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Tumor-Specific Expression of Vascular Endothelial Growth Factor Receptor 2 but Not Vascular Endothelial Growth Factor or Human Epidermal Growth Factor Receptor 2 Is Associated With Impaired Response to Adjuvant Tamoxifen in Premenopausal Breast Cancer

From the Department of Surgery, Helsingborgs Lasarett, Helsingborg; Department of Laboratory Medicine, Pathology, University Hospital, Malmö; Department of Oncology, University Hospital, Lund; Department of Oncology, University Hospital, Linköping; Department of Pathology and Cytology, Kalmar County Hospital, Kalmar; and South Swedish and Southeast Swedish Breast Cancer Groups, Sweden

Address reprint requests to Göran Landberg, MD, Department of Laboratory Medicine, Pathology, Lund University, Malmö University Hospital, SE-205 02 Malmö, Sweden. e-mail: goran.landberg{at}pat.mas.lu.se

PURPOSE: Vascular endothelial growth factor A (VEGF-A) and vascular endothelial growth factor receptor 2 (VEGFR2) are often coexpressed in breast cancer, and potentially affect cellular pathways and key proteins such as the estrogen receptor (ER) targeted by endocrine treatment. We therefore explored the association between adjuvant tamoxifen treatment in breast cancer and expression of VEGF-A and VEGFR2, as well as human epidermal growth factor receptor 2 (HER2), which represents a candidate gene product involved in tamoxifen resistance.

PATIENTS AND METHODS: Immunohistochemical expression of tumor-specific VEGF-A, VEGFR2, and HER2 was evaluated in tumor specimens from premenopausal breast cancer patients randomly assigned to 2 years of tamoxifen or no treatment (n = 564), with 14 years of follow-up. Hormone receptor status was determined in 96% of the tumors.

RESULTS: VEGF-A, VEGFR2, and HER2 were assessable in 460, 472, and 428 of the tumors, respectively. In patients with ER–positive and VEGFR2-low tumors, adjuvant tamoxifen significantly increased recurrence-free survival (RFS; [HR] hazard ratio for RFS, 0.53; P = .001). In contrast, tamoxifen treatment had no effect in patients with VEGFR2-high tumors (HR for RFS, 2.44; P = .2). When multivariate interaction analyses were used, this difference in treatment efficacy relative to VEGFR2 expression status was statistically significant for both ER-positive (P = .04) plus ER-positive and progesterone receptor–positive tumors. We found no significant difference in tamoxifen treatment effects in relation to VEGF-A or HER2 status.

CONCLUSION: Tumor-specific expression of VEGFR2 was associated with an impaired tamoxifen effect in hormone receptor–positive premenopausal breast cancer. Tamoxifen in combination with VEGFR2 inhibitors might be a novel treatment approach for VEGFR2-expressing breast cancer, and such a treatment might restore the tamoxifen response.

Supported by grants from the Swedish Cancer Society, Malmö University Hospital funds, Gunnar Nilssons Cancerstiftelse, the Zoega Fund, the Gorthon Fund, Kristianstad School of Higher Education Foundation, and a project grant from Swegene/Wallenberg Consortium North.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

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