title: Tumor-specific VEGF-A and VEGFR2 in postmenopausal breast cancer patients with long-term follow-up. Implication of a link between VEGF pathway and tamoxifen response.
abstract: Vascular endothelial growth factor (VEGF-A) is considered a prognostic indicator for clinical outcome in breast cancer. Conflicting results nevertheless exist and there is a need for larger studies including untreated patients in order to clarify the importance of tumor-specific VEGF-A regarding prognosis as well as potential links to predictive treatment information. VEGF-A and its receptor, vascular endothelial growth receptor 2 (VEGFR2), were therefore analyzed by immunohistochemistry in postmenopausal breast cancers enrolled in a clinical trial where patients were randomized to adjuvant tamoxifen treatment (n = 124) for 2 years or no treatment (n = 127) with a median follow-up of 18 years. The tumors were arranged in a tumor tissue microarray system enabling parallel analysis of the angiogenic factors and hormone receptor status. Tumor-specific expression of VEGFR2 correlated strongly with expression of VEGF-A and progesterone receptor (PR) negativity, whereas VEGF-A was not associated with hormone receptor status. Among patients with estrogen receptor (ER) positive (fraction > 10%) tumors, there was a statistically significant tamoxifen response in VEGF-A negative tumors at both 10-year and 18-year disease-free survival (DFS), contrasting to VEGF-A positive tumors who had no beneficial effect of tamoxifen. A treatment-interaction variable indicated a marked difference in tamoxifen response depending on VEGFA-status in terms of DFS at 10 and 18 years of follow-up, p = 0.046 and p = 0.039, respectively. VEGFR2 status did not yield significant predicitve information for tamoxifen response in patients with ER fraction > 10%, whereas in patients with ER fraction > 90% both VEGF-A and VEGFR2 status were associated with tamoxifen treatment effect.
authors.affiliation: Division of Pathology, Department of Laboratory Medicine, Lund University, Malmö, University Hospital, SE - 205 02 Malmö, Sweden. lisa.ryden@pat.mas.lu.se
authors.forename: Lisa
authors.initials: L
authors.lastname: Rydén
authors.forename: Maria
authors.initials: M
authors.lastname: Stendahl
authors.forename: Håkan
authors.initials: H
authors.lastname: Jonsson
authors.forename: Stefan
authors.initials: S
authors.lastname: Emdin
authors.forename: Nils O
authors.initials: NO
authors.lastname: Bengtsson
authors.forename: Göran
authors.initials: G
authors.lastname: Landberg
mesh_terms: D000368:Aged; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology* / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000032:analysis*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D017024:Chemotherapy, Adjuvant; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007150:Immunohistochemistry; D008875:Middle Aged; D017698:Postmenopause; D011379:Prognosis; D013629:Tamoxifen / Q000494:pharmacology* / Q000627:therapeutic use*; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A / Q000097:blood*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000097:blood*
chemical_list: D018931:Antineoplastic Agents, Hormonal; D014408:Biomarkers, Tumor; D042461:Vascular Endothelial Growth Factor A; D013629:Tamoxifen; D040301:Vascular Endothelial Growth Factor Receptor-2