Combination of low plasma stromal cell-derived factor-1 and phosphorylated-CXCR4: independent prognostic marker for breast cancer.

CTRC-AACR San Antonio Breast Cancer Symposium: 2008 Abstracts Abstract #1069 Background: Stromal cell-derived factor (SDF)-1, a chemoattractant cytokine, has been shown to be overexpressed in those organs to which breast cancer metastasizes, and serves to home in cancer cells which express its receptor, CXCR4. We have previously reported the role of low plasma SDF-1 levels as a host-derived marker predictive of distant metastasis. Low plasma SDF-1 levels are predictive of the formation of distant metastases independently of tumor production of SDF-1. In order to further characterize this cohort of patients with an innate susceptibility for poorer prognosis, we combined low plasma SDF-1 levels with tumor-derived markers. CXCR4 has been shown to be an independent prognostic marker, however it is plausible that activated CXCR4, or phosphorylated (p)-CXCR4 may be able to better discriminate metastatic risk. We hypothesized that the prognostic value of low plasma SDF-1 would be particularly informative in patients with tumors having high CXCR4 or p-CXCR4 expression. Materials and Methods: Using the same cohort of patients in whom we previously measured plasma SDF-1 levels, we built a tissue microarray containing paraffin-embedded tissue blocks of the primary tumor for 237 patients. There were 212 patients for whom plasma and tissue blocks were both available. Plasma SDF-1 levels were previously measured using an ELISA, and tumor protein expression was detected using immunohistochemistry. Survival analysis was calculated using cox regression analysis. Results: We found that tumor p-CXCR4 was a stronger prognostic marker than CXCR4. Patients with high expression of p-CXCR4 demonstrated a 4-fold higher rate of mortality (hazard ratio (HR) 3.95, 95% confidence interval (CI), 1.55-10.03; P=0.004) in comparison to patients who highly expressed CXCR4 (HR, 3.20; 95% CI, 1.09-9.37; P=0.03) in univariate analysis. In the subset of patients for whom plasma and tissue were both available, we confirmed the poor prognostic value of low plasma SDF-1 (HR for breast cancer-specific survival, 3.59; 95% CI, 1.33-9.74; P=0.01), and high p-CXCR4 (HR, 3.98; 95% CI, 1.57-10.13; P=0.004). There appeared to be an enhancing effect of the combination of low plasma SDF-1 and high p-CXCR4 upon prognostic significance (HR, 5.96; 95% CI, (2.57-13.81); P<0.001). This remained significant with multivariate analysis (HR, 3.78; 95% CI, (1.31-10.94); P=0.01). Discussion: We report here for the first time the prognostic value of phosphorylated-CXCR4 in breast cancer, and its superiority over CXCR4 expression. Furthermore, the combination of p-CXCR4 and low-plasma SDF-1 levels was determined to be an independent prognostic marker, stronger than either factor alone, suggesting that low plasma SDF-1 may especially favor the metastatic process in patients with tumors containing its activated CXCR4 receptor. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 1069.