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Correlation Between TS, MTHFR, And ERCC1 Gene Polymorphisms And The Efficacy Of Platinum In Combination With Pemetrexed First-line Chemotherapy In Mesothelioma Patients.

T. Powrózek, D. Kowalski, P. Krawczyk, R. Ramlau, T. Kucharczyk, E. Kalinka-Warzocha, Magdalena Knetki-Wróblewska, K. Winiarczyk, W. Dyszkiewicz, M. Krzakowski, J. Milanowski
Published 2014 · Medicine

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INTRODUCTION The combination of pemetrexed and platinum compound represents the standard regimen for first-line chemotherapy in malignant pleural mesothelioma patients. Pemetrexed is a multitarget antifolate agent that inhibits folate-dependent enzymes (eg, thymidylate synthase [TS]) and thus synthesis of nucleotides and DNA. Expression of TS and folate availability, regulated by gene polymorphisms, have implications for effectiveness of chemotherapy and the outcome of mesothelioma patients. The aim of this retrospective multicenter study was to assess the correlation between TS, 5,10-methylenetetrahydrofolate reductase (MTHFR) and excision repair cross-complementing group 1 (ERCC1) gene polymorphisms and the efficacy of pemetrexed-based first-line chemotherapy of mesothelioma patients. PATIENTS AND METHODS Fifty-nine mesothelioma patients (31 men with a median age of 62 years) treated in first-line chemotherapy with platinum in combination with pemetrexed or pemetrexed monotherapy were enrolled. Genomic DNA was isolated from peripheral blood. Using polymerase chain reaction and high resolution melt methods, the variable number of tandem repeat, the G>C single nucleotide polymorphism (SNP) in these repeats, and 6-base pair (bp) insertion/deletion polymorphism of the TS gene, the SNP of 677C>T in MTHFR, and 19007C>T in the ERCC1 gene were analyzed and correlated with disease control rate, progression-free survival (PFS), and overall survival (OS) of mesothelioma patients. RESULTS Greater risk of early disease progression (PD), and shortening of PFS and OS were associated with several clinical factors (eg, anemia for early PD and OS), weight loss (for PFS and OS), and previous surgical treatment (for early PD, PFS, and OS). Insertion of 6-bp in both alleles of the TS gene (1494del6) was the only genetic factor that increased the incidence of early progression (P = .028) and shortening of median PFS (P = .06) in patients treated with pemetrexed-based chemotherapy. In multivariate analysis, the 1494del6 in the 3' untranslated region (UTR) of the TS gene also had a predictive role for PFS (P = .0185; hazard ratio, 2.3258 for +6/+6 homozygotes) in analyzed mesothelioma patients. CONCLUSION Most analyzed polymorphisms in TS, MTHFR, and ERCC1 genes failed to predict outcome in mesothelioma patients treated with pemetrexed-based chemotherapy. However, different variants of 1494del6 in the 3' UTR of the TS gene were associated with differences in disease control rate and PFS of our patients.
This paper references
10.1054/bjoc.2001.2007
A polymorphism in the enhancer region of the thymidylate synthase promoter influences the survival of colorectal cancer patients treated with 5-fluorouracil
B. Iacopetta (2001)
10.1200/JCO.2005.03.5253
Tumor thymidylate synthase 1494del6 genotype as a prognostic factor in colorectal cancer patients receiving fluorouracil-based adjuvant treatment.
E. Dotor (2006)
A novel single nucleotide polymorphism within the 5' tandem repeat polymorphism of the thymidylate synthase gene abolishes USF-1 binding and alters transcriptional activity.
Michael V Mandola (2003)
10.1158/1078-0432.CCR-10-2873
Thymidylate Synthase and Excision Repair Cross-Complementing Group-1 as Predictors of Responsiveness in Mesothelioma Patients Treated with Pemetrexed/Carboplatin
P. A. Zucali (2011)
10.1093/JNCI/94.14.1091
An analysis of DNA repair as a determinant of survival in patients with non-small-cell lung cancer.
C. H. Bosken (2002)
10.1093/ANNONC/MDM501
Phase II study of pemetrexed in combination with carboplatin in patients with malignant pleural mesothelioma (MPM).
B. Castagneto (2008)
10.1158/1535-7163.MCT-06-0343
Pemetrexed: biochemical and cellular pharmacology, mechanisms, and clinical applications
