Elevated chemokine receptor CXCR4 expression in primary tumors following neoadjuvant chemotherapy predicts poor outcomes for patients with locally advanced breast cancer (LABC)

Abstract

Purpose Patients with locally advanced breast cancer (LABC) have a poor outcome. A molecular predictor to identify at-risk patients is sorely needed. CXCR4 is a chemokine receptor that has been linked to breast cancer invasion and metastasis. We postulate that in patients with LABC, CXCR4 overexpression levels in cancer specimens following neoadjuvant chemotherapy predict cancer outcome. Experimental design 54 patients with LABC were prospectively accrued and analyzed. All had neoadjuvant chemotherapy and definitive surgical therapy. Study homogeneity was maintained by standardized treatment, surveillance, and compliance protocols. A 1 cm(3) cancer from the surgical specimens of each patient was retrieved for analysis. CXCR4 levels were detected using Western blots, and results were quantified against 1 mug of protein from HeLa cells. CXCR4 expression was defined as low (<6.6-fold) or high (> or =6.6-fold). Primary endpoints were cancer recurrence and death. Statistical analysis performed included independent samples t-test, chi-square test, Spearman Rank analysis, Kaplan-Meier survival analysis, log-rank test, and Cox proportional hazard model. Results With a median follow-up of 30 months, patients with high CXCR4 overexpression (> or =6.6-fold) had a significantly higher incidence of recurrence (P = 0.0006) and cancer death (P = 0.0128) than those with low CXCR4 overexpression (<6.6-fold). The relative risks for recurrence and death in the high CXCR4 group were 27.3-fold (95% CI: 6.2-120.8; P = 0.001) and 4.8-fold (95% CI: 1.5-15.0; P = 0.0076) higher, respectively than those in the low CXCR4 group. Conclusion High CXCR4 overexpression in specimens from LABC patients receiving neoadjuvant chemotherapy was predictive of cancer outcome.

Interrogating Tumor Metabolism and Tumor Microenvironments Using Molecular Positron Emission Tomography Imaging. Theranostic Approaches to Improve Therapeutics

“…More recent work has shown that CXCR4 membrane expression can be used as a prognostic marker for metastatic potential of node-negative breast tumors and patient survival (Blot et al, 2008). Similarly, locally advanced breast cancer patients receiving neoadjuvant PET Imaging of Tumor Biology chemotherapy who had high expression of CXCR4, had a significantly higher incidence of recurrence and cancer death compared with patients with tumors expressing low CXCR4 (Holm et al, 2009). Collectively, the data on CXCR4 in cancer suggest that this receptor increases tumor cell survival and/or growth and/or metastasis, making it a potentially attractive therapeutic target (Wald et al, 2013;Weiss and Jacobson, 2013).…”

CXCR4-Blockade for Treatment of Breast Cancer

“…Several papers looking at CXCR4 expression in primary human breast cancers have shown an association with tumour grade [ 58 ] , the degree of lymph node metastases [ 8,33,35 ] , bone metastases [ 6,34 ] and poor patient overall survival [ 10,28,44 ] . These data also support the role of the SDF1-CXCR4 ligand-receptor pathway in the pathogenesis of breast cancer metastases and encourage investigation into the usefulness of disrupting this pathway for the treatment of breast cancer.…”

Molecular Imaging of CXCR4 Receptor Expression in Tumors

“…CXCR4 expression in breast cancers has been well characterized. Overexpression of CXCR4 in primary tumors is directly correlated to the degree of lymph node metastasis and poor survival rates in breast cancer patients [26][27][28] . A study by Holm et al, demonstrated that CXCR4 overexpression occurs in most breast cancer patients and HER2-negative breast tumors with CXCR4 overexpression demonstrate more aggressive behavior and are more likely to recur than tumors that do not express elevated levels of CXCR4 [ 29 ] .…”