Alternating 17beta-estradiol and aromatase inhibitor therapies is efficacious in post-menopausal women with advanced endocrine-resistant ER+ breast cancer

Author Department


Document Type

Article, Peer-reviewed

Publication Date



Purpose: Strategies to implement estrogen therapy for advanced estrogen receptor (ER)-positive breast cancer are under-developed. Preclinical data suggest that cycling treatment with 17b-estradiol followed by estrogen deprivation can control tumor growth long-term.

Experimental design: Post-menopausal women with advanced ER+/HER2- breast cancer with recurrence or progression on ≥1 anti-estrogen- or aromatase inhibitor (AI)-based therapy were eligible. Patients received 17b-estradiol (2 mg orally TID) for 8 weeks followed by AI (physician's choice) for 16 weeks, alternating treatments on an 8-week/16-week schedule until disease progression. Patients then optionally received continuous single-agent treatment until a second instance of disease progression. Endpoints included 24-week clinical benefit and objective response per RECIST, and tumor genetic alterations.

Results: Of 19 evaluable patients, clinical benefit rate was 42.1% (95% CI: 23.1-63.9%) and objective response rate was 15.8% (95% CI: 5.7-37.9%). One subject experienced a grade 3 adverse event related to 17b-estradiol. Among patients who received continuous single-agent treatment until a second instance of disease progression, clinical benefit was observed in 5/12 (41.7%) cases. Tumor ER (ESR1) mutations were found by whole-exome profiling in 4/7 (57.1%) vs. 2/9 (22.2%) patients who did vs. did not experience clinical benefit from alternating 17b-estradiol/AI therapy. The only two patients to experience objective responses to initial 17b-estradiol had tumor ESR1 mutations.

Conclusions: Alternating 17b-estradiol/aromatase inhibitor therapy may be a promising treatment for endocrine-refractory ER+ breast cancer, including following progression on CDK4/6 inhibitors or everolimus. Further study is warranted to determine whether the anti-tumor activity of 17b-estradiol differs according to ESR1 mutation status.