Immunologic Mechanisms Mediate Benefits of Lutenizing Hormone-Releasing Hormone (LH-RH) in High Risk Premenopausal Breast Cancer Patients (HR-Pre-BC).
Authors: Recchia F. , Recchia F. , Candeloro G. , Bisegna R. , Necozione S. , Recchia C. , Rea S. , Rea S. 
Published: December 2010

Abstract
Background: Systematic reviews have found that LH-RH agonists are effective in the treatment of premenopausal women with early breast cancer. In an extended phase II study, 180 premenopausal women with HR-Pre-BC were treated with an LH-RH analogue in order to protect ovaries from the damage of chemotherapy. We hypothesized that the benefits of LH-RH administration could extend, far beyond ovarian protection, to the improvement of immune function and to the decrease of vascular endothelial growth factor (VEGF). In fact estradiol (E2) at physiological doses not only expands T regulatory cells (T-regs) in different tissues but also increases expression of the Foxp3 gene, a hallmark for CD4+CD25+ T-reg cell function, and the interleukin-10 gene as well. In addition, recent studies indicate that E2 modulates VEGF expression in breast cancer cells through transcriptional activation.Methods: From 05-1997 to 05-2007 180 patients with HR-Pre-BC were entered into the study. At baseline, one week before chemotherapy, patients received an LH-RH analogue which was continued for five years. Adjuvant chemotherapy was tailored to the peculiar biologic features of each patient, including cyclophosphamide, methotrexate, and 5-fluorouracil in 24 patients, an anthracycline and taxane based regimens in 156 patients (40 with positive c-erb-2 tumors). Seventeen patients with &gt; 10 positive axillary lymph nodes and 36 patients with triple negative tumors, received a platinum-based consolidation high-dose chemotherapy with or without autologous peripheral blood progenitor cell transplantation, respectively. Radiation therapy was administered to 145 patients. During the 5 years of LH-RH analogue, patients received a strong psychological support, biphosphonates, and after the end of chemotherapy, estrogen receptor positive (ER+) patients received an aromatase inhibitor.Results: Characteristics of patients. The mean patient age was 42 years (range, 26–50 yrs). One hundred-twenty five women were ER+, 55 were estrogen receptor negative (ER-). Total number of positive nodes was 479, with a mean of 2.6 for each patient (range 0-25). UICC stage was II in 114 women and III in 66 women. All patients had their serum E2 suppressed to values &lt; 40 pg/mL. A statistically significant improvement was observed in lymphocyte number (p&lt; 0.005), and a decrease in T-reg number (p&lt; 0.005) and VEGF (p&lt; 0.005) with respect to baseline values, after LH-RH administration. After a median follow-up of 97 months, 10-years overall progression-free survival and overall survival rate were both 83.2% with no statistical significant difference between ER+ and ER- patients.Conclusions: These data show that the administration of an LH-RH analogue improves lymphocyte number, decreases T-regs and VEGF, and seems to improve the expected outcome of HR-Pre-BC patients through immunologic mediated mechanisms.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 4092.