Cyclic estrogen therapy/anti-estrogen therapy could be a promising strategy for the treatment of metastatic ER+ breast cancer


Advanced or metastatic estrogen receptor-positive (ER+) breast cancer is usually treated with medications that block the estrogen receptor. However, the receptor-stimulating estrogen hormone can also be effective. Building on their previous studies, researchers at Dartmouth Cancer Center recently concluded a Phase II clinical trial aimed at testing effectiveness Alternating between estrogen stimulation and estrogen deprivation in patients with metastatic ER+ breast cancer, and identifying tumor characteristics that predict who might benefit from this strategy. The results were recently published ahead of print Clinical Cancer Researcha journal of the American Association for Cancer Research, supports cyclic estrogen/anti-estrogen therapy as a promising strategy for the treatment of advanced/metastatic ER+ breast cancer.

The POLLY trial represents “a phase II study of the protective fluctuation of ER activity levels by alternating estradiol/anti-estrogen treatments prior to disease progression in metastatic or advanced ER+/HER2- breast cancer.” Of the 19 patients enrolled in the trial, 3 (16%) experienced tumor shrinkage during cyclic treatment and another 5 (26%) had disease stabilization for at least 24 weeks, resulting in an overall benefit rate of 42%. The treatments were well tolerated, and no patient discontinued drug therapy due to side effects. After cancer progression on cyclic therapy, 12 patients were randomized to receive one-drug one-off treatment—5 of these patients (42%) had further stabilization of the disease for at least 24 weeks.

Estrogen therapy has been used for more than 50 years to treat breast cancer. Strategies for maximizing estrogen efficacy and minimizing side effects, as well as research on cancers that develop resistance to new tumor-targeting drugs that have come to market in the past decade such as Ibrance, Kisqali, Verzenio, and Afinitor, remain undeveloped. Polly’s study has addressed this gap.”

Gary N. Schwartz, MD, a breast oncologist at Dartmouth Cancer Center and lead author

“Tumor features called biomarkers that predict which patients will benefit from estrogen therapy have also not been reported,” adds cancer researcher and co-author Todd W. Miller, PhD. “In the POLLY trial, we found that mutations in the gene encoding ER, which are often seen in tumors that become resistant to antiestrogen drugs, were present in tumors from only two patients whose tumors shrank in response to estrogen therapy during the first 8 weeks. This indicates that ER mutations are present. They may be useful in identifying patients who are likely to benefit from this treatment strategy.

The team will build on POLLY’s findings by conducting a follow-up clinical study, “Estradiol therapy to target mutant ER and wild-type ER+.” Metastatic breast cancer (Esther), “will test the efficacy of estrogen therapy in patients with or without tumor mutations in the ER.


Journal reference:

Schwartz, G.N., et al. (2023) Alternating therapy with 17-beta-estradiol and an aromatase inhibitor is effective in postmenopausal women with advanced endocrine-resistant ER+ breast cancer. Clinical Cancer Research.


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