Thymidylate Synthase expression as a predictor of clinical response to fluoropyrimidine-based chemotherapy in advanced colorectal cancer

Thymidylate Synthase (TS) is a rate-limiting enzyme in the DNA synthetic pathway and represents the cellular target of the antimetabolite drug 5-fluorouracil (FUra). Both preclinical and clinical studies have shown that the level of expression of this enzyme and the ability to achieve its inhibition are the major determinants of sensitivity and resistance to fluoropyrimidines (FP). In particular, five recent studies have consistently demonstrated an inverse correlation between the level of TS gene or protein expression measured in colorectal cancer metastases and the clinical response to either FUra or 5-fluorodeoxyuridine (FUdR). Patients with low levels of TS expression in their metastases have indeed shown response rates that are three to ten times higher compared to those obtained in patients with high TS levels. The independent predictive value demonstrated in a logistic regression model, the longer survival shown by patients with low TS levels in three of five studies and the consistency of the results obtained by independent groups using different techniques to quantitate TS expression, strengthen the predictive role of TS. Targeted treatment of colorectal cancer based on TS quantitation has thus been hypothesized similar to the use of hormone receptor in breast cancer. In this review preclinical and clinical data supporting the use of TS quantitation to predict for the clinical response to FUra will be described and unresolved problems including assays standardization, response prediction based on TS levels measured in primary tumors, intrapatient variations in TS levels and biological/biochemical limitations of this strategy will be discussed.