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

Clin Cancer Res. 2019 Feb 15;25(4):1369-1378. doi: 10.1158/1078-0432.CCR-18-2482. Epub 2018 Nov 13.


Purpose: 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.

Experimental design: 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.

Results: 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).

Conclusions: These findings warrant further investigation as they provide a rationale for novel diagnostic or therapeutic approaches.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Biomarkers, Tumor / blood
  • Bone Neoplasms / blood*
  • Bone Neoplasms / genetics
  • Bone Neoplasms / pathology
  • Bone Neoplasms / secondary
  • Breast Neoplasms / blood*
  • Breast Neoplasms / genetics
  • Breast Neoplasms / pathology
  • Disease-Free Survival
  • Female
  • Gene Expression Regulation, Neoplastic / genetics
  • Humans
  • Immunohistochemistry
  • Middle Aged
  • Osteoprotegerin / blood*
  • Osteoprotegerin / genetics
  • Prognosis
  • RANK Ligand / blood*
  • RANK Ligand / genetics


  • Biomarkers, Tumor
  • Osteoprotegerin
  • RANK Ligand
  • TNFRSF11B protein, human
  • TNFSF11 protein, human