P4-08-02: Estradiol (E2) Mediated Secretion of Vascular Endothelial Growth Factor (VEGF) and Stimulation of T-Regulatory Cells (T-Regs): Their Role for the Worse Prognosis of Breast Cancer (BC) in Premenopause.
Authors: Recchia F , Candeloro G , Desideri G , Necozione S , Recchia COC , Rea S 
Published: June 2012

Abstract
Background: E2 plays a key role in all the phases of human reproduction, including promotion of uterine basal membrane erosion, embryo implantation, placental villi development, and pregnancy maintenance. E2 mediates all these functions through the induction of VEGF secretion and stimulation of T-Regs with increased tolerance for the eterologous embryo. BC might utilize the same pathways for its growth and for disease progression: Modulation of VEGF expression in BC cells through transcriptional activation and regulation of the peripheral development of CD4+CD25+ T-Regs cells. Both VEGF and T-Regs are important prognostic factors: In fact high levels of VEGF expression are associated with significantly worse survival in breast cancer patients, even in sub-groups expected to have a better prognosis and T-Regs quantification in breast tumors is valuable for assessing disease prognosis and progression. However few clinical studies investigated the association between E2, VEGF and T-Regs in humans. Objective of this study was to evaluate whether E2 suppression with an LH-RH analogue was able to down regulate VEGF expression, and decrease T-Regs in premenopausal patients with high-risk estrogen receptor positive (ER+) and negative (ER-) early BC. Material and Methods: From 04–2003 to 10–2008, 100 premenopausal early BC patients were entered into the study. At baseline, in the follicular phase of the menstrual cycle, after surgery, plasma E2, VEGF and T-Regs were measured. Measurements were repeated every six months. Treatment: LH-RH analogue for 5 years, chemotherapy tailored to the biological characteristics of each patient, radiation therapy, and 5-year hormonal therapy in ER+ tumors. Primary end-point was the evaluation of VEGF and T-Regs. Secondary end points were progression-free survival (PFS) and overall survival (OS). Results: Median age was 43 years (range 26–45). Median number of positive axillary nodes was 3.3. Eighty-three patients were ER+, 17 were ER - and progesterone receptor negative (PGR-), 10 were triple negative, 20 were Herb-2 positive. Median KI-67 was 33% (range 15%-100%). A statistically significant decrease of E2,VEGF and T-Regs was observed after 1 and 5 years, in ER+ and ER- patients: In particular, VEGF (P&lt;0.001) and T-Regs (P&lt;0.001) decreased in 95% of patients that were disease-free. No unexpected toxicity of chemotherapy was observed, while hot flashes and G1 osteopenia occurred after LH-RH analogues administration. After a median follow-up of 55 months (range 30–95), 5-year PFS and OS rate were 95% and 100%, respectively. Discussion: E2 deprivation with an LH-RH analogue is able to decrease plasma VEGF and T-Regs levels in premenopausal high risk ER+ and ER- BC patients. These data show how E2, through VEGF and T-Regs modulation, may be responsible for the worst prognosis that is observed in premenopausal BC.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-08-02.