Evaluation of the prognostic value of RANK, RANKL, OPG and OPN mRNA expression in high-risk early breast cancer patients treated with anthracycline-containing adjuvant chemotherapy.

e23244 Background: Prevention of bone metastases is a major issue for breast cancer patients, as it would improve quality of life in a population where long survival with metastatic disease is anticipated. Therefore, development of bone metastasis biomarkers is of paramount importance. Methods: High-risk early breast cancer patients who had previously been treated within two randomized trials (HE10/97 and HE10/00) by the Hellenic Cooperative Oncology Group were included in the study. Chemotherapy consisted of epirubicin and CMF with or without paclitaxel, given concurrently or sequentially to epirubicin with G-CSF support. We evaluated, by qRT-PCR, 819 fixed tumor tissue samples for mRNA expression of RANK, RANKL, OPG and OPN for potential prognostic significance for the development of bone metastases and also for disease-free survival (DFS) and overall survival (OS). Results: Median age was 53 years, while 54.2% of the patients were postmenopausal, 76.5% ER/PgR-positive and 81.1% received either tamoxifen with ovarian ablation or anastrozole for 5 years. After a median follow-up of 119.9 months, 242 patients (29.5%) recurred and 226 (27.6%) died, while 93 patients (11.4%) developed bone metastases. Low mRNA expression of RANKL and high expression of OPN were associated with postmenopausal status, while high expression of RANK, RANKL and OPG with the luminal A subtype. All correlations among the studied markers were positive (Spearman’s Rho > 0). Low mRNA expression of RANKL was found to be associated with bone metastases (Fisher’s exact test, p = 0.026) and unfavorable DFS (HR = 1.33, 95% CI 1.05-1.68, Wald’s p = 0.018). In addition, high mRNA expression of OPN was associated with shorter DFS (HR = 1.26, 95% CI 1.00-1.59, Wald’s p = 0.050) and OS (HR = 1.37, 95% CI 1.05-1.78, p = 0.019). OPN retained its significance in the multivariate analysis, in terms of DFS and OS. Conclusions: Low RANKL mRNA expression in high-risk early breast cancer patients may predict increased risk for bone metastases. Further investigations for the potential prognostic value of RANK, RANKL and T-cell markers assessed by immunohistochemistry are currently under way.