Elevated Levels of Chemokine Receptor CXCR4 in HER-2 Negative Breast Cancer Specimens Predict Recurrence

Neal T. Holm, Kerry Byrnes, Benjamin D.L. Li, Richard H. Turnage, Fleurette Abreo, James Michael Mathis, Quyen D. Chu

Research output: Contribution to journalArticle

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Abstract

Introduction: CXCR4 is a chemokine receptor that has recently been implicated to play a pivotal role in breast cancer growth and metastasis. In animal models, reduction of CXCR4 expression significantly abrogated metastatic disease and prolonged survival. In human breast cancers, CXCR4 overexpression may portend a worse clinical course. Recent data suggest that HER-2 up-regulates CXCR4, but whether this is applicable in the clinical setting is not known. In this study, we evaluated the role of CXCR4 overexpression in breast cancer and determined whether it can serve as a potential marker of tumor recurrence in HER-2 negative tumors. Methods: One hundred three patients with stages I to III breast cancers and 6 benign breast tissues were prospectively accrued and analyzed. Study homogeneity was maintained by standardized treatment, surveillance, and compliance protocols. CXCR4 levels were detected using Western blots and results were quantified against 1 μg of HeLa cells (positive controls). HER-2 expression was evaluated using the Hercep program, (Dako Corp., Carpinteria, CA) with a positive result defined as ≥2. CXCR4 expression was defined as low (<6.6-fold) or high (≥6.6-fold). Primary endpoints were cancer recurrence and death. Statistical analysis performed included Spearman's correlation, independent samples t-test, Kaplan-Meier survival analysis, and log-rank test. Results: All 103 cancer specimens had CXCR4 overexpression (mean 6.6 ± 4.7), while none of the 6 benign breast tissues had detectable level of CXCR4. There were 36 HER-2 (+) tumors and 67 HER-2 (-) tumors. There was no statistical significance in mean CXCR4 overexpression between HER-2 (+) [5.6] and HER-2 (-) [6.6] cancers (P = 0.3; independent samples t-test). Recurrences occurred in 18 of 103 patients (17%); 10 occurred in HER-2 (+) tumors, and 8 occurred in HER-2 (-) patients. CXCR4 expression level was not predictive of cancer recurrence (P = 0.80) or overall survival (P = 0.70) in the HER-2 (+) group. However, among HER-2 negative tumors, 7 of 8 recurrences occurred in the high CXCR4 group (P = 0.037). There was no correlation between the degree of CXCR4 overexpression with tumor size (r = 0.13, P = 0.22), nodal status (r = 0.019, P = 0.4), ER/PR status (r = 0.12, P = 0.29), and HER-2 status (r = 0.091, P = 0.36). Conclusions: CXCR4 overexpression was observed in all 103 breast cancer specimens but was undetectable in benign breast tissues. CXCR4 overexpression does not correlate with tumor size, nodal status, ER/PR status, and HER-2 status. High CXCR4 overexpression had a significant impact on disease-free survival in HER-2 negative breast cancer patients and may help identify a subset of HER-2 negative breast cancers that have a more aggressive biological behavior.

Original languageEnglish
Pages (from-to)53-59
Number of pages7
JournalJournal of Surgical Research
Volume141
Issue number1
DOIs
StatePublished - 1 Jul 2007

Fingerprint

Chemokine Receptors
Breast Neoplasms
Recurrence
Neoplasms
Breast
Survival
Kaplan-Meier Estimate
Survival Analysis
Tumor Biomarkers
Clinical Protocols
HeLa Cells
Compliance
Disease-Free Survival
Up-Regulation
Animal Models
Western Blotting
Neoplasm Metastasis

