Estetrol (E4) for Breast Cancer
High Dose Estetrol (HDE4) for advanced breast cancer treatment has successfully achieved proof-of-concept in human. The Phase IB/IIA ABCE4 study has demonstrated promising anti-tumor activity and improvement in patient’s wellbeing (“dual efficacy”).
The fetal estrogen estetrol (E4) is a potential new high dose estrogen (HDE) treatment for anti-estrogen resistant ER+/HER- advanced breast cancer. The term “estetrol” refers to estra-1,3,5(10)-triene-3,15α,16α,17β-tetrol, an estrogenic steroid, produced under physiological conditions only during human pregnancy by the fetoplacental unit1. It is also known as E4, referring to the four OH groups in the molecule at positions 3, 15, 16 and 17 (Fig. 1).
Pantarhei discovered the favourable pharmaceutical properties and clinical profile of this fetal estrogen. Estetrol has a high oral bioavailability and a long oral elimination half-life2. Therefore E4 is suitable as a once-a-day oral drug. It is a metabolic end product, without active and potentially toxic metabolites3. Very importantly, E4 has little interaction with liver function4 and coagulation factors5 and is expected to have a better cardiovascular safety profile compared to other natural and synthetic estrogens.
Pre-clinical and clinical E4 data collected by Pantarhei Bioscience during the first years of development have been summarised in a Supplement of Climacteric in 2008. Pre-clinical in vitro studies in human breast cancer cell lines (MCF-7 and LTED) demonstrated that E4 is a weak estrogen agonist, but behaves as an antagonist on the breast in the presence of E26, 7. DMBA in vivo studies have shown that E4 is able to prevent tumor development in a dose dependent way and existing tumors decrease in size or even disappear, also dose dependently8.
High dose estrogens (HDE) such as diethylstilboestrol (DES), estradiol (E2) and ethinylestradiol (EE) was the endocrine treatment of choice in postmenopausal women with advanced breast cancer for several decades until tamoxifen entered the market in the seventies9. The mechanism of action in women with advanced breast cancer is considered to be estrogen-induced apoptosis in tumors that have been deprived of estrogens for a long time, either because the patient is more than 5 years postmenopausal, or because the patient has been treated with anti-estrogens and became resistant to this type of treatment10–12.
The use and effects of HDE have recently been summarised by Coelingh Bennink et al (2017)13. Because of side-effects, especially thrombosis and other CV complications, HDE treatment has been replaced by anti-estrogens such as tamoxifen, aromatase inhibitors and fulvestrant 14–17. However, due to their strong anti-estrogenicity, these compounds induce serious unwanted signs and symptoms of estrogen deficiency, interfering with quality of life and especially with long term drug compliance18–20. Lately, CDK4/6 inhibitors have obtained an important position in the treatment of advanced breast cancer after failure of anti-estrogens, but these compounds also have side-effects and interfere with quality of life21–23.
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 deprivation24–26.
The fetal estrogen E4 is a potential new HDE treatment for anti-estrogen resistant ER+/HER- advanced breast cancer. In view of its pharmaceutical properties (no toxic metabolites, low impact on coagulation and haemostatic liver factors) and its favourable safety profile3–5, 27, 28, Pantarhei expects that E4 will be safer for the treatment of breast cancer compared to other estrogens that has been used extensively in the past. So far, E4-related CV adverse events were uncommon in clinical studies for menopausal hormone therapy and oral contraception29–31 and in the Pantarhei studies for the oncological indications.
The objective is to develop HDE4 as a second line combination therapy with aromatase inhibitors. This treatment is suitable for ER+/HER2- breast cancer patients who became resistant to endocrine treatment (tamoxifen, aromatase inhibitors, fulvestrant, CDK4/6i and/or Everolimus) and/or who are at least 5 years postmenopausal (spontaneous or breast cancer treatment induced). Alternatively, E4 could be used as a third line for the treatment/prevention of estrogen deficiency signs and symptoms (supportive care) during chemotherapy. This treatment is suitable for patients with advanced ER+/HER2- breast cancer, who are resistant to anti-estrogen therapy, have progressed, and who are eligible for chemotherapy.
In both treatment strategies, E4 is expected to produce enhanced efficacy over the aromatase inhibitor or chemotherapy alone. E4 is also expected to counteract signs and symptoms of estrogen deficiency after disease progression and thus enhance patient well-being and quality of life.
Studies in healthy women
The safety profile and the tolerability of E4 alone have been evaluated in two Phase I clinical studies performed in healthy postmenopausal women. E4 was well tolerated and safe up to 100 mg given as a single dose and up to 40 mg given once daily during 28 days 28, 29, 32. In these studies, it was also demonstrated that E4 was able to mature the vaginal epithelium in these women and E4 demonstrated efficacy in treating vasomotor symptoms.
A first pilot neo-adjuvant study in breast cancer patients by Prof. Christian Singer and Prof. Ernst Kubista in Vienna was performed in 30 women who were recently diagnosed with ER+ early breast cancer. In this Phase IIA randomised, double-blind, placebo-controlled study patients received 14 days pre-operative treatment with 20 mg E4 per day or placebo. E4 treatment had a significant pro-apoptotic effect on tumor tissues and increased the expression of the anti-proliferative estrogen ß-receptor. The treatment was well tolerated in all 30 pre- and postmenopausal women with ER positive early breast cancer33.
The ABCE4 study is an open-label, dose-escalating study with a 3+3 cohort design IB/IIA study with E4 in women with advanced, ER+/HER2- end stage breast cancer, who had become resistant to other treatments including anti-estrogens. This study was performed in two clinics in Mainz, Germany. Three doses of E4 were tested; 20, 40 and 60 mg per day for 12 weeks by oral administration.
A total of 9 patients with advanced BC completed the 12 weeks treatment of E4, with three patients in each dose group. Summary of results are:
- Safety: highly daily doses of 20, 40 and 60 mg E4 were safe without dose limiting toxicity (DLT) or serious side effects related to E4 and were well tolerated by all patients.
- Anti-tumor effect (evaluated according to RECIST criteria): 5 of 9 patients showed objective anti-tumor effect with complete remission in one patient and stable disease in 4 patients (50+% efficacy!)
- Wellbeing: 6 of 9 patients “feel very well/much better” according to the treating gynaecologists/oncologists; no validated questionnaires were used at this stage of development.
Overall, there were no discontinuations due to drug related adverse events during the 12 weeks treatment period. Six patients requested continuation of E4 treatment beyond this study period. One patient is still continuing treatment with 20 mg E4 (more than 3 years on treatment), with the other patients in the follow-up treatment period discontinuing after 13-48 weeks of treatment due to progression of the disease.
In conclusion, high doses of E4 was safe and well tolerated during 12 weeks of treatment without dose limiting toxicity and with anti-tumor effects in five of nine patients with progressive, anti-estrogen resistant, advanced breast cancer (end stage disease).
Study results have been presented at several scientific congresses, among others at the breast cancer conference the San Antonio Breast Cancer Symposium (SABCS). Recently, the results were published in the Journal of Cancer Research and Clinical Oncology34.
A scientific advisory board has been installed with the following members:
Monique Bos (the Netherlands), Fatima Cardoso (Portugal), Charles Coombes (UK), Matthew Ellis (USA), Hope Rugo (USA), Christian Singer (Austria) and Marcus Schmidt (Germany).
List of References
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