Tumor suppression, dose-limiting toxicity and wellbeing with the fetal estrogen estetrol in patients with advanced breas
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ORIGINAL ARTICLE – CLINICAL ONCOLOGY
Tumor suppression, dose‑limiting toxicity and wellbeing with the fetal estrogen estetrol in patients with advanced breast cancer Marcus Schmidt1 · Hans Lenhard2 · Arnd Hoenig2 · Yvette Zimmerman3 · Jan Krijgh3 · Monique Jansen3 · Herjan J. T. Coelingh Bennink3 Received: 29 September 2020 / Accepted: 13 November 2020 © The Author(s) 2020
Abstract Purpose The aim of this study (the ABCE4 study) was to assess dose-limiting toxicity (DLT), safety, tolerability and preliminary efficacy of high doses of the fetal estrogen estetrol (E4) in postmenopausal patients with heavily pretreated, locally advanced and/or metastatic ER+/HER2−breast cancer, resistant to anti-estrogens. Methods This was a multicenter, open-label, phase IB/IIA, dose-escalation study with a 3 + 3 cohort design, whereby successive cohorts of three patients received 20 mg, 40 mg or 60 mg E4 per day for 12 weeks by oral administration. DLTs, safety and wellbeing were evaluated after 4, 8 and 12 weeks of treatment. Anti-tumor effects were investigated by computer tomography scanning and evaluated according to RECIST criteria before and after 12 weeks of treatment. Wellbeing was judged weekly by the investigator and by quality-of-life questionnaires by the patients. In view of the small number of patients, no statistical testing was performed. Results All 12 patients enrolled had progressive, heavily pre-treated advanced breast cancer. No treatment-related serious adverse events or DLTs occurred during the first 4 weeks of E4 treatment allowing the investigation of all three doses. Five of nine patients completing 12 weeks of E4 treatment showed objective anti-tumor effects and six of nine patients reported improved wellbeing. Conclusion High doses of estetrol seem to be safe and are well tolerated during 12 weeks of treatment without dose-limiting toxicity and with anti-tumor effects in five of nine heavily treated patients with progressive, anti-estrogen resistant, advanced breast cancer. Keywords Advanced breast cancer · Estetrol (E4) · High-dose estrogen (HDE) treatment
Introduction Breast cancer is the most commonly diagnosed cancer and the leading cause of cancer death in women (Bray et al. 2018), with metastatic disease accounting for the majority of deaths (Dillekas et al. 2019). In most women treated with anti-estrogens, the mainstay of initial treatment, recurrence due to the development of drug resistance occurs, * Herjan J. T. Coelingh Bennink [email protected] 1
Department of Obstetrics and Gynecology, University Medical Center Mainz, 55122 Mainz, Germany
2
Department of Obstetrics and Gynecology, Katholisches Klinikum Mainz, 55131 Mainz, Germany
3
Pantarhei Oncology BV, Boulevard 17, 3707 BK Zeist, The Netherlands
especially in the metastatic setting (D’Souza et al. 2018; Haque and Desai 2019; Szostakowska et al. 2019). Resistance to endocrine therapy is a major challenge, prompting the need for new treatment options (D’Souza et al. 2018; Haque and Desai 2019; Szostakowska et al. 2
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