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”).
Background
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).
Figure 1 The four natural estrogens
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.
Breast cancer
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.
Treatment concept
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.
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.
Pilot study
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.
Proof-of-Concept study
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
1. Hagen AA, Barr M and Diczfalusy E. Metabolism of 17-beta-oestradiol-4-14-C in early infancy. Acta Endocrinol (Copenh) 1965; 49:207-220
2. Visser M, Holinka CF and Coelingh Bennink HJ. First human exposure to exogenous single-dose oral estetrol in early postmenopausal women. Climacteric 2008; 11 Suppl 1:31-40
3. Coelingh Bennink HJ, Heegaard AM, Visser M, Holinka CF and Christiansen C. Oral bioavailability and bone-sparing effects of estetrol in an osteoporosis model. Climacteric 2008; 11 Suppl 1:2-14
4. Mawet M, Maillard C, Klipping C, Zimmerman Y, Foidart JM and Coelingh Bennink HJ. Unique effects on hepatic function, lipid metabolism, bone and growth endocrine parameters of estetrol in combined oral contraceptives. Eur J Contracept Reprod Health Care 2015; 1-13
5. Kluft C, Zimmerman Y, Mawet M, Klipping C, Duijkers IJ, Neuteboom J, Foidart JM and Bennink HC. Reduced hemostatic effects with drospirenone-based oral contraceptives containing estetrol vs. ethinyl estradiol. Contraception 2017; 95:140-147
6. Giretti MS, Montt Guevara MM, Cecchi E, Mannella P, Palla G, Spina S, Bernacchi G, Di Bello S, Genazzani AR, Genazzani AD and Simoncini T. Effects of Estetrol on Migration and Invasion in T47-D Breast Cancer Cells through the Actin Cytoskeleton. Front Endocrinol 2014; 5:80
7. Gerard C, Blacher S, Communal L, Courtin A, Tskitishvili E, Mestdagt M, Munaut C, Noel A, Gompel A, Pequeux C and Foidart JM. Estetrol is a weak estrogen antagonizing estradiol-dependent mammary gland proliferation. J Endocrinol 2015; 224:85-95
8. Visser M, Kloosterboer HJ and Bennink HJ. Estetrol prevents and suppresses mammary tumors induced by DMBA in a rat model. Horm Mol Biol Clin Investig 2012; 9:95-103
9. Haddow A, Watkinson JM, Paterson E and Koller PC. Influence of Synthetic Oestrogens on Advanced Malignant Disease. Br Med J 1944; 2:393-398
10. Song RX, Mor G, Naftolin F, McPherson RA, Song J, Zhang Z, Yue W, Wang J and Santen RJ. Effect of long-term estrogen deprivation on apoptotic responses of breast cancer cells to 17beta-estradiol. J Natl Cancer Inst 2001; 93:1714-1723
11. Jordan VC. The new biology of estrogen-induced apoptosis applied to treat and prevent breast cancer. Endocr Relat Cancer 2015; 22:R1-31
12. Jordan VC. Molecular Mechanism for Breast Cancer Incidence in the Women’s Health Initiative. Cancer Prev Res (Phila) 2020; 13:807-816
13. Coelingh Bennink HV, C; Dutman, AE; Thijssen,J. The use of high-dose estrogens for the treatment of breast cancer. Maturitas 2017; 95:11-23
14. Ingle JN, Ahmann DL, Green SJ, Edmonson JH, Bisel HF, Kvols LK, Nichols WC, Creagan ET, Hahn RG, Rubin J and Frytak S. Randomized clinical trial of diethylstilbestrol versus tamoxifen in postmenopausal women with advanced breast cancer. N Engl J Med 1981; 304:16-21
15. Peethambaram PP, Ingle JN, Suman VJ, Hartmann LC and Loprinzi CL. Randomized trial of diethylstilbestrol vs. tamoxifen in postmenopausal women with metastatic breast cancer. An updated analysis. Breast Cancer Res Treat 1999; 54:117-122
16. Reinert T and Barrios CH. Overall survival and progression-free survival with endocrine therapy for hormone receptor-positive, HER2-negative advanced breast cancer: review. Ther Adv Med Oncol 2017; 9:693-709
17. Croxtall JD and McKeage K. Fulvestrant: a review of its use in the management of hormone receptor-positive metastatic breast cancer in postmenopausal women. Drugs 2011; 71:363-380
18. Makubate B, Donnan PT, Dewar JA, Thompson AM and McCowan C. Cohort study of adherence to adjuvant endocrine therapy, breast cancer recurrence and mortality. Br J Cancer 2013; 108:1515-1524
19. Kwan ML, Roh JM, Laurent CA, Lee J, Tang L, Hershman D, Kushi LH and Yao S. Patterns and reasons for switching classes of hormonal therapy among women with early-stage breast cancer. Cancer Causes Control 2017; 28:557-562
