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.