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 (P < 0.0001) and RANKL/OPG ratios higher in lymph node-positive patients (P < 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; P = 0.005] and OPG was an independent prognostic marker for breast cancer-specific survival (BCSS; multivariate analyses, P = 0.035). RANKL levels were 33% higher (P < 0.0001) in DTCpos patients (41%), whereas high levels were associated with a significantly better BCSS in DTCneg patients as compared with low levels (HR 0.524; 95% CI 0.30-0.95; P = 0.04). RANKL serum levels were significantly increased in patients who developed bone metastases (P = 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; P = 0.03). These findings warrant further investigation as they provide a rationale for novel diagnostic or therapeutic approaches.
Highlights
Despite major improvements in diagnosis and treatment, patients with breast cancer are prone to bone metastasis, which often occur many years after the initial diagnosis [1]
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; P 1⁄4 0.005] and OPG was an independent prognostic marker for breast cancer–specific survival (BCSS; multivariate analyses, P 1⁄4 0.035)
receptor activator of NFkB ligand (RANKL) levels were 33% higher (P < 0.0001) in DTCpos patients (41%), whereas high levels were associated with a significantly better BCSS in DTCneg patients as compared with low levels (HR 0.524; 95% CI 0.30–0.95; P 1⁄4 0.04)
Summary
Despite major improvements in diagnosis and treatment, patients with breast cancer are prone to bone metastasis, which often occur many years after the initial diagnosis [1]. This relapse may be explained by an early micrometastatic spread of. Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/). The malignant character of DTCs has already been demonstrated and the presence and persistence of these cells have been widely accepted as an independent prognostic marker of decreased progression-free survival (PFS) and overall survival For routine monitoring of disease progression and prognosis, more convenient and cost-effective serum or plasma-based tests are warranted to estimate the risk of bone metastases
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