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

• Published in: Clinical breast cancer 2016-08, Vol.16 (4), p.256-261
• Main Authors: Wisinski, Kari B., Xu, Wei, Tevaarwerk, Amye J., Saha, Sandeep, Kim, KyungMann, Traynor, Anne, Dietrich, Leah, Hegeman, Robert, Patel, Dhimant, Blank, Jules, Harter, Josephine, Burkard, Mark E.
• Format: Article
• Language: English
• Subjects: Administration, Oral; Adult; Aged; Aged, 80 and over; Disease-Free Survival; Drug Administration Schedule; Early Termination of Clinical Trials; Estradiol; Estradiol - administration & dosage; Estradiol - adverse effects; Estradiol - therapeutic use; Estrogen receptor beta; Estrogen Receptor beta - agonists; Estrogen Receptor beta - metabolism; Estrogens - administration & dosage; Estrogens - adverse effects; Estrogens - therapeutic use; Female; Humans; Middle Aged; Molecular Targeted Therapy; Neoplasm Staging; Prospective Studies; Treatment Outcome; Triple Negative Breast Neoplasms - drug therapy; Triple Negative Breast Neoplasms - mortality; Triple Negative Breast Neoplasms - pathology; Triple-negative breast cancer; Wisconsin
• ISSN: 1526-8209; 1938-0666
• DOI: 10.1016/j.clbc.2016.03.005

Estrogen receptor beta (ERβ) is a potential therapeutic target in triple-negative breast cancer (TNBC). This 2-stage phase 2 study investigated estradiol in advanced TNBC. The study was closed after 17 patients completed the first stage. One patient with an ERβ-positive tumor experienced a prolonged confirmed partial response. Future study of ERβ agonists in selected TNBC may be warranted. 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. 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. 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. 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.