Low-dose estradiol is an effective and well tolerated endocrine option in postmenopausal women with advanced breast cancer and evidence of prolonged sensitivity to aromatase inhibitor therapy, a new study published online ahead of print in the European Journal of Cancer has shown.1

Although high-dose estrogen is effective in postmenopausal women with advanced breast cancer, it is toxic. Therefore, researchers sought to evaluate the safety and efficacy of low-dose estradiol in women who had prolonged estrogen deprivation via third-generation aromatase inhibitor therapy. The researchers hypothesized that the aromatase inhibitors would sensitize breast cancers to low-dose estradiol.

For the single-arm, phase 2 study, researchers enrolled 21 postmenopausal women with estrogen receptor-positive advanced breast cancer. All patients received estradiol valerate 2 mg daily.

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If low-dose estradiol was ineffective, patients could receive high-dose estrogen. If low-dose estradiol was effective, patients who experienced disease progression could be retreated with the aromatase inhibitor they had before estradiol.

The trial was closed early due to slow accrual. Results showed that among the evaluable 19 patients, 26% (95% CI, 9.1 – 51.2) achieved clinical benefit, all with prolonged stable disease. Of those, 4 restarted pre-estradiol aromatase inhibitor therapy and 3 achieved clinical benefit, 1 of whom achieved a partial response.

Researchers found that those with clinical benefit to low-dose estradiol had a significantly longer duration of first-line endocrine therapy for advanced breast cancer compared with those without clinical benefit (P < .01).

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“Re-challenge with the [pre-low-dose estradiol aromatase inhibitor] following progression confirms re-sensitization as a true phenomenon,” the authors noted.

In regard to safety, 4 of the 19 patients discontinued treatment due to toxicities and 8 of 11 without hysterectomy experienced vaginal bleeding.


  1. Zucchini G, Armstrong AC, Wardley AM, et al. A phase II trial of low-dose estradiol in postmenopausal women with advanced breast cancer and acquired resistance to aromatase inhibition [published online ahead of print on November 17, 2015]. Eur J Cancer. doi: 10.1016/j.ejca.2015.08.028.