Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
BMC Cancer
Published in: BMC Cancer 1/2014

Open Access 01-12-2014 | Research article

The pemetrexed-containing treatments in the non-small cell lung cancer, is -/low thymidylate synthase expression better than +/high thymidylate synthase expression: a meta-analysis

Authors: Lei Wang, Rui Wang, Yunjian Pan, Yihua Sun, Jie Zhang, Haiquan Chen

Published in: BMC Cancer | Issue 1/2014

Login to get access

Abstract

Background

The predictive value of thymidylate synthase (TS) for clinical sensitivity to pemetrexed-containing chemotherapy in patients with non-small cell lung cancer (NSCLC) remains controversial. This meta-analysis is performed to provide an assessment of whether expression variations of TS are associated with objective response in patients with NSCLC treated with pemetrexed-containing chemotherapy.

Methods

An electronic search was conducted using the databases MEDLINE, EMBASE and CNKI, from inception to June 10th, 2013. A systemic review of the studies on the association between TS expression in NSCLC and objective response of pemetrexed-containing regimen was performed. Pooled odds ratios (OR) for the response rate were calculated using the software Revman 5.0.

Results

There were a total of 526 patients in the eight studies that met our criteria for evaluation. +/high expression of TS was found in 269 patients (51.1%), and -/low expression for this gene was found in 257 (48.9%) patients. The objective response rate for pemetrexed-containing chemotherapy was significantly higher in patients with -/low expression TS expression (OR = 0.45; 95% CI, 0.29–0.70; p = 0.0004). Although patients with -/low expression of TS have a longer median overall survival time and progression free survival time than those with +/high expression of TS, the difference was not statistically significant.

