Abstract P1-13-04: Immunohistochemical Evaluation of RANK/RANKL/OPG Axis and CXCR4 in Primary Breast Cancer and Their Role in Bone Metastasization

Abstract

Abstract Background: The RANK/RANKL/OPG axis plays an important role in the bone metastasization process. CXCL12 is overexpressed in bone and, like its receptor, CXCR4, is a determinant of organ tropism. The objective of the present study was to evaluate whether the expression of these markers in primary breast cancer can predict the onset of bone metastases. Methods: Marker expression was evaluated by immunohistochemical staining in paraffin-embedded sections of primary breast cancers from 40 individuals: 10 patients (median age 64 years, range 48-78) showed no evidence of disease (NED — control group) at a median of 9.8 (range 6.9-11.5) years, while 30 (median age 67 years, range 42-87) had relapsed. In the latter group, 10 (median age 66 years, range 42-87) had visceral metastases (VM — control group) and 20 (median age 69 years, range 42-87) had bone metastases (BM — case group), both confirmed radiologically. The 3 patient subgroups (NED, visceral lesions, bone lesions) were matched for age classes (≥60 years, > 60 years). The study design was reviewed and approved by the local ethics committee. Results: In the overall series, 17.5% of tumors were positive for RANK, 22.5% for OPG and 25% for CXCR4. None of the patients expressed RANKL. RANK and OPG resulted equally expressed in 20% of NED patients, while CXCR4 was expressed in only 10% of this group. OPG was expressed in 20% of VM patients, whereas RANK or CXCR4 were not detected. RANK and OPG positivity was present in 25% of BM patients, while CXCR4 was expressed in 45% of cases. CXCR4 was the only marker with a significantly higher frequency of expression in bone metastases than in visceral lesions (p=0.013). Taking into consideration all the patients without bone involvement (NED plus VM patients), it was observed that CXCR4 expression, alone and in combination with RANK, significantly discriminated between BM patients and the control group (p=0.008 and P<0.001, respectively). ER-positivity and HER2-negative status were observed in 80% and 95% of BM patients, respectively, but neither discriminated between cases and controls. Conclusions: In our study, ER-positivity and HER2- negativity identified a high percentage of bone relapse patients, but also highlighted patients who did not have bone involvement. RANK and CXCR4 expression, on the other hand, would appear to be a more accurate predictor of bone relapse. Such evidence could help to identify patients with a high probability of developing bone metastases, which can be treated with bisphosphonates or other bone-targeted therapies, such as denosumab, in an attempt to prevent distant metastases. Our results are currently being validated in a larger series of breast cancer patients. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P1-13-04.