Immunohistochemical Evaluation of Thymidylate Synthase (TS) and p16 super(INK4a) in Advanced Colorectal Cancer: Implication of TS Expression in 5-FU-based Adjuvant Chemotherapy

BACKGROUND: Our previous analyses on the expression of thymidylate synthase (TS) and p16 super(INK4a) in colorectal cancer patients administered 5-fluorouracil (5-FU) pre-operatively demonstrated that a high level of TS expression was a predictor of 5-FU resistance, and that the combination of a low level of TS expression and induction of p16 super(INK4a) after chemotherapy implicated chemosensitivity. The present study aimed to assess the relationship between the biological behavior of advanced colorectal cancer treated post-operatively by 5- FU-based chemotherapy and the expression of TS and p16 super(INK4a) in primary tumors. METHODS: Formalin-fixed, paraffin-embedded specimens from 132 colorectal cancers (Dukes' B, 36 cases; Dukes' C, 60 cases; and Dukes' D, 36 cases) treated by 5-FU post-operatively were immunostained for TS and p16 super(INK4a). Antigenicities were suitably retrieved. RESULTS: Primary tumors expressing high levels of TS in the Dukes' C group showed a significantly shorter recurrence- free interval (RFI) (P = 0.0002). The overall survival (OS) was shorter in high TS expressors than in low TS expressors (P = 0.001). A high level of TS expression also correlated with advanced Dukes' staging and the severity of nodal metastasis (Dukes' B versus Dukes' D, P = 0.001; Dukes' C versus Dukes' D, P = 0.008; N0 versus N2, P = 0.002; N1 versus N2, P = 0.03). p16 super(INK4a) expression was not correlated with the prognosis or clinicopathological features. CONCLUSIONS: Appropriate immunohistochemical evaluation is essentially important. We suggest that, in the Dukes' C group, a 5-FU-based regimen can be chosen as a first-line chemotherapy for low TS expressors. TS-high cancer should be treated with anti-cancer agents acting through different mechanisms. Further research should be conducted on applying TS immunostaining to the treatment strategy.