Correlation between thymidylate synthase gene polymorphisms and efficacy of pemetrexed in advanced non-small cell lung cancer

Hu,Qiong; Li,Xuefei; Su,Chunxia; Chen,Xiaoxia; Gao,Guanghui; Zhang,Jie; Zhao,Yinmin; Li,Jiayu; Zhou,Caicun

doi:10.3892/etm.2012.730

Correlation between thymidylate synthase gene polymorphisms and efficacy of pemetrexed in advanced non-small cell lung cancer

Authors:
- Qiong Hu
- Xuefei Li
- Chunxia Su
- Xiaoxia Chen
- Guanghui Gao
- Jie Zhang
- Yinmin Zhao
- Jiayu Li
- Caicun Zhou
View Affiliations

Affiliations: Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, P.R. China, Tongji University Medical School Cancer Institute, Shanghai 200433, P.R. China
Published online on: September 28, 2012 https://doi.org/10.3892/etm.2012.730
Pages: 1010-1016

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

One of the target genes of pemetrexed (PEM), thymidylate synthase (TS), has been shown to have a close association with its efficacy. TS gene polymorphisms have been shown to be associated with the efficacy of antifolate treatment in enteron tumors. The purpose of this study was to investigate the clinical significance of TS gene polymorphisms in patients with advanced NSCLC receiving PEM-based treatment. The variable nucleoid tandem repeat in the 5'-UTR region was amplified and detected using fluorescently labeled multiplex short tandem repeat polymerase chain reaction. The polymorphism in the 3'-UTR region of the TS gene was detected using the Taqman probe. Efficacy of PEM was assessed according to the Response Evaluation Criteria in Solid Tumors, version 1.1. None of the genotypes were associated with gender, smoking status and age. Disease control rate (DCR), objective response rate (ORR) and progression-free survival (PFS) were similar between patients harboring 2R and 3R alleles (PFS, p=0.518; DCR, p=0.631; ORR, p=0.541), as well as those with a 6‑bp insertion and 6‑bp deletion (PFS, p=0.776; DCR, p=0.626; ORR, p=0.330). To study the combined effect of TS polymorphisms, the study population was divided into three groups: 2R&6 del, 2R&6 ins and 3R&6 del. No significant differences were observed among the different groups according to DCR (p=0.517), ORR (p=0.611) and PFS (p=0.938). In conclusion, polymorphisms of the TS gene do not appear to be a prognostic marker for advanced NSCLC patients receiving PEM-based treatment.

