278P Association between tamoxifen and endoxifen plasma levels and clotting proteins in patients with primary breast cancer

Tamoxifen is effective for the adjuvant treatment of primary breast cancer, but increases the risk for venous thromboembolism. Tamoxifen decreases anticoagulant proteins, including antithrombin (AT), protein C (PC) and tissue factor pathway inhibitor, and increases thrombin generation (TG). However, the relation between levels of both tamoxifen and its active metabolite endoxifen and coagulation is unknown. To gain insight in the prothrombotic effects of tamoxifen and to guide safe dose-escalation, which may be performed in case of sub-therapeutic endoxifen levels, we studied the association between tamoxifen and endoxifen levels and various clotting proteins. Tamoxifen and endoxifen levels were measured in 148 patients from the prospective TOTAM study (NL6918) after 3 months (m) and 6m of tamoxifen treatment. Plasma levels of the anticoagulants AT and PC, the procoagulant tissue factor (TF), and TG parameters were determined at both timepoints if samples were available (n=65-138 per analysis). Levels of clotting proteins and TG parameters were compared between: 1) quartiles of tamoxifen and endoxifen levels with ANOVA or Kruskall-Wallis with Dunnett’s test, and 2) 3m and 6m of treatment in patients without dose adjustments with paired sample t-tests or Wilcoxon signed rank tests. After 3m of tamoxifen, levels of AT, PC, TF and TG parameters were not associated with tamoxifen nor endoxifen levels. At 6m, median TF levels were lower in patients in the 3rd (45 [range: 101] pg/mL), and 4th (50 [90] pg/mL) endoxifen quartiles compared to the 1st (lowest) quartile (70 [143] pg/mL) (adjusted P of 0.024 and 0.012, respectively), but no differences in anticoagulants or TG were observed. An increase in both median TF levels (3m: 46 [94], 6m: 54 [143] pg/mL, P<0.001) and TG parameters was observed at the 6m treatment period, while the AT and PC levels remained stable. Our results indicate that higher tamoxifen and endoxifen levels are not associated with increased coagulation system activation, suggesting that both tamoxifen dose-escalation and high endoxifen levels do not have an additional prothrombotic effect. The time-dependent effect of tamoxifen on coagulation warrants further study.