Conclusions

−/low expression of TS was associated with higher objective response in NSCLC patients treated with pemetrexed-containing chemotherapy. TS may be a suitable marker of sensitivity to pemetrexed-based chemotherapy in patients with NSCLC.
Appendix
Available only for authorised users
Literature
1.
Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ: Cancer statistics, 2009. CA Cancer J Clin. 2009, 59 (4): 225-249. 10.3322/caac.20006.CrossRefPubMed
2.
Socinski MA, Schell MJ, Peterman A, Bakri K, Yates S, Gitten R, Unger P, Lee J, Lee JH, Tynan M, Moore M, Kies MS: Phase III trial comparing a defined duration of therapy versus continuous therapy followed by second-line therapy in advanced-stage IIIB/IV non-small-cell lung cancer. J Clin Oncol. 2002, 20 (5): 1335-1343. 10.1200/JCO.20.5.1335.CrossRefPubMed
3.
Park JO, Kim SW, Ahn JS, Suh C, Lee JS, Jang JS, Cho EK, Yang SH, Choi JH, Heo DS, Park SY, Shin SW, Ahn MJ, Yun YH, Lee JW, Park K: Phase III trial of two versus four additional cycles in patients who are nonprogressive after two cycles of platinum-based chemotherapy in non small-cell lung cancer. J Clin Oncol. 2007, 25 (33): 5233-5239. 10.1200/JCO.2007.10.8134.CrossRefPubMed
4.
Schiller JH, Harrington D, Belani CP, Langer C, Sandler A, Krook J, Zhu J, Johnson DH: Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med. 2002, 346 (2): 92-98. 10.1056/NEJMoa011954.CrossRefPubMed
5.
Chen LK, Liang Y, Yang QY, Xu F, Zhou NN, Xu GC, Liu GZ: Triplet platinum-based combination sequential chemotherapy improves survival outcome and quality of life of advanced non-small cell lung cancer patients. Asian Pac J Cancer Prev. 2012, 13 (5): 1863-1867. 10.7314/APJCP.2012.13.5.1863.CrossRefPubMed
6.
Bepler G, Sommers KE, Cantor A, Li X, Sharma A, Williams C, Chiappori A, Haura E, Antonia S, Tanvetyanon T, Simon G, Obasaju C, Robinson LA: Clinical efficacy and predictive molecular markers of neoadjuvant gemcitabine and pemetrexed in resectable non-small cell lung cancer. J Thorac Oncol. 2008, 3 (10): 1112-1118. 10.1097/JTO.0b013e3181874936.CrossRefPubMedPubMedCentral
7.
Pfister DG, Johnson DH, Azzoli CG, Sause W, Smith TJ, Baker S, Olak J, Stover D, Strawn JR, Turrisi AT, Somerfield MR: American Society of Clinical Oncology treatment of unresectable non-small-cell lung cancer guideline: update 2003. J Clin Oncol. 2004, 22 (2): 330-353.CrossRefPubMed
8.
Hanna N, Shepherd FA, Fossella FV, Pereira JR, De Marinis F, von Pawel J, Gatzemeier U, Tsao TC, Pless M, Muller T, Lim HL, Desch C, Szondy K, Gervais R, Shaharyar , Manegold C, Paul S, Paoletti P, Einhorn L, Bunn PA: Randomized phase III trial of pemetrexed versus docetaxel in patients with non-small-cell lung cancer previously treated with chemotherapy. J Clin Oncol. 2004, 22 (9): 1589-1597. 10.1200/JCO.2004.08.163.CrossRefPubMed
9.
Scagliotti GV, Parikh P, von Pawel J, Biesma B, Vansteenkiste J, Manegold C, Serwatowski P, Gatzemeier U, Digumarti R, Zukin M, Lee JS, Mellemgaard A, Park K, Patil S, Rolski J, Goksel T, Marinis F, Simms L, Sugarman KP, Gandara D: Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer. J Clin Oncol. 2008, 26 (21): 3543-3551. 10.1200/JCO.2007.15.0375.CrossRefPubMed
10.
Ciuleanu T, Brodowicz T, Zielinski C, Kim JH, Krzakowski M, Laack E, Wu YL, Bover I, Begbie S, Tzekova V, Cucevic B, Pereira JR, Yang SH, Madhavan J, Sugarman KP, Peterson P, John WJ, Krejcy K, Belani CP: Maintenance pemetrexed plus best supportive care versus placebo plus best supportive care for non-small-cell lung cancer: a randomised, double-blind, phase 3 study. Lancet. 2009, 374 (9699): 1432-1440. 10.1016/S0140-6736(09)61497-5.CrossRefPubMed
11.
Mendelsohn LG, Shih C, Chen VJ, Habeck LL, Gates SB, Shackelford KA: Enzyme inhibition, polyglutamation, and the effect of LY231514 (MTA) on purine biosynthesis. Semin Oncol. 1999, 26 (2 Suppl 6): 42-47.PubMed
