Correlation between expression of thymidylate synthase and clinical outcome of advanced gastric cancer treated with capecitabine alone chemotherapy
Thymidylate synthase (TS) is a prognostic marker in various tumors. However, the results of previous investigations in gastric cancer (GC) were controversial. The objective of this article is to investigate whether TS expression is associated with clinical outcome in advanced GC receiving capecitabine alone chemotherapy. The study reviewed 58 cases of advanced GC in patients aged ≥65 years between December 2008 and June 2012. All patients were treated with capecitabine alone chemotherapy. Immunohistochemical staining for TS protein expression was performed. The relationships between TS expression and clinicopathological characteristics (included age, gender, number of metastatic sites, Eastern Cooperative Oncology Group (ECOG) score, differentiation, and lymph node metastatic status), chemotherapy response, progression-free survival (PFS), and overall survival (OS) were evaluated. There was no association between TS expression and age, gender, number of metastatic sites, ECOG score, differentiation, and lymph node metastatic status (P > 0.05). The chemotherapy response rates among patients with low- and high-level expression of TS protein were 52.0 % (13/25) and 21.2 % (7/33), respectively (χ 2 = 5.968, P = 0.015). The median PFS and OS in patients with low-level TS expression were significantly longer than those with high-level TS expression (PFS 8.0 vs 2.8 m, P = 0.001; OS 13.3 vs 7.9 m, P = 0.002, respectively). Multivariate Cox regression analysis revealed that TS expression was independent risk factor for OS (hazard ratio (HR) 0.237; 95 % confidence interval (CI) 0.108 to 0.520; P = 0.000). The present study demonstrates that TS expression is associated with chemotherapy response, PFS, and OS in advanced GC patients treated with capecitabine alone chemotherapy.
KeywordsGastric neoplasm Thymidylate synthase Capecitabine Immunohistochemistry
Eastern Cooperative Oncology Group
Polymerase chain reaction
We thank the staffs of the affiliated Nanfang Hospital of Southern Medical University for their help.
The present study was supported by research grants from the Health Department of Hunan Province (no. B2011-138).
Conflicts of interest
- 5.Yamaguchi K, Sawaki A, Doi T, Satoh T, Yamada Y, Omuro Y, et al. Efficacy and safety of capecitabine plus cisplatin in Japanese patients with advanced or metastatic gastric cancer: subset analyses of the AVAGAST study and the ToGA study. Gastric Cancer. 2013;16(2):175–82.PubMedCentralPubMedCrossRefGoogle Scholar
- 7.Qiu MZ, Wei XL, Zhang DS, Jin Y, Zhou YX, Wang DS, et al. Efficacy and safety of capecitabine as maintenance treatment after first-line chemotherapy using oxaliplatin and capecitabine in advanced gastric adenocarcinoma patients: a prospective observation. Tumour Biol. 2014;35(5):4369–75.PubMedCrossRefGoogle Scholar
- 10.Gronberg BH, Lund-Iversen M, Strom EH, Brustugun OT, Scott H. Associations between TS, TTF-1, FR-alpha, FPGS, and overall survival in patients with advanced non-small-cell lung cancer receiving pemetrexed plus carboplatin or gemcitabine plus carboplatin as first-line chemotherapy. J Thorac Oncol. 2013;8(10):1255–64.PubMedCrossRefGoogle Scholar
- 13.Koizumi W, Tanabe S, Azuma M, Ishido K, Nishimura K, Sasaki T, et al. Impacts of fluorouracil-metabolizing enzymes on the outcomes of patients treated with S-1 alone or S-1 plus cisplatin for first-line treatment of advanced gastric cancer. Int J Cancer. 2010;126(1):162–70.PubMedCrossRefGoogle Scholar
- 15.Kim KH, Kwon HC, Oh SY, Kim SH, Lee S, Kwon KA, et al. Clinicopathologic significance of ERCC1, thymidylate synthase and glutathione S-transferase P1 expression for advanced gastric cancer patients receiving adjuvant 5-FU and cisplatin chemotherapy. Biomarkers. 2011;16(1):74–82.PubMedCrossRefGoogle Scholar
- 16.Kim JS, Kim MA, Kim TM, Lee SH, Kim DW, Im SA, et al. Biomarker analysis in stage III-IV (M0) gastric cancer patients who received curative surgery followed by adjuvant 5-fluorouracil and cisplatin chemotherapy: epidermal growth factor receptor (EGFR) associated with favourable survival. Br J Cancer. 2009;100(5):732–8.PubMedCentralPubMedCrossRefGoogle Scholar
- 18.Fisher SB, Fisher KE, Patel SH, Lim MG, Kooby DA, El-Rayes BF, et al. Excision repair cross-complementing gene-1, ribonucleotide reductase subunit M1, ribonucleotide reductase subunit M2, and human equilibrative nucleoside transporter-1 expression and prognostic value in biliary tract malignancy. Cancer. 2013;119(2):454–62.PubMedCrossRefGoogle Scholar
- 20.Christoph DC, Asuncion BR, Hassan B, Tran C, Maltzman JD, O'Shannessy DJ, et al. Significance of folate receptor alpha and thymidylate synthase protein expression in patients with non-small-cell lung cancer treated with pemetrexed. J Thorac Oncol. 2013;8(1):19–30.PubMedCentralPubMedCrossRefGoogle Scholar
- 23.Donada M, Bonin S, Nardon E, De Pellegrin A, Decorti G, Stanta G. Thymidilate synthase expression predicts longer survival in patients with stage II colon cancer treated with 5-flurouracil independently of microsatellite instability. J Cancer Res Clin Oncol. 2011;137(2):201–10.PubMedCrossRefGoogle Scholar
- 27.Mirza A, Brown M, McNulty C, Valentine J, Annesley A, Galloway S, et al. A pilot study to investigate the role of thymidylate synthase as a marker of prognosis for neoadjuvant chemotherapy in gastric and gastro-oesophageal junction adenocarcinoma. Gastroenterol Res Pract. 2013;2013:502153.PubMedCentralPubMedCrossRefGoogle Scholar
- 28.Kamoshida S, Matsuoka H, Ishikawa T, Maeda K, Shimomura R, Inada K, et al. Immunohistochemical evaluation of thymidylate synthase (TS) and p16INK4a in advanced colorectal cancer: implication of TS expression in 5-FU-based adjuvant chemotherapy. Jpn J Clin Oncol. 2004;34(10):594–601.PubMedCrossRefGoogle Scholar