Immunohistochemical evaluation of thymidylate synthase (TS) and p16_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^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^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^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^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^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.