Abstract OT1-04-01: Estetrol for treatment of advanced ER+ breast cancer
Authors: Verhoeven C , Schmidt M , Hönig A , Dünnebacke J , Dutman E , Krijgh J , Coelingh Bennink H 
Published: February 2018

Abstract
Background information
Estrogen therapy was the endocrine treatment of choice in postmenopausal women with advanced breast cancer for several decades since 1944. In the 1970s, estrogen therapy was replaced by tamoxifen. Tamoxifen showed similar regression rates but less toxicity as compared to estrogen therapy and was therefore considered preferred. Recently, estrogen therapy has gained new interest as several clinical studies showed clinical benefit in heavily pre-treated patients with advanced breast cancer after long-term estrogen deprivation. Estrogen therapy is an effective treatment for breast cancer but it has a negative safety reputation, especially related to the cardiovascular (CV) system. The fetal estrogen estetrol (E4) might be a new treatment option for patients with advanced breast cancer. It has less interference with liver function and is expected to be less harmful for the CV system compared to other estrogens whereas data from non-clinical and clinical studies suggest anti-tumor effects of E4 in breast tumors.
Hypothesis
The fetal estrogen E4 may have anti-tumor effects in patients with advanced ER+ breast cancer. It will most likely also reduce symptoms and signs of estrogen deficiency such as hot flushes, arthralgia, sleep disturbances, bone loss and cognition and improve patient's quality of life.
Trial design and methods
This is a multi-center, open-label, phase I/IIa, dose-escalation study with a 3 + 3 cohort design to determine the recommended dose of E4 for the treatment of patients with advanced breast cancer. Cohorts of at least 3 patients will receive doses of 20 mg, 40 mg and 60 mg E4 respectively, until the non-tolerable dose is determined or the maximum dose of 60 mg is reached. Patients will be treated once daily by oral administration for 12 weeks. In total 9-18 patients with advanced ER+ breast cancer will be enrolled at three centers in Germany.
Objectives
The main objectives of this study are to evaluate the safety, the effects on estrogen deficiency symptoms and the preliminary anti-tumor activity of E4 in patients with advanced breast cancer.
Eligibility criteria
Women who are more than 5 years postmenopausal, with ER+ and HER2-negative locally advanced and/or metastatic breast cancer are eligible for inclusion. In addition, patients should have failed on anti-estrogen treatment with tamoxifen and aromatase inhibitors. Patients with a history of venous or arterial thromboembolic disease or a known defect in the blood coagulation system will be excluded as well as patients who have used treatment with fulvestrant within 6 months prior to start of E4 treatment.
Statistical methods
Statistical tests used in this study are exploratory only. No confirmatory statistical test procedure is envisaged.
Contact information
For further information regarding the study, please contact Dr Carole Verhoeven (cv@pantarheibio.com).
Citation Format: Verhoeven C, Schmidt M, Hönig A, Dünnebacke J, Dutman E, Krijgh J, Coelingh Bennink H. Estetrol for treatment of advanced ER+ breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr OT1-04-01.