Targeting Estrogen Receptor Beta in a Phase 2 Study of High-Dose Estradiol in Metastatic Triple-Negative Breast Cancer: A Wisconsin Oncology Network Study.

BACKGROUND Estrogen receptor beta (ERβ) is expressed by 50% to 80% of triple-negative breast cancers (TNBC). Agonism of ERβ has antiproliferative effects in TNBC cells expressing ERβ. This phase 2 study evaluated single-agent high-dose estradiol in patients with advanced TNBC. PATIENTS AND METHODS Adult women with measurable advanced TNBC were treated with estradiol 10 mg oral 3 times daily provided continuously for 28-day cycles. A Simon optimal 2-stage design was used. The primary end point was objective response (OR). Secondary end points included progression-free survival (PFS), clinical benefit (CB), and safety. OR, CB, and PFS by ERβ status were also examined. RESULTS Seventeen evaluable women were enrolled. Median age was 58 years (range, 34-90 years); the median number of prior systemic therapies was 2 (range, 0-6). One patient had a confirmed partial response (OR rate, 5.9%) and remained on the study for > 24 weeks. Three patients had stable disease, with one lasting more than 16 weeks. ERβ expression was detected in 77% (13 patients). The CB rate at 16 weeks was 15% (2 of 13) in ERβ-positive patients and 0% (0 of 4) in ERβ-negative patients (P = 1). PFS was poor (median, 1.9 months) and not statistically significantly different between ERβ-positive versus -negative patients. No new adverse events from estradiol were identified. The study closed after the first stage as a result of limited responses in these unselected patients. CONCLUSION In unselected TNBC, high-dose estradiol has limited efficacy. However, further evaluation of ERβ selective agonists in TNBC selected by ERβ expression may be warranted.