Abstract PS4-01-18: Prognostic Role of CXCR6 and RANKL for Bone Metastasis in Early Breast Cancer

Abstract Background: Bone is the most common site of metastasis in breast cancer, and patients developing skeletal-related events show poor prognosis. Bone metastasis is a complex process involving interactions between many different molecules, which include receptors and proteins related to chemokine signaling, cell adhesion and migration, or bone metabolism regulation. We aimed to demonstrate the correlation between bone metastasis and expression of these molecules in breast cancer. Methods: Clinicopathologic parameters were collected from 1,440 stage I-III breast cancer patients (1,436 female and 44 male, median age 50 years, range 25-90) who underwent curative surgery at Seoul National University Hospital from October 2000 to December 2013. Immunohistochemistry (IHC) for CXCR4, CXCR6, MGP, osteocalcin, periostin, PTH1R, PTHLH and RANKL were performed on tissue microarray (TMA) constructed from the resected breast cancer tissue. The expression levels of each marker were assessed as H-scores, and we applied cut-off values of 0, 100, 200, and 300 to dichotomize into positive or negative. Results: There were 966 patients (67.1%) with hormone receptor (HR)-positive and HER2-negative breast cancer, 225 patients (15.6%) with HER2-positive breast cancer, and 249 patients (17.3%) with triple negative breast cancer (TNBC). As of February 2024, at median follow-up duration of 138 months, 196 patients (13.6%) had experienced recurrence. This included 65 patients with local recurrence and 131 patients with distant metastasis (49 patients had bone-only metastasis and 82 patients had visceral metastasis as well). There were 186 patients (12.9%) who died from any cause. CXCR6 H-scores were higher in HR-positive breast cancer (mean H-score 33.90) compared to HER2-positive breast cancer (mean H-score 15.58, p=0.0006) or TNBC (mean H-score 16.78, p=0.0056). CXCR6 positivity was significantly associated with longer overall survival (OS) (5-year survival rate (5YSR) 95.8% vs. 95.0%, p=0.049 for cutoff 0). In HR-positive breast cancer, CXCR6 positivity was also correlated with longer bone-specific relapse-free survival (RFS) (5YSR 98.0% vs. 96.8%, p=0.024 for cutoff 0). In contrast, CXCR6 positivity was correlated with shorter bone-specific RFS in HER2-positive breast cancer and TNBC across various cutoff values. RANKL positivity was correlated with shorter OS (5YSR 95.6% vs. 93.9%, p=0.049 for cutoff 200) and RFS (5YSR 92.8% vs. 88.5%, p=0.026 for cutoff 200). In contrast, bone-specific RFS prolonged as RANKL positivity increased (5YSR 97.4% vs. 96.8%, p=0.044 for cutoff 100). The positive correlation to bone-specific RFS was maintained in RANKL-positive, HR-positive breast cancer (5YSR 98.2% vs. 96.3%, p=0.018 for cutoff 100). However, in TNBC, the RANKL score was negatively correlated with RFS across various cutoff values. Periostin was significantly less expressed in TNBC (mean H-score 23.79) compared to other subtypes (mean H-score 48.37, p<0.001 for HR-positive breast cancer and mean H-score 49.14, p<0.001 for HER2-positive breast cancer). Periostin positivity was related to longer OS (5YSR 97.7% vs. 95.6%, p=0.03 for cutoff 0) and bone-specific RFS (5YSR 99.5% vs. 96.7%, p=0.014 for cutoff 100) in HR-positive breast cancer, but not in other subtypes. Conclusion: Expression levels of CXCR6, RANKL, and periostin were correlated with prognosis and bone-specific survival in breast cancer. Interestingly, the clinical impact of each marker differed with respect to each breast cancer subtypes, possibly suggesting a different underlying mechanism of bone metastasis in HR-positive breast cancer compared to the others. Further investigations into the differences between subtypes and establishing proper cutoff values are warranted. Citation Format: H. Yi, K. Lee, C. Park, D. Lee, S. Cho, J. Koh, H. Ryu, S. Im. Prognostic Role of CXCR6 and RANKL for Bone Metastasis in Early Breast Cancer [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS4-01-18.