20. Ciruelos E, Pascual T, Arroyo Vozmediano ML, Blanco M, Manso L, Parrilla L, Muñoz C, Vega E, Calderón MJ, Sancho B and Cortes-Funes H. The therapeutic role of fulvestrant in the management of patients with hormone receptor-positive breast cancer. Breast 2014; 23:201-208
21. Howie LJ, Singh H, Bloomquist E, Wedam S, Amiri-Kordestani L, Tang S, Sridhara R, Sanchez J, Prowell TM, Kluetz PG, King-Kallimanis BL, Gao JJ, Ibrahim A, Goldberg KB, Theoret M, Pazdur R and Beaver JA. Outcomes of Older Women With Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor-Negative Metastatic Breast Cancer Treated With a CDK4/6 Inhibitor and an Aromatase Inhibitor: An FDA Pooled Analysis. J Clin Oncol 2019; 37:3475-3483
22. Lasheen S, Shohdy KS, Kassem L and Abdel-Rahman O. Fatigue, alopecia and stomatitis among patients with breast cancer receiving cyclin-dependent kinase 4 and 6 inhibitors: a systematic review and meta-analysis. Expert Rev Anticancer The 2017; 17:851-856
23. Messina C, Cattrini C, Buzzatti G, Cerbone L, Zanardi E, Messina M and Boccardo F. CDK4/6 inhibitors in advanced hormone receptor-positive/HER2-negative breast cancer: a systematic review and meta-analysis of randomized trials. Breast Cancer Res Treat 2018; 172:9-21
24. Lønning PE, Taylor PD, Anker G, Iddon J, Wie L, Jørgensen LM, Mella O and Howell A. High-dose estrogen treatment in postmenopausal breast cancer patients heavily exposed to endocrine therapy. Breast Cancer Res Treat 2001; 67:111-116
25. Ellis MJ, Gao F, Dehdashti F, Jeffe DB, Marcom PK, Carey LA, Dickler MN, Silverman P, Fleming GF, Kommareddy A, Jamalabadi-Majidi S, Crowder R and Siegel BA. Lower-dose vs high-dose oral estradiol therapy of hormone receptor-positive, aromatase inhibitor-resistant advanced breast cancer: a phase 2 randomized study. JAMA 2009; 302:774-780
26. Iwase H, Yamamoto Y, Yamamoto-Ibusuki M, Murakami KI, Okumura Y, Tomita S, Inao T, Honda Y, Omoto Y and Iyama KI. Ethinylestradiol is beneficial for postmenopausal patients with heavily pre-treated metastatic breast cancer after prior aromatase inhibitor treatment: a prospective study. Br J Cancer 2013; 109:1537-1542
27. Coelingh Bennink HJ, Holinka CF and Diczfalusy E. Estetrol review: profile and potential clinical applications. Climacteric 2008; 11 Suppl 1:47-58
28. Coelingh Bennink HJT, Verhoeven C, Zimmerman Y, Visser M, Foidart JM and Gemzell-Danielsson K. Pharmacodynamic effects of the fetal estrogen estetrol in postmenopausal women: results from a multiple-rising-dose study. Menopause 2017; 24:677-685
29. Coelingh Bennink HJ, Verhoeven C, Zimmerman Y, Visser M, Foidart JM and Gemzell-Danielsson K. Clinical effects of the fetal estrogen estetrol in a multiple-rising-dose study in postmenopausal women. Maturitas 2016; 91:93-100
30. Gaspard U, Taziaux M, Mawet M, Jost M, Gordenne V, Coelingh Bennink HJT, Lobo RA, Utian WH and Foidart JM. A multicenter, randomized study to select the minimum effective dose of estetrol (E4) in postmenopausal women (E4Relief): part 1. Vasomotor symptoms and overall safety. Menopause 2020; 27:848-857
31. Apter D, Zimmerman Y, Beekman L, Mawet M, Maillard C, Foidart JM and Coelingh Bennink HJ. Bleeding pattern and cycle control with estetrol-containing combined oral contraceptives: results from a phase II, randomised, dose-finding study (FIESTA). Contraception 2016; 94:366-373
32. Coelingh Bennink HJT, Verhoeven C, Zimmerman Y, Visser M, Foidart JM and Gemzell-Danielsson K. Pharmacokinetics of the fetal estrogen estetrol in a multiple-rising-dose study in postmenopausal women. Climacteric 2017; 20:285-289
33. Singer CF, Bennink HJ, Natter C, Steurer S, Rudas M, Moinfar F, Appels N, Visser M and Kubista E. Antiestrogenic effects of the fetal estrogen estetrol in women with estrogen-receptor positive early breast cancer. Carcinogenesis 2014; 35:2447-2451
34. Schmidt M, Lenhard H, Hoenig A, Zimmerman Y, Krijgh J, Jansen M and Coelingh Bennink HJT. Tumor suppression, dose-limiting toxicity and wellbeing with the fetal estrogen estetrol in patients with advanced breast cancer. Journal of cancer research and clinical oncology 2020; doi: 10.1007/s00432-020-03472-8. Online ahead of print.