Cxcr4 expression and risk of bone metastasis in patients with early breast cancer

Abstract

10610 Background: CXCR4, a receptor for SDF1, has been reported to be involved in early metastatic process. This study aimed at evaluating i. prognostic value of CXCR4, ii. correlation between CXCR4 expression in primary tumors and occurrence of metastases in SDF1- expressing organs. Patients and Methods: CXCR4 expression in the primary tumor was analyzed by immunohistochemistry (Human CXCR4 MAb 170, R& D System, MN, USA) in 823 patients included in two randomized trials evaluating efficacy of anthracyclines-based chemotherapy over a no-chemotherapy arm. The prognostic value of CXCR4 expression was assessed by the Cox regression model adjusted for tumour grade, stage, estrogen-receptor (ER) status and age. Distant metastasis rates for a specific site (either as first event or as subsequent metastases) were calculated by time untill occurrence of metastasis or death. We predefined 4 recurrence sites of interest: liver, brain, lung and bone that are organs expressing SDF1. Results: CXCR4 was expressed in 92 of 794 assessable primary tumors (12%). There was no significant association between CXCR4 expression and clinical characteristics, except a trend for a higher rate of ER- positive disease in CXCR4+ tumors (p=0.05). CXCR4 was not prognostic for neither overall survival (Hazard Ratio (HR) = 1.03 CI95%=[0.63 - 1.67], p=0.90), disease-free survival (HR = 0.93 CI95%=[0.63 - 1.37] , p=0.93), nor incidence of overall metastases (HR= 1.36 CI95%=[0.87–2.12], p=0.17). We next assessed the incidence of metastases in SDF1-producing organs according to CXCR4 staining. While CXCR4 was not associated with an increased risk of liver (HR=0.67 [0.27–1.70] p=0.40), lung (HR=0.89 [0.20–3.87] p=0.87) or brain metastases (HR=1.04 [0.40–2.70] p=0.94), CXCR4+ tumors presented a higher risk of bone metastases (HR=2.17 [1.30–3.65] p<0.01). The 10 year incidence of bone metastases were 23% [14–33%] and 12% (10–15%] in CXCR4+ and CXCR4- tumors respectively. Conclusions: This study suggests that expression of CXCR4 in breast cancer is associated with higher rate of bone metastases, a finding concordant with data from mouse models (Kang et al, Cancer Cell). This finding might lead to further development of adjuvant strategies using bone-targeting agents (e.g. biphosphonates, CXCR4 inhibitors). No significant financial relationships to disclose.

Distinguished biomimetic dECM system facilitates early detection of metastatic breast cancer cells

“…VEGF was a cytokine associated with angiogenesis, and CXCR4 was a critical chemokine receptor of CXCL12. All three genes have been reported to be highly expressed in breast cancer bone metastatic cells 33–36 . Here, the mRNA levels of BSP were the highest in 4T1 cells on BM‐ECM on Day 3, but no significant differences were found on Day 1 (Figure 5a).…”

“…All three genes have been reported to be highly expressed in breast cancer bone metastatic cells. 33 , 34 , 35 , 36 Here, the mRNA levels of BSP were the highest in 4T1 cells on BM‐ECM on Day 3, but no significant differences were found on Day 1 (Figure 5a ). Besides that, the mRNA levels of both VEGF and CXCR4 were the highest in 4T1 cells on BM‐ECM on Days 1 and 3 (Figure 5b,c ).…”

“…All three genes have been reported to be highly expressed in breast cancer bone metastatic cells. [33][34][35][36] Here, the mRNA levels of BSP were the highest in 4T1 cells on BM-ECM on Day 3, but no significant differences were found on Day 1 (Figure 5a).…”