Predictive role of thymidylate synthase, dihydropyrimidine dehydrogenase and thymidine phosphorylase expression in colorectal cancer patients receiving adjuvant 5-fluorouracil.

OBJECTIVE: The combined assessment of thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD) and thymidine phosphorylase (TP) gene expressions in metastatic colorectal cancer has been reported to be able to predict the efficacy of fluoropyrimidine-based chemotherapy. In order to evaluate the prognostic role in the adjuvant setting, we investigated the TS, DPD and TP expression in primary tumors of colorectal cancer patients treated with 5-fluorouracil (5-FU). METHODS: TS, DPD and TP expression levels were determined by immunohistochemistry in paraffin-embedded primary tumor tissues from 62 patients with Dukes' stage B and C colorectal cancers who underwent surgery and received adjuvant systemic chemotherapy with 5-FU. The median follow-up was 90 months (range 17-127). RESULTS: Dukes' stage C cancer and high TS expression were independent markers of poor prognosis for disease-free survival (DFS; p = 0.0009 and p = 0.007, respectively) and overall survival (OS; p = 0.0005 and p = 0.011, respectively). By multivariate analysis, patients with high DPD expression had significantly shorter DFS (p = 0.007) and OS (p = 0.005) compared to patients with low DPD expression. In the combined analysis of 2 markers, patients with low TS and low DPD had the best outcome in terms of DFS (p = 0.007) and OS (p = 0.03). The analysis of all 3 proteins showed that the patients with low expression of all 3 markers had significantly longer DFS (p = 0.04) and OS (p = 0.01) than patients with a high value of any one of the protein expressions. However, the joint analysis of 3 markers (group with TS-/DPD-/TP-) could not identify a subgroup of patients with a better prognosis compared to the analysis of 2 markers (group with TS-/DPD-). The analysis of Dukes' stage C cancer patients confirmed a significant benefit in terms of DFS and OS (p = 0.001 and p = 0.006, respectively) when all 3 markers had low expression. We also found a positive significant correlation between TS and TP protein expression (p = 0.033). CONCLUSIONS: This retrospective investigation suggests that the combined assessment of TS and DPD may be useful to evaluate the prognosis of patients with Dukes' B and C colon carcinoma receiving 5-FU adjuvant chemotherapy. The role of TP as a predictor for 5-FU-based therapy needs further investigations.

Predictive value of thymidylate synthase expression in resected metastases of colorectal cancer.

Recent investigations have focused on the prognostic value of thymidylate synthase (TS) assessment in metastases of colorectal carcinoma (CRC). In order to evaluate the prognostic impact of TS expression after resection of metastases of colorectal cancer followed by systemic adjuvant chemotherapy, we performed an immunohistochemical characterisation of TS in the primary tumours and in the corresponding radically resected hepatic and pulmonary metastases. An additional objective was to compare the levels of TS in primary and metastatic disease. TS expression was assessed by immunohistochemistry using the monoclonal antibody TS 106. The study population consisted of 60 patients: 48 underwent liver and 12 lung resection. All of them received adjuvant chemotherapy after metastasectomy according to the Mayo Clinic schedule. In the 49 evaluable primary tumours, TS score was high in 53% and low in 47% of patients, while in the 60 metastatic samples TS immunostaining was high in 33% and low in 67%. There was a significantly smaller number of high TS expressors in metastatic than in primary tumours (P<0.04). No correlation was observed between TS expression and the site of the metastasis. TS status did not significantly correlate with the median disease-free interval (DFI) after metastasectomy, although this parameter was longer for patients with low TS immunoreactivity in the resected metastases than for those with high TS lesions (19.6 versus 13.8 months). Patients with high TS levels, however, had a significantly shorter median overall survival (OS) (27.6 months) than those with low TS expression (36.3 months) (P<0.008). TS status in the resected metastases confirmed its independent prognostic value in the multivariate analysis and was the only prognostic marker of OS in the subgroup of patients with resected liver metastases. These results suggest that high TS levels in resected metastases of colorectal cancer are associated with a poor outcome after surgery and 5-FU adjuvant therapy; therefore, a prospective assessment of TS levels in resected colorectal metastases could be useful to define which patients will most likely benefit from 5-FU adjuvant therapy after metastasectomy. Chemotherapeutic agents that target TS may not be the appropriate adjuvant treatment after metastasectomy for patients with a high TS expression in the resected metastases of colorectal cancer.