Keywords

  • breast cancer
  • cancer recurrence
  • CXCR4
  • HER-2

Cite this

Holm, Neal T. ; Byrnes, Kerry ; Li, Benjamin D.L. ; Turnage, Richard H. ; Abreo, Fleurette ; Mathis, James Michael ; Chu, Quyen D. / Elevated Levels of Chemokine Receptor CXCR4 in HER-2 Negative Breast Cancer Specimens Predict Recurrence. In: Journal of Surgical Research. 2007 ; Vol. 141, No. 1. pp. 53-59.
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title = "Elevated Levels of Chemokine Receptor CXCR4 in HER-2 Negative Breast Cancer Specimens Predict Recurrence",
abstract = "Introduction: CXCR4 is a chemokine receptor that has recently been implicated to play a pivotal role in breast cancer growth and metastasis. In animal models, reduction of CXCR4 expression significantly abrogated metastatic disease and prolonged survival. In human breast cancers, CXCR4 overexpression may portend a worse clinical course. Recent data suggest that HER-2 up-regulates CXCR4, but whether this is applicable in the clinical setting is not known. In this study, we evaluated the role of CXCR4 overexpression in breast cancer and determined whether it can serve as a potential marker of tumor recurrence in HER-2 negative tumors. Methods: One hundred three patients with stages I to III breast cancers and 6 benign breast tissues were prospectively accrued and analyzed. Study homogeneity was maintained by standardized treatment, surveillance, and compliance protocols. CXCR4 levels were detected using Western blots and results were quantified against 1 μg of HeLa cells (positive controls). HER-2 expression was evaluated using the Hercep program, (Dako Corp., Carpinteria, CA) with a positive result defined as ≥2. CXCR4 expression was defined as low (<6.6-fold) or high (≥6.6-fold). Primary endpoints were cancer recurrence and death. Statistical analysis performed included Spearman's correlation, independent samples t-test, Kaplan-Meier survival analysis, and log-rank test. Results: All 103 cancer specimens had CXCR4 overexpression (mean 6.6 ± 4.7), while none of the 6 benign breast tissues had detectable level of CXCR4. There were 36 HER-2 (+) tumors and 67 HER-2 (-) tumors. There was no statistical significance in mean CXCR4 overexpression between HER-2 (+) [5.6] and HER-2 (-) [6.6] cancers (P = 0.3; independent samples t-test). Recurrences occurred in 18 of 103 patients (17{\%}); 10 occurred in HER-2 (+) tumors, and 8 occurred in HER-2 (-) patients. CXCR4 expression level was not predictive of cancer recurrence (P = 0.80) or overall survival (P = 0.70) in the HER-2 (+) group. However, among HER-2 negative tumors, 7 of 8 recurrences occurred in the high CXCR4 group (P = 0.037). There was no correlation between the degree of CXCR4 overexpression with tumor size (r = 0.13, P = 0.22), nodal status (r = 0.019, P = 0.4), ER/PR status (r = 0.12, P = 0.29), and HER-2 status (r = 0.091, P = 0.36). Conclusions: CXCR4 overexpression was observed in all 103 breast cancer specimens but was undetectable in benign breast tissues. CXCR4 overexpression does not correlate with tumor size, nodal status, ER/PR status, and HER-2 status. High CXCR4 overexpression had a significant impact on disease-free survival in HER-2 negative breast cancer patients and may help identify a subset of HER-2 negative breast cancers that have a more aggressive biological behavior.",
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Elevated Levels of Chemokine Receptor CXCR4 in HER-2 Negative Breast Cancer Specimens Predict Recurrence. / Holm, Neal T.; Byrnes, Kerry; Li, Benjamin D.L.; Turnage, Richard H.; Abreo, Fleurette; Mathis, James Michael; Chu, Quyen D.

In: Journal of Surgical Research, Vol. 141, No. 1, 01.07.2007, p. 53-59.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Elevated Levels of Chemokine Receptor CXCR4 in HER-2 Negative Breast Cancer Specimens Predict Recurrence

AU - Holm, Neal T.

AU - Byrnes, Kerry

AU - Li, Benjamin D.L.

AU - Turnage, Richard H.

AU - Abreo, Fleurette

AU - Mathis, James Michael

AU - Chu, Quyen D.

