Data from Immunomodulation of FOXP3<sup>+</sup> Regulatory T Cells by the Aromatase Inhibitor Letrozole in Breast Cancer Patients

Abstract

<div>Abstract<p><b>Purpose:</b> We have shown previously that tumor infiltration by FOXP3<sup>+</sup> regulatory T cells (Treg) is associated with increased relapse and shorter survival of patients with both <i>in situ</i> and invasive breast cancer. Because estrogen regulates Treg numbers in mice and promotes the proliferation of human Tregs, we hypothesized that blocking estrogen receptor-α signaling would abrogate Tregs and be associated with response to hormonal therapy and increased survival.</p><p><b>Experimental Design:</b> FOXP3<sup>+</sup> Tregs were quantified in tumor samples collected at baseline by incisional biopsy and after 6 months at definitive surgery in 83 elderly breast cancer patients (T<sub>2-4</sub> N<sub>0-1</sub>) enrolled in a randomized phase II trial based on 6 months of primary letrozole (2.5 mg/d) or 6 months of letrozole plus oral “metronomic” cyclophosphamide (50 mg/d).</p><p><b>Results:</b> Treg number ranged from 0 to 380 (median, 30) before treatment and from 0 to 300 (median, 8) after treatment. There was a significant reduction in Tregs in letrozole and letrozole-cyclophosphamide patients (<i>P</i> < 0.0001 and <i>P</i> < 0.002, respectively) after treatment. Treg number at residual histology was inversely related with response (<i>P</i> < 0.03 and <i>P</i> = 0.50, respectively) and a greater Treg reduction was observed in responding patients (<i>P</i> < 0.03).</p><p><b>Conclusion:</b> This study suggests that aromatase inhibitors may have an indirect antitumor mechanism of action through reducing Tregs in breast tumors and may be of use in estrogen receptor-α-negative tumors in combination with immunotherapy approaches.</p></div>