcription-PCR method (TaqMan) was used 
to measure the expression of TS, DPD, TP and OPRT genes (DTP 
method). We analyzed whether there was a relationship between these 
genes expression and post-operative survival in NSCLC. 
Result: There was not the relationship between the quantity of each 
gene expression and stages. The mRNA expression of DPD and TS was 
correlated to the activity of DPD and TS (r=0.846, 0.757). TS negative 
expression group had a signiﬁcantly better prognosis than TS posi-
tive expression group (p<0.001) by IHC. Especially the tendency was 
remarkable in pStage I (10-year survival rate: 95.5% vs22.7 %). There 
was not a relationship between DPD expression and post-operative 
survival in NSCLC. TP low expression group (<5.5) had a signiﬁcantly 
better prognosis than TP high expression group (>5.5) (p=0.03) by DTP 
method. There was not a relationship between TS, DPD and OPRT 
expression and post-operative survival in NSCLC. Though it was not 
signiﬁcant p value, TS low expression group (<1.0) had a better prog-
nosis than TS high expression group (>1.0) by DTP method. This result 
by DTP method was similar to the result by IHC.
Conclusions: Oral administration of UFT in a postoperative adjuvant 
setting yields a signiﬁcant improvement in survival in patients with 
TS negative expression by IHC or TS low expression group by DTP 
method, especially in pathological stage I NSCLC. TP low expression 
group had a signiﬁcantly better prognosis. The high or low expression 
of DPD and OPRT did not let inﬂuence extend to prognosis in NSCLC. 
Therefore, the uracil of UFT may be able to inhibit DPD activity, and 
there is a possibility that it can promote an effect of 5-FU.
P2-087 BSTB: Prognostic Factors Posters, Tue, Sept 4 
Elevated levels of thioredoxin (Trx) in serum correlate with poor 
outcome in docetaxel (doc)/cisplatin (cis)-treated stage IV non-
small-cell lung cancer (NSCLC) patients (p)
Molina, Miguel A.1 de las Peñas, Ramon2 Alberola, Vicente3 Blasco, 
Ana4 López-Vivanco, Guillermo5 Brea, Marta L.6 González-Larriba, 
José-Luis7 Salazar, Fernanda1 Ramírez, José L.1 Rosell, Rafael1 
1 Institut Catala d’Oncologia, Hospital Germans Trias i Pujol, Bad-
alona, Spain 2 Hospital Provincial de Castellón, Castellón, Spain 3 Hos-
pital Arnau de Vilanova, Valencia, Spain 4 Hospital General Universita-
rio de Valencia, Valencia, Spain 5 Hospital de Cruces, Baracaldo, Spain 
6 Hospital Marqués de Valdecilla, Santander, Spain 7 Hospital Clínico 
San Carlos, Madrid, Spain 
Background: Chemotherapy causes the production of reactive oxygen 
species (ROS), which facilitates cancer cell death. Trx protein func-
tions as a ROS scavenger and a negative regulator of apoptosis signal 
regulating kinase-1 (ASK-1). High levels of Trx are associated with 
chemoresistance. 14-3-3σ proteins are involved in cell cycle control 
and protein trafﬁcking. 
Methods: Trx ELISA and 14-3-3σ methylation-speciﬁc PCR were 
performed in baseline serum from 107 stage IV NSCLC p treated with 
doc/cis. 
Results: Median age, 60 (range, 32-79); male, 87 (81.3%). PS: 0, 27 
(25.2%); 1, 80 (74.8%). Adenocarcinoma, 46 (43.8%); squamous cell 
carcinoma, 40 (38.1%); 21 p had large cell or unspeciﬁed histology. 
Complete response, 1 p; partial response, 20 p; overall response rate, 
20%. Median Trx level, 97.4 (range, 18.8-763.1). Serum was available 
for 14-3-3σ methylation analysis in only 88 p. 14-3-3σ was methyl-
ated in 43 p (48.9%). A signiﬁcant correlation was observed between 
14-3-3σ methylation status and Trx levels (Table). 4 p with methylated 
and 17 with unmethylated 14-3-3σ had Trx levels >182.8 (P=0.003). 
Median Trx levels were 103.5 in responders and 94.3 in non-respond-
ers (P=0.96). Time to progression (TTP) was 5.6 months (m) for 27 
p with Trx <49.6, 4.4 m for 53 p with Trx 49.6-182.8, and 3.8 m for 
27 p with Trx >182.8 (P=0.02). In a Cox multivariate analysis, Trx 
levels emerged as an independent variable for TTP when 14-3-3σ was 
included in the model. Hazard ratios: 1.3 for PS1 (P=0.84); 1.05 for 
14-3-3σ unmethylated (P=0.22); 1.4 for Trx 49.6-182.8 and 1.95 for 
Trx >182.8 (P=0.04). 
 TRX Levels Trx Levels Trx Levels
14-3-.3 sigma < 49.7 49.7-182.8 >182.8
methylated 11 (25.6%) 28 (65.1%) 4(9.3%)
 (47.8%) (63.6%) (19%)
unmethylated 12 (26.7%) 16 (35.6%) 17 (37.8%)
 (52.2%) (36.4%) (81%)
Conclusions: Serum Trx levels can predict TTP in doc/cis-treated p. 
The additional role of 14-3-3σ methylation may be more clearly dem-
onstrated in cis/gemcitabine regimens. 


P2-087: Elevated levels of thioredoxin (Trx) in serum correlate with poor outcome in docetaxel (doc)/cisplatin (cis)-treated stage IV non-small-cell lung cancer (NSCLC) patients (p) 

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P2-087: Elevated levels of thioredoxin (Trx) in serum correlate with poor outcome in docetaxel (doc)/cisplatin (cis)-treated stage IV non-small-cell lung cancer (NSCLC) patients (p)

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