Thymidylate synthase protein expression in primary colorectal cancer compared with the corresponding distant metastases and relationship with the clinical response to 5-fluorouracil.

Thymidylate synthase (TS) expression in colorectal cancer metastases has been shown to predict for the clinical response to 5-fluorouracil. Because primary tumors may easily provide accessible sources of tissue for marker analysis, we have investigated the stability of TS expression between primary colorectal cancer and the corresponding distant metastases and compared their relative ability to predict response to chemotherapy on a series of 27 patients homogeneously treated with biochemically modulated fluorouracil for advanced disease. By immunohistochemistry, high levels of TS expression were observed in 19 of 27 (70%) primary tumors and in 13 of 27 (48%) metastatic samples. Overall, TS levels observed in primary tumors did not correlate with those measured in the corresponding metastases (r = 0.30, P = 0.13), with higher TS levels in primary tumors in 8 of 10 discordant cases. Accordingly, the degree of TS immunoreactivity was significantly higher in primary tumors compared with the corresponding metastases (mean TS score 3.8; median, 4 versus 2.8; median 3; P = 0.001). Response rates after chemotherapy for metastatic disease were similar for patients with low and high TS levels in their primary tumors (37% versus 53%, P = 0.47). In contrast, response rates were 71% and 23% in patients with low and high TS in metastatic samples (P = 0.012), respectively. In summary, TS levels measured in primary colorectal cancer do not reflect those observed in the corresponding metastases and cannot be used to predict their response to chemotherapy. The basis for the higher TS content of primary colorectal cancer compared with the corresponding metastases needs clarification.