Introduction: The overexpression of chemokine receptor CXCR4 has been shown to play a pivotal role in breast cancer metastasis. In vitro and animal studies have demonstrated decreased cell migration and abrogation of metastatic disease when agents that specifically block CXCR4 are given. Its clinical significance, however, is still being elucidated. Studies have shown CXCR4 to be overexpressed in human breast cancer tissue versus benign breast tissue. In recent literature, CXCR4 overexpression has also been associated with lymph node metastasis. In this study, we examined the effect of neoadjuvant chemotherapy on CXCR4 overexpression in breast cancer patients.

Methods: A prospective database of 1202 breast cancer patients was culled for this study. Eleven patients were identified with both pre- and post-neoadjuvant chemotherapy tissue specimens in our tissue bank. The patients were all diagnosed with locally advanced breast cancer (Stage IIB - III), and were found to have no evidence of systemic metastasis on subsequent staging work-up. The standard neoadjuvant chemotherapy regimen was four cycles of adriamycin and cyclophosphamide. Ten patients underwent post-neoadjuvant modified radical mastectomy, and one underwent breast conservation therapy. All eleven patients had either complete or partial response to chemotherapy. CXCR4 overexpression was quantified by western blot analysis and reported as x-fold elevated compared to Hela cells. Statistical analysis included Wilcoxon Rank Sum, Chi Square, Kaplan-Meier survival analysis and log-rank test.

Results: The mean CXCR4 level was 8.8 ± 5 fold (mean ± standard deviation over benign controls). Neoadjuvant chemotherapy reduced the mean CXCR4 level to 3.2 ± 2.7 fold, resulting in a mean difference of 5.6 ± 4.0 (62% reduction) and a statistically significant reduction in CXCR4 levels (p=0.002 Wilcoxon Rank Sum Test). Both pre-neoadjuvant and post-neoadjuvant CXCR4 levels were found to have no statistically significant correlation to tumor size, nodal, HER2, ER, PR status, or pathological stage (Chi Square Analysis). A persistently elevated post-neoadjuvant chemotherapy CXCR4 level above the mean (3.2) was associated with an increased risk of cancer recurrence (p=0.041 Log-rank test).

Conclusions: Neoadjuvant chemotherapy significantly reduces levels of CXCR4 overexpression in breast cancer. Elevated post-neoadjuvant chemotherapy CXCR4 expression appears to predict cancer recurrence in breast cancer patients, but a larger patient sample is necessary for proper evaluation.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA