Introduction: A high dose of the fetal estrogen estetrol (E4) is anticipated to have anti-tumor effects in patients with advanced, anti-estrogen resistant, ER+/HER2- breast cancer (BC). It will most likely also improve patient’s quality of life by reducing symptoms of estrogen deficiency such as hot flushes, arthralgia, sleep disturbances, vaginal dryness, mood changes and depression, bone loss and fractures and cognition. The ABCE4 study is performed in Germany in this patient population. The main objectives of the study are to assess safety and tolerability of three doses of E4, to determine anti-tumor response and to evaluate estrogen deficiency symptoms. Study design: This is a multi-center, open-label, phase IB/IIA, dose-escalation study with a 3 + 3 cohort design, whereby successive cohorts of 3 patients receive 20 mg, 40 mg and 60 mg E4 per day by oral administration. Dose limiting toxicity (DLT), safety and wellbeing are evaluated after 4, 8 and 12 weeks of treatment. Occurrence of DLT at completion of phase IB after 4 weeks treatment determines escalation to the next higher dose. Objective anti-tumor effects are assessed by computer tomography scanning and evaluated according to RECIST criteria before and after 12 weeks of treatment. Thereafter treatment may continue based on an evaluation of the patient and her treating physician. In view of the small numbers required for this study design no statistical testing was performed. Results: A total of 12 postmenopausal women with progressive, heavily pre-treated advanced BC have been enrolled. Nine patients completed Phase IB. One patient in the 20 mg group discontinued the study during Phase IIA due to disease progression after 9,5 weeks of E4 treatment. She died 3 weeks later. Eight patients completed both the Phase IB and IIA part of the study. None of the patients experienced a DLT. All three E4 doses were well tolerated by all patients. In total 38 adverse events were reported. Adverse events were mainly of mild or moderate intensity. The following 8 events were considered possibly related to E4 treatment: increased endometrial thickness, spotting (2 patients), dry skin, pruritus, edema, fatigue (2 patients), alopecia and acid regurgitation. Seven events fulfilled the criteria of seriousness from which one was considered to be related to E4 treatment. This patient experienced moderate vaginal bleeding after 36 weeks treatment with 20 mg E4 and was hospitalized for hysteroscopy and endometrial ablation with full recovery thereafter. Importantly five of the eight patients who completed treatment with E4 reported subjective improvement and “felt much better” than before the start of E4 treatment. This was described by one of the patients as: ‘”feeling less down and exhausted; instead feeling much more optimistic, powerful and positive when taking E4”. Five patients completing 12 weeks E4 treatment showed objective anti-tumor effects with stable disease (n=4) and one remission. All five continued E4 treatment. Tumor assessment after 24 weeks of E4 treatment showed again stable disease in 4 patients. Conclusion: We conclude that daily doses of 20 mg, 40 mg and 60 mg E4 are well tolerated without DLTs. The majority of patients experienced favorable subjective effects and four patients treated for 24 weeks or longer showed stable disease and tumor remission respectively. Treatment with E4 meets the criteria for further investigation and development of E4 as a new drug for the treatment of anti-estrogen resistant advanced breast cancer. Final dose selection of E4 will take place in September 2019.
Citation Format: Marcus Schmidt, Arnd Hönig, Yvette Zimmerman, Carole Verhoeven, Katrin Almstedt, Marco Battista, Hans Georg Lenhard, Jan Krijgh, Herjan Coelingh Bennink. Estetrol for treatment of advanced ER+/HER2- breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-11-15.