S. Chattopadhyay (2007)
10.1097/JTO.0b013e318293e45b
"One marker does not fit all": additional translational and validation studies are needed to identify faithful predictors of pemetrexed activity in mesothelioma.
E. Giovannetti (2013)
10.1097/JTO.0b013e31817c73d6
Pemetrexed Plus Cisplatin or Pemetrexed Plus Carboplatin for Chemonaïve Patients with Malignant Pleural Mesothelioma: Results of the International Expanded Access Program
A. Santoro (2008)
10.1016/j.lungcan.2011.08.011
Second-line chemotherapy in malignant pleural mesothelioma: results of a retrospective multicenter survey.
P. Zucali (2012)
10.1016/S1470-2045(11)70149-8
Extra-pleural pneumonectomy versus no extra-pleural pneumonectomy for patients with malignant pleural mesothelioma: clinical outcomes of the Mesothelioma and Radical Surgery (MARS) randomised feasibility study
T. Treasure (2011)
10.1007/s10637-007-9060-9
In vitro chemosensitivity of freshly explanted tumor cells to pemetrexed is correlated with target gene expression
Axel-Rainer Hanauske (2007)
10.1247/CSF.20.191
Functional analysis and DNA polymorphism of the tandemly repeated sequences in the 5'-terminal regulatory region of the human gene for thymidylate synthase.
N. Horie (1995)
10.1200/JCO.2009.25.9275
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.
L. Righi (2010)
10.1007/s12032-010-9443-1
Predictive value of ERCC1 and XPD polymorphism in patients with advanced non-small cell lung cancer receiving platinum-based chemotherapy: a systematic review and meta-analysis
S. Wei (2011)
10.1097/00008571-200405000-00007
A 6 bp polymorphism in the thymidylate synthase gene causes message instability and is associated with decreased intratumoral TS mRNA levels.
Michael V Mandola (2004)
10.1073/pnas.191502998
Classification of human lung carcinomas by mRNA expression profiling reveals distinct adenocarcinoma subclasses
Arindam Bhattacharjee (2001)
10.1200/JCO.2003.11.136
Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma.
N. Vogelzang (2003)
10.1093/annonc/mdq253
New tricks for old biomarkers: thymidylate synthase expression as a predictor of pemetrexed activity in malignant mesothelioma.
P. Zucali (2010)
10.1634/theoncologist.2008-0232
The differential efficacy of pemetrexed according to NSCLC histology: a review of two Phase III studies.
G. Scagliotti (2009)
10.1007/s11033-014-3197-3
Thymidylate synthase polymorphisms are associated to therapeutic outcome of advanced non-small cell lung cancer patients treated with platinum-based chemotherapy
Aurea Lima (2014)
10.1510/ICVTS.2005.123430
The MARS trial: mesothelioma and radical surgery.
T. Treasure (2006)
10.3892/or.2013.2696
Predictive value of ERCC1 and RRM1 gene single-nucleotide polymorphisms for first-line platinum- and gemcitabine-based chemotherapy in non-small cell lung cancer patients.
R. Mlak (2013)
10.1093/annonc/mdr324
The influence of platinum pathway polymorphisms on the outcome in patients with malignant mesothelioma.
N. Erčulj (2012)
10.1200/JCO.2004.22.90140.7192
Pemetrexed in combination with cisplatin in the treatment of chemonaive patients with malignant pleural mesothelioma (MPM): Outcomes on Expanded Access Program (EAP)
A. J. Wozniak (2004)
10.1200/JCO.2005.04.3190
Phase II study of pemetrexed plus carboplatin in malignant pleural mesothelioma.
G. Ceresoli (2006)
10.1093/ANNONC/MDI187
Second-line (post-study) chemotherapy received by patients treated in the phase III trial of pemetrexed plus cisplatin versus cisplatin alone in malignant pleural mesothelioma.
C. Manegold (2005)
10.1200/JCO.2005.02.0495
Studying the predictive/prognostic role of thymidylate synthase genotypes in patients with colorectal cancer: Is one polymorphism enough?
F. Graziano (2005)
10.1038/NG0595-111
A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase
P. Frosst (1995)
10.3978/j.issn.2225-319X.2012.10.05
Chemotherapy for malignant pleural mesothelioma: a review of current management and a look to the future.
A. Nowak (2012)
10.1002/cncr.22208
Squamous cell carcinoma of the lung compared with other histotypes shows higher messenger RNA and protein levels for thymidylate synthase
P. Ceppi (2006)



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