Abstract
The relationship between thymidylate synthase (TS) expression and outcomes in gastric cancer (GC) patients remains controversial, although most studies reported poor survival and reduced response to fluoropyrimidine were related to high TS in tumors. We carried out a systematic review of the literature with meta-analysis to estimate the predictive value of TS expression from published studies. We identified 24 studies analysing the outcome data in gastric cancer stratified by TS expression. Effect measures of outcome were hazard ratios (HRs) for overall survival (OS) and event-free survival (EFS), or the odds ratio (OR) for overall response rate (ORR). HRs and ORs from these eligible studies were pooled using random-effects meta- analysis. Fifteen studies investigated outcomes in a total of 844 patients with advanced GC, and nine studies investigated outcomes in a total of 1,235 patients with localized GC undergoing adjuvant therapy. Meta- analysis of estimates showed high TS expression was significantly associated with poor OS in the advanced setting (HR: 1.43, 95%CI: 1.08 - 1.90), and poor EFS in the adjuvant setting (HR: 1.53, 95%CI: 1.01 - 2.32). Subgroup analysis demonstrated TS expression to have even greater value in predicting OS, EFS and ORR in advanced GC patients treated with fluoropyrimidine monotherapy (HR for OS: 2.32, 95%CI: 1.53 - 3.50; HR for EFS: 1.76, 95%CI: 1.19 - 2.60; OR for ORR: 0.32, 95%CI: 0.11 - 0.95). High levels of TS expression were associated with a poorer OS for advanced GC patients compared with low levels. In the adjuvant setting, high TS expression was also associated with a worse EFS. Additional studies with consistent methodology are needed to define the precise predictive value of TS.
Highlights
Gastric cancer (GC) is the 4th most common cancer and the 2nd most common cause of cancer mortality in the world (Jemal et al, 2011)
Results of Meta-Analysis in the Advanced Disease Setting The pooled hazard ratios (HRs) for overall survival (OS) across twelve advanced studies was 1.43 (95%CI: 1.08 - 1.90), indicating that patients with high thymidylate synthase (TS) expression had a risk of death 1.43 times greater than patients with low TS expression (Figure 2)
HR pooled from studies in which all patients received fluoropyrimidine monotherapy was 2.32 (95%CI: 1.53 - 3.50, I2 =40.7%), indicating that the statistical link between high TS expression and poor OS was rather stronger
Summary
Gastric cancer (GC) is the 4th most common cancer and the 2nd most common cause of cancer mortality in the world (Jemal et al, 2011). It has been proven that fluoropyrimidine can significantly improve survival in GC patients. In the advanced GC, fluoropyrimidine has been widely used as the mainstay of chemortherapeutic agent (Van Cutsem et al, 2006; Koizumi et al, 2008). A large proportion of patients who were at risk of relapse after curative resection have benefited from adjuvant therapy. Adjuvant chemotherapy with fluoropyrimidine is an accepted standard of care in many parts of the world (Sakuramoto et al, 2007). The antitumor effect of fluoropyrimidine mainly stems from its competitive inhibition of thymidylate synthase (TS). Intratumoral TS expression in vivo may be pivotal in predicting tumor sensitivity to fluoropyrimidine, as TS expression has been revealed to be determinant in such predictions in vitro (Berger et al, 1985; Johnston et al, 1992)
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