Abstract P1-01-26: Procoagulant biomarkers may direct axillary nodal surgery

Abstract

Abstract Background: Preoperative accurate staging of the axilla (through identifying invasive breast cancers with subclinical nodal metastases) will reduce the need for repeat axillary surgery. Tissue factor (TF) is overexpressed in cancer and is shed into the circulation leading to activation of the thrombin (extrinsic clotting) pathway. D-dimer is a fibrin degradation product and reliable systemic marker of thrombin pathway activation. TF and d-dimer are raised in breast cancer and may act as biomarkers to identify invasive cancer patients with undiagnosed lymph node (LN) metastases requiring axillary nodal clearance. Methods: Plasma d-dimer and TF were measured pre-operatively using ELISA in patients undergoing curative surgery and sentinel node biopsy (SNB) for invasive breast cancer (n = 125). D-dimer was considered to be raised if it was above the clinically used upper limit of normal of 500ng/ml and if TF was above 200pg/ml. D-dimer and TF were correlated with the presence or absence of axillary metastases at sentinel node biopsy. Results: Median age was 61 years (range 24–84). Mean invasive tumour size was 16.7 mm (range 1.6–70). One hundred and eleven (79%) invasive cancers were oestrogen receptor positive, 93 (67%) were progesterone receptor positive and 17(12%) were HER2 receptor positive. Pre-operative d-dimer was higher in LN positive (mean 599 ng/ml, 95% CI 415–864, n=32) versus LN negative (454ng/ml, 95% CI 400–514, n=93, p = 0.068) invasive cancer. TF was not significantly higher in LN positive cancer (vs LN negative), although TF did show weak correlation with d-dimer (r = 0.2, p = 0.03). Sixty eight patients (54%) had raised TF and 59 (47%) had raised d-dimer. On multivariate analysis (age, tumour size, invasive grade, ER status and presence of lymphovascular invasion as covariates) a raised pre-operative d-dimer combined with a raised pre-operative TF was a significant independent predictor of node positivity (odds ratio 6.43, CI 1.70–24.27, p = 0.006). Markers of systemic thrombin pathway activity (i.e. a combination of plasma d-dimer and TF) had a sensitivity of 91%, specificity of 32%, positive predictive value of 32% and negative predictive value of 92%. Conclusion: High levels of clotting activation are seen in breast cancer patients. Over 90% of patients with no axillary lymph node metastases had normal pre-operative levels of plasma TF and d-dimer. Combination of systemic markers of thrombin pathway activation may help predict axillary nodal involvement. The role of thrombin pathway activation in breast cancer metastasis is under ongoing investigation. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-01-26.