View Figures

View References

1	Rahman L, Voeller D, Rahman M, et al: Thymidylate synthase as an oncogene: a novel role for an essential DNA synthesis enzyme. Cancer Cell. 5:341–351. 2004. View Article : Google Scholar : PubMed/NCBI
2	Scagliotti GV, Parikh P, von Pawel J, et al: 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. 26:3543–3551. 2008. View Article : Google Scholar : PubMed/NCBI
3	Hanna N, Shepherd FA, Fossella FV, et al: Randomized phase III trial of pemetrexed versus docetaxel in patients with non-small-cell lung cancer previously treated with chemotherapy. J Clin Oncol. 22:1589–1597. 2004. View Article : Google Scholar : PubMed/NCBI
4	Ciuleanu T, Brodowicz T, Zielinski C, et al: Maintenance pemetrexed plus best supportive care versus placebo plus best supportive care for non-small-cell lung cancer: a randomised, double-blind, phase III study. Lancet. 374:1432–1440. 2009. View Article : Google Scholar : PubMed/NCBI
5	Scagliotti G, Brodowicz T, Shepherd FA, et al: Treatment-byhistology interaction analyses in three phase III trials show superiority of pemetrexed in nonsquamous non-small cell lung cancer. J Thorac Oncol. 6:64–70. 2011.PubMed/NCBI
6	Tanaka F, Wada H, Fukui Y and Fukushima M: Thymidylate synthase gene expression in primary lung cancer patients: a large-scale study in Japanese population. Ann Oncol. 22:1791–1797. 2011. View Article : Google Scholar : PubMed/NCBI
7	Kaira K, Ohde Y, Nakagawa K, Okumura T, et al: Thymidylate synthase expression is closely associated with outcomes in patients with pulmonary adenocarcinoma. Med Oncol. 29:1663–1672. 2012. View Article : Google Scholar : PubMed/NCBI
8	Sun JM, Han J, Ahn JS, Park K and 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 treatment. J Thorac Oncol. 6:1392–1399. 2011. View Article : Google Scholar : PubMed/NCBI
9	De Bock CE, Garg MB, Scott N, Sakoff JA, Scorgie FE, Ackland SP and Lincz LF: Association of thymidylate synthase enhancer region polymorphisms with thymidylate synthase activity in vivo. Pharmacogenomics J. 11:307–314. 2011.PubMed/NCBI
10	Mandola MV, Stoehlmacher J, Zhang W, et al: A 6 bp polymorphism in the thymidylate synthase gene causes message instability and is associated with decreased intratumoral TS mRNA levels. Pharmacogenetics. 14:319–327. 2004. View Article : Google Scholar : PubMed/NCBI
11	Mandola MV, Stoehlmacher J, Muller-Weeks S, Cesarone G, Yu MC, Lenz HJ and Ladner RD: Ladner, a novel single nucleotide polymorphism within the 5′ tandem repeat polymorphism of the thymidylate synthase gene abolishes USF-1 binding and alters transcriptional activity. Cancer Res. 63:2898–2904. 2003.
12	Lurje G, Manegold PC, Ning Y, Pohl A, Zhang W and Lenz HJ: Thymidylate synthase gene variations: predictive and prognostic markers. Mol Cancer Ther. 8:1000–1007. 2009. View Article : Google Scholar : PubMed/NCBI
13	Shitara K, Muro K, Ito S, et al: Folate intake along with genetic polymorphisms in methylenetetrahydrofolate reductase and thymidylate synthase in patients with advanced gastric cancer. Cancer Epidemiol Biomarkers Prev. 19:1311–1319. 2010. View Article : Google Scholar
14	Kumar K, Vamsy M and Jamil K: Thymidylate synthase gene polymorphisms effecting 5-FU response in breast cancer patients. Cancer Biomark. 6:83–93. 2010.PubMed/NCBI
15	Takehara A, Kawakami K, Ohta N, Oyama K, Ota Y, Oda M and Watanabe G: Prognostic significance of the polymorphisms in thymidylate synthase and methylenetetrahydrofolate reductase gene in lung cancer. Anticancer Res. 25:4455–4461. 2005.
16	Sobin LH, Gospodarowicz MK and Wittekind CH: International Union Against Cancer (UICC) TNM Classification of Malignant Tumours. 7th edition. Wiley-Blackwell; Oxford: pp. 1–256. 2009
17	Edge SB, Byrd DR, Carducci MA, et al: American Joint Committee on Cancer (AJCC) Cancer Staging Handbook. 7th edition. Springer-Verlag; New York: pp. 1–195. 2009
18	Eisenhauer EA, Therasse P, Bogaerts J, et al: New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 45:228–247. 2009. View Article : Google Scholar
19	Lu JW, Gao CM, Wu JZ, Cao HX, Tajima K and Feng JF: Polymorphism in the 3′-untranslated region of the thymidylate synthase gene and sensitivity of stomach cancer to fluoropyrimidine-based chemotherapy. J Hum Genet. 51:155–160. 2006.
20	Ettinger DS, Akerley W, Borghaei H, et al: NCCN Clinical Practice Guidelines in Oncology. version 2.2012. National Comprehensive Cancer Network; Fort Washington, PA: pp. 1–112. 2011, Available at https://www.nccn.com.
21	Huang ZH, Hua D and Li LH: The polymorphisms of TS and MTHFR predict survival of gastric cancer patients treated with fluorouracil-based adjuvant chemotherapy in Chinese population. Cancer Chemother Pharmacol. 63:911–918. 2009. View Article : Google Scholar
22	Giovannetti E, Backus HH, Wouters D, et al: Changes in the status of p53 affect drug sensitivity to thymidylate synthase (TS) inhibitors by altering TS levels. Br J Cancer. 96:769–775. 2007. View Article : Google Scholar : PubMed/NCBI
23	Gorlick R, Metzger R, Danenberg KD, et al: Higher levels of thymidylate synthase gene expression are in pulmonary as compared with hepatic metastases of colorectal adenocarcinoma. J Clin Oncol. 16:1465–1469. 1998.PubMed/NCBI