Immunohistochemical expression of thymidylate synthase and prognosis in gastric cancer patients submitted to fluoropyrimidine-based chemotherapy

Abstract

Objective: Adjuvant chemotherapy with 5-fluorouracil (5-FU) has been widely used in gastric cancer (GC) patients to prevent relapse after curative resection. 5-FU acts by inhibiting thymidylate synthase (TS), and high levels of TS correlate with resistance to treatment with fluoropyrimidines. The aim of this study was to evaluate the expression of TS in GC patients, and its relation with clinicopathological characteristics and prognosis in adjuvant chemotherapy with 5-FU. Methods: We retrospectively evaluated 285 patients who underwent D2-gastrectomy with curative intent. TS expression was determined by immunohistochemistry (IHC) in tumor cells by tissue microarray (TMA). TS level was evaluated according to the intensity and percentage of cells marked by a score system. Patients were divided in three groups according to their TS-score: negative, low and high. Results: TS expression was positive in 92.3% of GC. TS-high, TS-low and TS-negative were observed in 46.3%, 46.0% and 7.7% of patients, respectively. High-TS GC were associated with older age (P=0.007), high neutrophil/lymphocyte ratio (P=0.048), well/moderately differentiated histology (P=0.001), intestinal Lauren type (P<0.001) and absence of perineural invasion (P=0.003). Among 285 patients, 133 stage II/III patients (46.7%) received chemotherapy with 5-FU. In survival analysis, TS-high was associated with worse disease-free survival (DFS) in stage III GC patients who received 5-FU-based chemotherapy (P=0.007). Multivariate analysis revealed that total gastrectomy, poorly differentiated tumors and high TS-score were associated with worse DFS in stage III GC patients. Conclusions: High TS-score in stage III GC was associated with poor DFS in patients treated with fluoropyrimidine-based chemotherapy.