Thymidylate synthase protein expression in advanced colon cancer: correlation with the site of metastasis and the clinical response to leucovorin-modulated bolus 5-fluorouracil

Abstract

Recently, we have demonstrated that thymidylate synthase (TS) protein expression predicts for the clinical response to a regimen of infusional 5-fluorouracil (5FU) in advanced colorectal cancer patients. Previous studies by other groups that showed a correlation between TS gene expression and response to the fluoropyrimidine also involved infusional regimens. Considering the putatively different mechanism of action of bolus compared with continuous infusion of 5FU, the aim of the present study was to test whether the correlation between TS expression and the clinical response to 5FU is valid for bolus regimens. A secondary aim was to compare TS levels between liver metastases and abdominal recurrences from colon cancer, because these sites have a distinctly different responsiveness to 5FU chemotherapy. The study population consisted of 41 patients (25 males and 16 females; median age, 60 years) with unresectable metastatic or recurrent colon cancer, homogeneously treated with 5FU (420 mg/m2 i.v., days 1-5) and leucovorin (20 mg/m2 i.v., days 1-5); cycles were repeated every 28 days. Twenty-seven patients (66%) showed high levels of TS expression as defined by TS scores equal to 3 and 4. The proportion of cases with high levels of TS expression was significantly higher in abdominal recurrences (18 of 22, 82%) compared with liver metastases (9 of 19, 47%; P = 0.02). Intratumoral TS protein expression was inversely correlated with response to chemotherapy (response rate: 7 of 14, 50%, versus 0 of 27 in patients with low and high levels of TS expression, respectively; P = 0.0001). These results confirm that the level of TS protein expression predicts for response to 5FU, even with a bolus schedule. The higher TS levels observed in abdominal compared with liver metastases may account for their different responsiveness to 5FU chemotherapy. Immunohistochemical quantitation of TS protein levels may thus allow us to change the therapeutic approach to advanced colorectal cancer from a general to an individual treatment strategy at a time when new non TS-targeted drugs have become available for this disease.