Department of Obstetrics and Gynecology, University Medical Center Mainz, 55122, Mainz, Germany.
Department of Obstetrics and Gynecology, Katholisches Klinikum Mainz, 55131, Mainz, Germany.
J Cancer Res Clin Oncol. 2021 Jun;147(6):1833-1842. doi: 10.1007/s00432-020-03472-8. Epub 2020 Nov 26.
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.
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.
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.
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.
本研究（ABCE4 研究）旨在评估高剂量胎儿雌激素雌四醇（E4）在抗雌激素耐药、经大量预处理的局部晚期和/或转移性 ER+/HER2 乳腺癌绝经后患者中的剂量限制性毒性（DLT）、安全性、耐受性和初步疗效。
这是一项多中心、开放性、Ib/IIA 期、剂量递增研究，采用 3+3 队列设计，连续 3 名患者的队列每天口服 20mg、40mg 或 60mg E4，持续 12 周。在治疗 4、8 和 12 周后评估 DLT、安全性和舒适度。通过计算机断层扫描评估抗肿瘤作用，并在治疗 12 周前后根据 RECIST 标准进行评估。研究者每周和患者通过生活质量问卷评估舒适度。由于患者人数较少，未进行统计学检验。
所有入组的 12 例患者均患有进展性、大量预处理的晚期乳腺癌。在 E4 治疗的前 4 周内未发生与治疗相关的严重不良事件或 DLT，允许研究所有 3 个剂量。9 例完成 12 周 E4 治疗的患者中有 5 例显示出客观抗肿瘤作用，9 例患者中有 6 例报告舒适度改善。
高剂量雌四醇在 12 周治疗期间似乎是安全且耐受良好的，无剂量限制性毒性，在 9 例接受大量预处理、进展性、抗雌激素耐药的晚期乳腺癌患者中，有 5 例患者具有抗肿瘤作用。
