title: 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.
abstract: OBJECTIVE
  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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors: Department of Surgery, Helsingborgs Lasarett, Helsingborg.
authors: Lisa
authors: L
authors: Rydén
authors: Karin
authors: K
authors: Jirström
authors: Pär-Ola
authors: PO
authors: Bendahl
authors: Mårten
authors: M
authors: Fernö
authors: Bo
authors: B
authors: Nordenskjöld
authors: Olle
authors: O
authors: Stål
authors: Sten
authors: S
authors: Thorstenson
authors: Per-Ebbe
authors: PE
authors: Jönsson
authors: Göran
authors: G
authors: Landberg
mesh_terms: D000328:Adult; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000737:chemistry* / Q000188:drug therapy*; D017024:Chemotherapy, Adjuvant; D066246:ErbB Receptors / Q000032:analysis; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008875:Middle Aged; D017697:Premenopause / Q000502:physiology; D011960:Receptors, Estrogen / Q000032:analysis; D011980:Receptors, Progesterone / Q000032:analysis; D013629:Tamoxifen / Q000627:therapeutic use*; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A / Q000032:analysis*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000032:analysis*
chemical_list: D018931:Antineoplastic Agents, Hormonal; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D042461:Vascular Endothelial Growth Factor A; D013629:Tamoxifen; D066246:ErbB Receptors; D040301:Vascular Endothelial Growth Factor Receptor-2