PY - 2007/7/1

Y1 - 2007/7/1

N2 - Introduction: CXCR4 is a chemokine receptor that has recently been implicated to play a pivotal role in breast cancer growth and metastasis. In animal models, reduction of CXCR4 expression significantly abrogated metastatic disease and prolonged survival. In human breast cancers, CXCR4 overexpression may portend a worse clinical course. Recent data suggest that HER-2 up-regulates CXCR4, but whether this is applicable in the clinical setting is not known. In this study, we evaluated the role of CXCR4 overexpression in breast cancer and determined whether it can serve as a potential marker of tumor recurrence in HER-2 negative tumors. Methods: One hundred three patients with stages I to III breast cancers and 6 benign breast tissues were prospectively accrued and analyzed. Study homogeneity was maintained by standardized treatment, surveillance, and compliance protocols. CXCR4 levels were detected using Western blots and results were quantified against 1 μg of HeLa cells (positive controls). HER-2 expression was evaluated using the Hercep program, (Dako Corp., Carpinteria, CA) with a positive result defined as ≥2. CXCR4 expression was defined as low (<6.6-fold) or high (≥6.6-fold). Primary endpoints were cancer recurrence and death. Statistical analysis performed included Spearman's correlation, independent samples t-test, Kaplan-Meier survival analysis, and log-rank test. Results: All 103 cancer specimens had CXCR4 overexpression (mean 6.6 ± 4.7), while none of the 6 benign breast tissues had detectable level of CXCR4. There were 36 HER-2 (+) tumors and 67 HER-2 (-) tumors. There was no statistical significance in mean CXCR4 overexpression between HER-2 (+) [5.6] and HER-2 (-) [6.6] cancers (P = 0.3; independent samples t-test). Recurrences occurred in 18 of 103 patients (17%); 10 occurred in HER-2 (+) tumors, and 8 occurred in HER-2 (-) patients. CXCR4 expression level was not predictive of cancer recurrence (P = 0.80) or overall survival (P = 0.70) in the HER-2 (+) group. However, among HER-2 negative tumors, 7 of 8 recurrences occurred in the high CXCR4 group (P = 0.037). There was no correlation between the degree of CXCR4 overexpression with tumor size (r = 0.13, P = 0.22), nodal status (r = 0.019, P = 0.4), ER/PR status (r = 0.12, P = 0.29), and HER-2 status (r = 0.091, P = 0.36). Conclusions: CXCR4 overexpression was observed in all 103 breast cancer specimens but was undetectable in benign breast tissues. CXCR4 overexpression does not correlate with tumor size, nodal status, ER/PR status, and HER-2 status. High CXCR4 overexpression had a significant impact on disease-free survival in HER-2 negative breast cancer patients and may help identify a subset of HER-2 negative breast cancers that have a more aggressive biological behavior.

AB - Introduction: CXCR4 is a chemokine receptor that has recently been implicated to play a pivotal role in breast cancer growth and metastasis. In animal models, reduction of CXCR4 expression significantly abrogated metastatic disease and prolonged survival. In human breast cancers, CXCR4 overexpression may portend a worse clinical course. Recent data suggest that HER-2 up-regulates CXCR4, but whether this is applicable in the clinical setting is not known. In this study, we evaluated the role of CXCR4 overexpression in breast cancer and determined whether it can serve as a potential marker of tumor recurrence in HER-2 negative tumors. Methods: One hundred three patients with stages I to III breast cancers and 6 benign breast tissues were prospectively accrued and analyzed. Study homogeneity was maintained by standardized treatment, surveillance, and compliance protocols. CXCR4 levels were detected using Western blots and results were quantified against 1 μg of HeLa cells (positive controls). HER-2 expression was evaluated using the Hercep program, (Dako Corp., Carpinteria, CA) with a positive result defined as ≥2. CXCR4 expression was defined as low (<6.6-fold) or high (≥6.6-fold). Primary endpoints were cancer recurrence and death. Statistical analysis performed included Spearman's correlation, independent samples t-test, Kaplan-Meier survival analysis, and log-rank test. Results: All 103 cancer specimens had CXCR4 overexpression (mean 6.6 ± 4.7), while none of the 6 benign breast tissues had detectable level of CXCR4. There were 36 HER-2 (+) tumors and 67 HER-2 (-) tumors. There was no statistical significance in mean CXCR4 overexpression between HER-2 (+) [5.6] and HER-2 (-) [6.6] cancers (P = 0.3; independent samples t-test). Recurrences occurred in 18 of 103 patients (17%); 10 occurred in HER-2 (+) tumors, and 8 occurred in HER-2 (-) patients. CXCR4 expression level was not predictive of cancer recurrence (P = 0.80) or overall survival (P = 0.70) in the HER-2 (+) group. However, among HER-2 negative tumors, 7 of 8 recurrences occurred in the high CXCR4 group (P = 0.037). There was no correlation between the degree of CXCR4 overexpression with tumor size (r = 0.13, P = 0.22), nodal status (r = 0.019, P = 0.4), ER/PR status (r = 0.12, P = 0.29), and HER-2 status (r = 0.091, P = 0.36). Conclusions: CXCR4 overexpression was observed in all 103 breast cancer specimens but was undetectable in benign breast tissues. CXCR4 overexpression does not correlate with tumor size, nodal status, ER/PR status, and HER-2 status. High CXCR4 overexpression had a significant impact on disease-free survival in HER-2 negative breast cancer patients and may help identify a subset of HER-2 negative breast cancers that have a more aggressive biological behavior.

KW - breast cancer

KW - cancer recurrence

KW - CXCR4

KW - HER-2

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