12.
Adjei AA: Pemetrexed (Alimta): a novel multitargeted antifolate agent. Expert Rev Anticancer Ther. 2003, 3 (2): 145-156. 10.1586/14737140.3.2.145.CrossRefPubMed
13.
Wu MF, Hsiao YM, Huang CF, Huang YH, Yang WJ, Chan HW, Chang JT, Ko JL: Genetic determinants of pemetrexed responsiveness and nonresponsiveness in non-small cell lung cancer cells. J Thorac Oncol. 2010, 5 (8): 1143-1151. 10.1097/JTO.0b013e3181e0b954.CrossRefPubMed
14.
Yang TY, Chang GC, Chen KC, Hung HW, Hsu KH, Wu CH, Sheu GT, Hsu SL: Pemetrexed induces both intrinsic and extrinsic apoptosis through ataxia telangiectasia mutated/p53-dependent and -independent signaling pathways. Mol Carcinog. 2011, doi:10.1002/mc.2184
15.
Ozasa H, Oguri T, Uemura T, Miyazaki M, Maeno K, Sato S, Ueda R: Significance of thymidylate synthase for resistance to pemetrexed in lung cancer. Cancer Sci. 2010, 101 (1): 161-166. 10.1111/j.1349-7006.2009.01358.x.CrossRefPubMed
16.
Rossi A, Ricciardi S, Maione P, de Marinis F, Gridelli C: Pemetrexed in the treatment of advanced non-squamous lung cancer. Lung Cancer. 2009, 66 (2): 141-149. 10.1016/j.lungcan.2009.06.006.CrossRefPubMed
17.
Sun JM, Han J, Ahn JS, Park K, Ahn MJ: Significance of thymidylate synthase and thyroid transcription factor 1 expression in patients with nonsquamous non-small cell lung cancer treated with pemetrexed-based chemotherapy. J Thorac Oncol. 2011, 6 (8): 1392-1399. 10.1097/JTO.0b013e3182208ea8.CrossRefPubMed
18.
Takezawa K, Okamoto I, Okamoto W, Takeda M, Sakai K, Tsukioka S, Kuwata K, Yamaguchi H, Nishio K, Nakagawa K: Thymidylate synthase as a determinant of pemetrexed sensitivity in non-small cell lung cancer. Br J Cancer. 2011, 104 (10): 1594-1601. 10.1038/bjc.2011.129.CrossRefPubMedPubMedCentral
19.
Wang ZK, Hu Y, Zhao H, Fu C: Thymidylate synthase expression and therapeutic effect analysis of pemetrexed in advanced lung adenocarcinoma. Nan Fang Yi Ke Da Xue Xue Bao. 2010, 30 (5): 978-980.PubMed
20.
Uramoto H, Onitsuka T, Shimokawa H, Hanagiri T: TS, DHFR and GARFT expression in non-squamous cell carcinoma of NSCLC and malignant pleural mesothelioma patients treated with pemetrexed. Anticancer Res. 2010, 30 (10): 4309-4315.PubMed
21.
Chen CY, Chang YL, Shih JY, Lin JW, Chen KY, Yang CH, Yu CJ, Yang PC: Thymidylate synthase and dihydrofolate reductase expression in non-small cell lung carcinoma: the association with treatment efficacy of pemetrexed. Lung Cancer. 2011, 74 (1): 132-138. 10.1016/j.lungcan.2011.01.024.CrossRefPubMed
22.
Park CK, Kim KS, Oh IJ, Tseden IM, Choi YD, Kwon YS, Kim YI, Lim SC, Kim YC: Efficacy of pemetrexed in relapsed non-small cell lung cancer and thymidylate synthase expression. Tuberc Respir Dis. 2009, 67 (3): 191-198. 10.4046/trd.2009.67.3.191.CrossRef
23.
Nakagawa T, Tanaka F, Otake Y, Yanagihara K, Miyahara R, Matsuoka K, Takata T, Yamada T, Fukushima M, Wada H: Prognostic value of thymidylate synthase expression in patients with p-stage I adenocarcinoma of the lung. Lung Cancer. 2002, 35 (2): 165-170. 10.1016/S0169-5002(01)00407-X.CrossRefPubMed
24.
Zheng Z, Chen T, Li X, Haura E, Sharma A, Bepler G: DNA synthesis and repair genes RRM1 and ERCC1 in lung cancer. N Engl J Med. 2007, 356 (8): 800-808. 10.1056/NEJMoa065411.CrossRefPubMed
25.
Millett GA, Flores SA, Marks G, Reed JB, Herbst JH: Circumcision status and risk of HIV and sexually transmitted infections among men who have sex with men: a meta-analysis. JAMA. 2008, 300 (14): 1674-1684. 10.1001/jama.300.14.1674.CrossRefPubMed
26.
Schoenleber SJ, Kurtz DM, Talwalkar JA, Roberts LR, Gores GJ: Prognostic role of vascular endothelial growth factor in hepatocellular carcinoma: systematic review and meta-analysis. Br J Cancer. 2009, 100 (9): 1385-1392. 10.1038/sj.bjc.6605017.CrossRefPubMedPubMedCentral
