Thymidine kinase and thymidylate synthase in advanced breast cancer: Response to tamoxifen and chemotherapy

Thmidylate synthase (TS) is a crucial target for 5-fluorouracil (5-FU) in t he de novo pathway of pyrimidine synthesis, which is necessary for DNA synt hesis. Thymidine kinase (TK) plays a key role in the complementary or alter native salvage pathway of pyrimidine synthesis in acute or pathological tis sue stress, In the present study, the activity levels of TS and TK were det ermined in 257 primary breast tumors of patients who received tamoxifen as first-line systemic therapy after diagnosis of advanced disease. In 155 (60 %) responding patients, the median response duration was 23 months for tumo rs with low TK activity, 15 months for tumors with intermediate TK activity , and 13 months for tumors with high Tg activity (P = 0.003), In Cox multiv ariate analysis corrected for classical predictive factors including estrog en receptor and progesterone receptor, patients with intermediate and high levels of TK activity in their tumors showed a rapid disease progression (P = 0.0002) and an early death (P = 0.002) after start of tamoxifen treatmen t. Tumor TS activity levels were not significantly associated with the effi cacy of tamoxifen treatment. In 121 patients who became resistant to tamoxi fen or additional endocrine treatments and who received 5-FU-containing pol ychemotherapy, tumor TK activity was not significantly related to the effic acy of chemotherapy, Of the 13 patients with low tumor TS activity, only 1 (8%) responded favorably, whereas 46% (43 of 93) of those with intermediate and 73% (11 of 15) of those with high TS activity responded (P = 0.001). I n Cox multivariate regression analysis in which TS was the only significant variable, intermediate and high TS activities were associated with a slow disease progression (P = 0.005) and prolonged survival (P = 0.016) on chemo therapy, In conclusion, for patients with recurrent breast cancer, high tum or TK activity is a significant marker of poor clinical outcome on tamoxife n therapy. Elevated tumor TS activity predicts a favorable outcome for 5-FU -containing polychemotherapy when applied after tumor progression on endocr ine therapy.