A new approach: treatment of breast cancer with the fetal Estetrol (E4)

Breast cancer is the most common cancer in women worldwide. Although overall 5 year survival rates are optimistic, one patient still dies from breast cancer every 74 seconds.

Consequently, Carole highlighted, it is critical that research continues in order to develop efficacious compounds that target the malignancy.

High dose oestrogen (HDE) was the endocrine treatment of choice in post-menopausal women with advanced breast cancer since 1944 until tamoxifen entered in the 1970s. Exemplifying this was Haddow's pre-eminent paper, which demonstrated a 30% reduction in tumour size when patients were treated with HDE.

Carole explained that in an unusual phenomenon, oestrogens can stimulate breast cancer, but on the other hand they can also be used to treat the disease. In one study from 1981, 143 patients with advanced breast cancer were treated with either tamoxifen or DES. Although toxicity was higher, patients treated with DES showed greater tumour regression and demonstrated significantly higher long term survival.

Patient selection is crucial:

  • Women with ER+ breast cancer
  • For first-line treatment, women should be at least 5 years post-menopausal
  • For second-line treatment, women should have recorded resistance to endocrine treatment

What is the mode of action?

Several research groups have conducted extensive research to understand the MoA for HDEs. It was found that high doses of oestrogens targeting tumours deficient in the hormone resulted in an increase in apoptosis. However, the issue of in vivo tolerability still persisted.

Of the 4 natural oestrogens, estetrol is a foetal oestrogen that is potentially tolerable with a long half-life, allowing oral dosing.

Estetrol in patients with advanced breast cancer - the ABCE4 study

To investigate this in an in vivo model, Carole and her colleagues are conducting an ongoing combined phase I/II trial to determine the safety and effectiveness of estetrol in advanced breast cancer.

The study has been divided into 2 parts:

  • Phase I: 4 weeks of treatment to assess dose limiting toxicity
  • Phase II: Followed by 8 weeks of treatment to assess initial anti-tumour respons

Although the trial recruited only 6 patients, results reported a tolerable safety profile with no patients experiencing dose-limiting toxicity. Of the 3 patients who reached phase II, 1 patient has demonstrated disease stability after 6 months of treatment.

Investigators are optimistic about the future of this new approach harnessing HT, and Carole informed the audience that she will be meeting with them to discuss next steps in the coming weeks.