Increased thymidylate synthase gene expression in liver metastases from colorectal carcinoma: implications for chemotherapeutic options and survival.

Objectives: To determine the association of intratumoral thymidylate synthase (TS) gene expression with resistance to fluoropyrimidines and to study the association of TS gene expression with outcome in patients with liver metastases from colorectal cancer.

Methods: Intratumoral TS gene expression was measured by reverse transcriptase and polymerase chain reaction in 33 patients with liver metastases from colorectal carcinoma. Fifteen patients underwent resection, and 18 were treated with chemotherapy only. Patients with high levels of TS gene expression were compared to those with low levels of TS gene expression.

Results: All patients with a high level of TS gene expression were nonresponders to fluoropyrimidine chemotherapy. Median survival in patients with unresectable disease was shorter in those who had high levels of TS gene expression (7 months vs 15 months, P = 0.02). After hepatic resection, median disease-free interval was shorter in patients with high levels of TS gene expression (5 months vs 18 months; P = 0.004). Similarly, survival was shorter after resection in those with high TS gene expression (17 months vs 43 months, P = 0.0002).

Discussion: Increased TS gene expression is associated with a poor outcome in patients with liver metastases from colorectal carcinoma, whether resected or treated by chemotherapy only. This is related in part to reduced responsiveness to chemotherapeutic agents, but it also reflects inherently more aggressive behavior of metastases.