Thymidylate Synthase Expression Predicts the Response to 5-Fluorouracil-based Adjuvant Therapy in Pancreatic Cancer

Purpose: Thymidylate synthase (TS) is the target enzyme for 5-fluorouracil (5-FU), and TS expression may determine clinical response and survival after therapy with 5-FU in colorectal cancer. 5-FU is also widely used in the adjuvant therapy of pancreatic cancer. Therefore, we explored the hypothesis that TS expression was associated with patient prognosis and the response to adjuvant therapy in pancreatic cancer. Experimental Design: Cylindrical tissue cores from a large retrospective, nonrandomized series covering 132 resected patients were used to build a pancreatic cancer tissue microarray. TS expression was determined using immunohistochemistry. Results: High intratumoral TS expression and low intratumoral TS expression were present in 83 of 132 (63%) and 49 of 132 (37%) tumors, respectively. Median survival among patients with low intratumoral TS expression (18 months) was longer than that among patients with high TS expression (12 months). In multivariate analysis, more advanced pathological stage [risk ratio (RR) = 1.70; P = 0.015], poorly differentiated histology (RR = 1.71; P = 0.015), management with adjuvant therapy (RR = 0.49; P = 0.011), and high TS expression [RR = 1.66; 95% confidence interval (CI) = 1.05–2.63; P = 0.029] were independent predictors of mortality. The risk of death was significantly reduced by any adjuvant therapy (RR = 0.40; 95% CI = 0.18–0.90; P = 0.001) among patients with high TS expression. This difference in survival among patients with low- and high-TS-expressing tumors became more significant when the analysis was restricted to the 73 patients receiving 5-FU-based adjuvant therapy (RR = 0.37; 95% CI = 0.16–0.86; P = 0.0006). In contrast, 5-FU-based adjuvant therapy did not influence survival among patients with low-TS-expressing pancreatic cancer. Conclusions: High TS expression is a marker of poor prognosis in resected pancreatic cancer. Patients with high intratumoral TS expression benefit from adjuvant therapy.