27.
Check ML, Check JH, Choel JK, Davies E, Kiefer D: Effect of antagonists vs agonists on in vitro fertilization outcome. Clin Exp Obstet Gynecol. 2004, 31 (4): 257-259.PubMed
28.
Chang MH, Ahn JS, Lee J, Kim KH, Park YH, Han J, Ahn MJ, Park K: The efficacy of pemetrexed as a third- or fourth-line therapy and the significance of thymidylate synthase expression in patients with advanced non-small cell lung cancer. Lung Cancer. 2010, 69 (3): 323-329. 10.1016/j.lungcan.2009.12.002.CrossRefPubMed
29.
Igawa S, Ryuge S, Wada M, Otani S, Maki S, Takakura A, Katono K, Sasaki J, Sato Y, Masuda N: Pemetrexed for previously treated patients with non-small cell lung cancer and differences in efficacy according to thymidylate synthase expression. Chemotherapy. 2012, 58 (4): 313-320. 10.1159/000343048.CrossRefPubMed
30.
Stang A: Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses. Eur J Epidemiol. 2010, 25 (9): 603-605. 10.1007/s10654-010-9491-z.CrossRefPubMed
31.
Kyrgiou M, Tsoumpou I, Vrekoussis T, Martin-Hirsch P, Arbyn M, Prendiville W, Mitrou S, Koliopoulos G, Dalkalitsis N, Stamatopoulos P, Paraskevaidis E: The up-to-date evidence on colposcopy practice and treatment of cervical intraepithelial neoplasia: the Cochrane colposcopy & cervical cytopathology collaborative group (C5 group) approach. Cancer Treat Rev. 2006, 32 (7): 516-523. 10.1016/j.ctrv.2006.07.008.CrossRefPubMed
32.
Chiappori AA, Zheng Z, Chen T, Rawal B, Schell MJ, Mullaney BP, Bepler G: Features of potentially predictive biomarkers of chemotherapeutic efficacy in small cell lung cancer. J Thorac Oncol. 2010, 5 (4): 484-490. 10.1097/JTO.0b013e3181ccb27b.CrossRefPubMedPubMedCentral
33.
Makimoto T, Tsuchiya S, Nakano H, Watanabe S, Minato K, Takise A, Ezawa K, Fueki N, Naruse I, Nomoto T, Takei Y, Ishihara S, Mori M, Saitoh R: A phase II study of carboplatin-cisplatin-etoposide combination chemotherapy in advanced non-small-cell lung cancer. Am J Clin Oncol. 1997, 20 (1): 51-54. 10.1097/00000421-199702000-00011.CrossRefPubMed
34.
Shih C, Chen VJ, Gossett LS, Gates SB, MacKellar WC, Habeck LL, Shackelford KA, Mendelsohn LG, Soose DJ, Patel VF, Andis SL, Bewley JR, Rayl EA, Moroson BA, Beardsley GP, Kohler W, Ratnam M, Schultz R: LY231514, a pyrrolo[2,3-d]pyrimidine-based antifolate that inhibits multiple folate-requiring enzymes. Cancer Res. 1997, 57 (6): 1116-1123.PubMed
35.
Takizawa M, Kawakami K, Obata T, Matsumoto I, Ohta Y, Oda M, Sasaki T, Watanabe G: In vitro sensitivity to platinum-derived drugs is associated with expression of thymidylate synthase and dihydropyrimidine dehydrogenase in human lung cancer. Oncol Rep. 2006, 15 (6): 1533-1539.PubMed
36.
Kitazono-Saitoh M, Takiguchi Y, Kitazono S, Ashinuma H, Kitamura A, Tada Y, Kurosu K, Sakaida E, Sekine I, Tanabe N, Tagawa M, Tatsumi K: Interaction and cross-resistance of cisplatin and pemetrexed in malignant pleural mesothelioma cell lines. Oncol Rep. 2012, 28 (1): 33-40.PubMed
37.
Ibe T, Shimizu K, Nakano T, Kakegawa S, Kamiyoshihara M, Nakajima T, Kaira K, Takeyoshi I: High-grade neuroendocrine carcinoma of the lung shows increased thymidylate synthase expression compared to other histotypes. J Surg Oncol. 2010, 102 (1): 11-17. 10.1002/jso.21576.CrossRefPubMed
38.
Monica V, Scagliotti GV, Ceppi P, Righi L, Cambieri A, Lo Iacono M, Saviozzi S, Volante M, Novello S, Papotti M: Differential thymidylate synthase expression in different variants of large-cell carcinoma of the lung. Clin Cancer Res. 2009, 15 (24): 7547-7552. 10.1158/1078-0432.CCR-09-1641.CrossRefPubMed
39.
