Low Thymidylate Synthase Expression in the Primary Tumor Predicts Favorable Clinical Outcome in Resected Gastric Cancer Patients Treated with Adjuvant Tegafur

Abstract

Objective: To assess the thymidylate synthase protein (TS) in tumor cells of resected gastric cancer patients treated with adjuvant tegafur (TG), we reviewed the outcome of 94 randomized patients treated either with adjuvant TG plus mitomycin C (MMC) or MMC alone. Methods: TS was determined in 76 out of 94 patients, previously randomized to receive adjuvant TG, 500 mg/m²/day p.o. for 6 months plus four courses of MMC, 10– 20 mg/m² i.v. every 6 weeks or MMC alone. An immunohistochemical assessment with the monoclonal antibody TS-106 was performed. Results: Low TS was observed in 38 patients (20 treated with TG-MMC and 18 with MMC) and high TS in the other 38 patients (21 treated with TG-MMC and 17 with MMC). After 10 years’ median follow-up time, 61% of adjuvant TG-MMC patients and 43% of MMC patients were alive and disease-free. Disease-free survival and overall survival were significantly better for patients treated with TG-MMC compared to MMC adjuvant (p = 0.0277 and p = 0.05), and low-TS compared to high-TS patients (p = 0.0184 and p = 0.0198). In 38 low-TS patients we observed an 83% chance to be disease-free in TG-MMC-treated patients and 55% in MMC-treated patients (p = 0.04). Conclusions: A low TS level determines a subset of patients that may benefit from adjuvant oral TG when added to MMC showing a 5-year cure rate of more than 80%.

Correlations between Thymidylate Synthase Expression and Chemosensitivity to 5-Fluorouracil, Cell Proliferation and Clinical Outcome in Head and Neck Squamous Cell Carcinoma

“…5%; 2, 5-20%, and 3, 1 20%. The multiplication of the intensity and distribution score was graded as negative (1-4) and positive (6)(7)(8)(9).…”

“…These studies have shown that the lower the TS activity, the greater the response rate to 5-FU-containing chemotherapy. In contrast, low tumor TS expression levels have been reported to be associated with a strong and high rate of response to 5-FU treatment [7] . Since TS is the main enzyme targeted by 5-FU, measurement of TS activity may be necessary to be able to evaluate the efficacy of 5-FU-based chemotherapy.…”

A long-time survivor of alpha-fetoprotein-producing gastric cancer successfully treated by fluoropyrimidine-based chemotherapy: a case study

“…Multiple clinical studies [4,[29][30][31][32][33] suggest that high expression of TS and DPD and low expression of OPRT are closely associated with resistance to fluoropyrimidinebased chemotherapy. In spite of the DPD expression in the current case, the tumor showed a good response.…”

Pharmacogenomics: road to anticancer therapeutics nirvana?

“…In another study, TSER variants were evaluated in the liver metastases of patients, and the analysis suggested that TSER*3 homozygotes demonstrated higher overall TS expression and a lower response rate compared to TSER*2 homozygotes (Marsh et al, 2001). There are other similar examples in the literature as well (Grau et al, 2003;Kawabe et al, 2003); however, most of the studies have been small retrospective studies; hence, their applicability in clinical practice is currently limited. Also, different studies have utilized different methods (ranging from real-time PCR to immunohistochemistry) and tissues (tumor versus surrogate peripheral tissues) to quantify TS levels, thus making direct comparisons of the results problematic.…”