Estrogen and vascular endothelial growth factor (VEGF): Their role in breast cancer (BC) carcinogenesis and disease progression in premenopause.

Abstract

540 Background: Estrogen has a key role in BC development and there is evidence in vitro, that it modulates VEGF expression in BC cells through transcriptional activation. However few clinical studies investigated the association between VEGF and estrogens in humans. Objective of this study was to evaluate wether estrogen suppression with an LH-RH analogue was able to down regulate VEGF expression, and thus decrease its plasma concentration, in premenopausal patients with high-risk estrogen receptor positive (ER+) and negative (ER−) early BC. Methods: From 04-2003 to 10-2008, 100 premenopausal early BC patients were entered into the study. At baseline, after surgery, plasma VEGF and sex hormones 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. Secondary end points were progression-free survival (PFS) and overall survival (OS). Results: Median age was 43 years (range 26-45). Mean number of positive axillary nodes was 3.3. Eighty-three patients were ER+, 17 were ER − and progesterone receptor (PGR) -. Median KI-67 was 33% (range 15%−100%). Twenty patients were Herb−2 positive. A statistically significant decrease of VEGF was observed after 1 and 5 years, both in ER+ and ER− patients: In particular, VEGF decreased (p<0.001) in 94% of patients that were disease-free, while in 6% of patients with disease relapse, it increased with respect to baseline values. 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 50 months (range 24-90), 5-year disease free survival and overall survival rate were 94% and 100%, respectively. Conclusions: Estrogen deprivation with an LH-RH analogue is able to decrease plasma VEGF levels in premenopausal high risk ER+ and ER- BC patients. These data show how estrogens, through VEGF modulation, may be responsible for the worst prognosis that is observed in premenopausal BC patients.