Hou J, Lambers M, den Hamer B, den Bakker MA, Hoogsteden HC, Grosveld F, Hegmans J, Aerts J, Philipsen S: Expression profiling-based subtyping identifies novel non-small cell lung cancer subgroups and implicates putative resistance to pemetrexed therapy. J Thorac Oncol. 2012, 7 (1): 105-114. 10.1097/JTO.0b013e3182352a45.CrossRefPubMed
40.
Nazki FH, Masood A, Banday MA, Bhat A, Ganai BA: Thymidylate synthase enhancer region polymorphism not related to susceptibility to acute lymphoblastic leukemia in the Kashmir population. Genet Mol Res. 2012, 11 (2): 906-917. 10.4238/2012.April.10.6.CrossRefPubMed
41.
Righi L, Papotti MG, Ceppi P, Bille A, Bacillo E, Molinaro L, Ruffini E, Scagliotti GV, Selvaggi G: 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. J Clin Oncol. 2010, 28 (9): 1534-1539. 10.1200/JCO.2009.25.9275.CrossRefPubMed
42.
Johnston PG, Lenz HJ, Leichman CG, Danenberg KD, Allegra CJ, Danenberg PV, Leichman L: Thymidylate synthase gene and protein expression correlate and are associated with response to 5-fluorouracil in human colorectal and gastric tumors. Cancer Res. 1995, 55 (7): 1407-1412.PubMed
43.
Yamachika T, Nakanishi H, Inada K, Tsukamoto T, Kato T, Fukushima M, Inoue M, Tatematsu M: A new prognostic factor for colorectal carcinoma, thymidylate synthase, and its therapeutic significance. Cancer. 1998, 82 (1): 70-77. 10.1002/(SICI)1097-0142(19980101)82:1<70::AID-CNCR8>3.0.CO;2-O.CrossRefPubMed
44.
Karlberg M, Ohrling K, Edler D, Hallstrom M, Ullen H, Ragnhammar P: Prognostic and predictive value of thymidylate synthase expression in primary colorectal cancer. Anticancer Res. 2010, 30 (2): 645-651.PubMed
45.
Qiu LX, Tang QY, Bai JL, Qian XP, Li RT, Liu BR, Zheng MH: Predictive value of thymidylate synthase expression in advanced colorectal cancer patients receiving fluoropyrimidine-based chemotherapy: evidence from 24 studies. Int J Cancer. 2008, 123 (10): 2384-2389. 10.1002/ijc.23822.CrossRefPubMed
46.
Shintani Y, Ohta M, Hirabayashi H, Tanaka H, Iuchi K, Nakagawa K, Maeda H, Kido T, Miyoshi S, Matsuda H: New prognostic indicator for non-small-cell lung cancer, quantitation of thymidylate synthase by real-time reverse transcription polymerase chain reaction. Int J Cancer. 2003, 104 (6): 790-795. 10.1002/ijc.11014.CrossRefPubMed
47.
Egger M, Davey Smith G, Schneider M, Minder C: Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997, 315 (7109): 629-634. 10.1136/bmj.315.7109.629.CrossRefPubMedPubMedCentral
Metadata
Title
The pemetrexed-containing treatments in the non-small cell lung cancer, is -/low thymidylate synthase expression better than +/high thymidylate synthase expression: a meta-analysis
Authors
Lei Wang
Rui Wang
Yunjian Pan
Yihua Sun
Jie Zhang
Haiquan Chen
Publication date
01-12-2014
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2014
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/1471-2407-14-205

Other articles of this Issue 1/2014

BMC Cancer 1/2014 Go to the issue

Research article

An epidemiological study assessing the prevalence of human papillomavirus types in women in the Kingdom of Bahrain

Research article

Tumor-associated macrophage-derived IL-6 and IL-8 enhance invasive activity of LoVo cells induced by PRL-3 in a KCNN4 channel-dependent manner

Research article

Biomarkers of thyroid function and autoimmunity for predicting high-risk groups of thyroid cancer: a nested case–control study

Research article

MicroRNA-1269 promotes proliferation in human hepatocellular carcinoma via downregulation of FOXO1

Research article

Identification of the collagen type 1 alpha 1 gene (COL1A1) as a candidate survival-related factor associated with hepatocellular carcinoma

Research article

Btbd7 contributes to reduced E-cadherin expression and predicts poor prognosis in non-small cell lung cancer
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits