Thymidylate synthase and excision repair cross-complementing group-1 as predictors of responsiveness in mesothelioma patients treated with pemetrexed/carboplatin.
OBJECTIVE
The pemetrexed/platinum agent combination represents the standard of care in first-line treatment for malignant pleural mesothelioma (MPM). However, there are no established indicators of responsiveness that can be used to optimize the treatment. This retrospective study aimed to assess the role of excision repair cross-complementing group-1 (ERCC1) and thymidylate synthase (TS) in tumors, and correlate expression levels and polymorphisms of these key determinants of drug activity with the outcome of MPM patients treated with carboplatin/pemetrexed in first-line setting.


METHODS
Analysis of TS and ERCC1 polymorphisms, mRNA and protein expression was done by PCR and immunohistochemistry [with the H-score (histologic score)] in tumor specimens from 126 MPM patients, including 99 carboplatin-/pemetrexed-treated patients.


RESULTS
A significant correlation between low TS protein expression and disease control (DC) to carboplatin/pemetrexed therapy (P = 0.027), longer progression-free survival (PFS; P = 0.017), and longer overall survival (OS; P = 0.022) was found when patients were categorized according to median H-score. However, patients with the higher tertile of TS mRNA expression correlated with higher risk of developing progressive disease (P = 0.022), shorter PFS (P < 0.001), and shorter OS (P < 0.001). At multivariate analysis, the higher tertile of TS mRNA level and TS H-score confirmed their independent prognostic role for DC, PFS, and OS. No significant associations were found among ERCC1 protein expression, TS and ERCC1 polymorphisms, and clinical outcome.


CONCLUSIONS
In our series of carboplatin-/pemetrexed-treated MPM patients, low TS protein and mRNA levels were significantly associated to DC, improved PFS, and OS. Prospective trials for the validation of the prognostic/predictive role of TS in MPM patients treated with pemetrexed-based regimens are warranted.
Department of Oncology, Biostatistics Unit, Istituto Clinico Humanitas IRCCS, Rozzano, Milan, Italy. paolo.zucali@humanitas.it
Paolo Andrea
PA
Zucali
Elisa
E
Giovannetti
Annarita
A
Destro
Manlio
M
Mencoboni
Giovanni Luca
GL
Ceresoli
Letizia
L
Gianoncelli
Elena
E
Lorenzi
Fabio
F
De Vincenzo
Matteo
M
Simonelli
Matteo
M
Perrino
Andrea
A
Bruzzone
Erik
E
Thunnissen
Gianni
G
Tunesi
Laura
L
Giordano
Massimo
M
Roncalli
Godefridus J
GJ
Peters
Armando
A
Santoro
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D016190:Carboplatin / Q000008:administration & dosage; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D004720:Endonucleases / Q000235:genetics* / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005787:Gene Frequency; D005838:Genotype; D005971:Glutamates / Q000008:administration & dosage; D006147:Guanine / Q000008:administration & dosage / Q000031:analogs & derivatives; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008654:Mesothelioma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D008875:Middle Aged; D015999:Multivariate Analysis; D000068437:Pemetrexed; D010997:Pleural Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D012189:Retrospective Studies; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016019:Survival Analysis; D013940:Thymidylate Synthase / Q000235:genetics* / Q000378:metabolism; D016896:Treatment Outcome
D004268:DNA-Binding Proteins; D005971:Glutamates; D000068437:Pemetrexed; D006147:Guanine; D016190:Carboplatin; D013940:Thymidylate Synthase; C071447:ERCC1 protein, human; D004720:Endonucleases