Thymidylate synthase but not excision repair cross-complementation group 1 tumor expression predicts outcome in patients with malignant pleural mesothelioma treated with pemetrexed-based chemotherapy.
OBJECTIVE
The relationship between thymidylate synthase (TS) expression and outcome in patients with malignant pleural mesothelioma (MPM) treated with pemetrexed (P) was retrospectively evaluated.


METHODS
Sixty histologically confirmed patients with MPM previously treated with P and platinum (45 of 60) or as single agent (15 of 60) were retrospectively considered. Eighty-one control patients with MPM not P-treated were also evaluated. TS and excision repair cross-complementation group 1 (ERCC1) gene expression levels were evaluated by real-time polymerase chain reaction and by immunohistochemistry using the H-score.


RESULTS
Median TS H-score value was 90 (range, 5 to 240). A significant correlation between low TS protein expression and longer time to progression (TTP; 17.9 v 7.9 months; hazard ratio [HR], 2.05, 95% CI, 1.19 to 3.77; P = .02) or overall survival (OS; 30 v 16.7 months; HR, 2.38; 95% CI, 1.15 to 4.91; P = .019) was found when patients were divided according to median H-score. Conversely, TS mRNA levels were not significantly correlated with outcome. In platinum-treated patients (n = 45), no correlation was found with survival according to ERCC1 median H-score, but patients in the lower tertile had a significantly shorter survival (HR, 3.06; 95% CI, 1.08 to 8.69; P = .035). In control MPMs, TS had no prognostic role. At multivariate analysis, TS protein levels were the only independent prognostic factor for both TTP (HR, 2.71; 95% CI, 1.13 to 6.49; P = .02) and OS (HR, 6.91; 95% CI, 1.90 to 25.07; P = .003).


CONCLUSIONS
In patients with MPM treated with P-based chemotherapy, low TS protein levels are predictive of improved TTP and OS. The role of TS assessment is worth of prospective validation in future studies on MPM.
Righi
Luisella
L
University of Torino, Division of Pathology, Thoracic Oncology, and Thoracic Surgery, Department of Clinical and Biological Sciences at San Luigi Hospital, Orbassano, Italy.
Papotti
Mauro G
MG
Ceppi
Paolo
P
Billè
Andrea
A
Bacillo
Elisa
E
Molinaro
Luca
L
Ruffini
Enrico
E
Scagliotti
Giorgio V
GV
Selvaggi
Giovanni
G
D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use*; D015415:Biomarkers / Q000378:metabolism; D004265:DNA Helicases / Q000096:biosynthesis; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D005971:Glutamates / Q000627:therapeutic use*; D006147:Guanine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D006801:Humans; D008297:Male; D008654:Mesothelioma / Q000188:drug therapy / Q000378:metabolism*; D008875:Middle Aged; D000068437:Pemetrexed; D010997:Pleural Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D011237:Predictive Value of Tests; D011379:Prognosis; D012189:Retrospective Studies; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D016896:Treatment Outcome
D000964:Antimetabolites, Antineoplastic; D015415:Biomarkers; D005971:Glutamates; D000068437:Pemetrexed; D006147:Guanine; D013940:Thymidylate Synthase; D004265:DNA Helicases