Prognostic Value of RANKL/OPG Serum Levels and Disseminated Tumor Cells in Nonmetastatic Breast Cancer.

Abstract

We assessed serum concentrations of the receptor activator of NFκB ligand (RANKL) and its decoy receptor, osteoprotegerin (OPG), two proteins implicated in the development and progression of breast cancer, in 509 patients with primary, nonmetastatic breast cancer. Then the results were evaluated with regards to the occurrence of bone metastases, the presence of disseminated tumor cells (DTC) in the bone marrow, survival, and risk of developing metastatic disease. Before surgery, two bone marrow aspirates were analyzed for DTC using density centrifugation followed by immunocytochemistry (pan-cytokeratin antibody A45-B/B3). RANKL and OPG levels in the serum were measured by ELISA. RANKL levels were significantly lower in women >60 years (<i>P</i> < 0.0001) and RANKL/OPG ratios higher in lymph node-positive patients (<i>P</i> < 0.05). High OPG serum levels were associated with a higher risk of death from breast cancer [HR 1.94; 95% confidence interval (CI) 1.23-3.07; <i>P</i> = 0.005] and OPG was an independent prognostic marker for breast cancer-specific survival (BCSS; multivariate analyses, <i>P</i> = 0.035). RANKL levels were 33% higher (<i>P</i> < 0.0001) in DTC^pos patients (41%), whereas high levels were associated with a significantly better BCSS in DTC^neg patients as compared with low levels (HR 0.524; 95% CI 0.30-0.95; <i>P</i> = 0.04). RANKL serum levels were significantly increased in patients who developed bone metastases (<i>P</i> = 0.01) and patients within the highest quartile of RANKL had a significantly increased risk of developing bone metastases compared with those in the lowest (HR 4.62; 95% CI 1.49-14.34; <i>P</i> = 0.03). These findings warrant further investigation as they provide a rationale for novel diagnostic or therapeutic approaches.