Abstract P5-04-15: Enhancing response to estrogen therapy in ER+ breast cancer with novel scheduling and dosing regimens
Authors: Traphagen NA , Hosford SR , Miller TW 
Published: May 2019

Abstract
Estrogen therapy was historically used as a standard breast cancer treatment from the 1940s until the introduction of tamoxifen in the 1970s. Although a clinical trial directly comparing the synthetic estrogen diethylstilbestrol and tamoxifen in post-menopausal patients demonstrated no significant difference in progression-free survival between the two, tamoxifen showed a more favorable toxicity profile and estrogens fell out of favor. However, 1 in 3 patients eventually recur and develop advanced disease that is resistant to all available anti-estrogens. Estrogen therapy is being resurrected in clinical trials for advanced, heavily pre-treated ER+ breast cancer. These studies demonstrate that ˜30% of patients respond to treatment with estrogens. However, little pharmacologic work has been done to optimize the schedule and method of hormone delivery.
Estrogen therapies such as 17b-estradiol (E2) and ethinylestradiol are typically administered orally several times daily. Toxicities have been observed with such regimens, and there is no evidence that the maximally efficacious doses or schedules are being used clinically. We used two in vivo tumor models to preclinically define the optimal dosing schedule and method of E2 delivery that maximizes response. WHIM16 patient-derived ER+ breast cancer xenografts (PDX) and C7-2-HI ER+ murine mammary adenocarcinoma allografts both grow in ovariectomized (“estrogen-deprived”) mice, and regress in response to E2 treatment.
We tested an array of E2 doses and delivery methods [e.g., oral gavage, subcutaneous (s.c.) injection, s.c. pellet, and s.c. osmotic pump] in mice bearing C7-2-HI and WHIM16 tumors to determine optimal methods for inducing maximal and sustained tumor regression. We found that oral dosing is less effective at inducing tumor regression than other methods. However, intermittent high-dose estrogen given as 1 mg of E2 orally every 14 days both prevented tumor growth and did not result in toxicity, suggesting that intermittent dosing should be further examined as a means to increase therapeutic index.
Although estrogen therapy induces clinical response in a subset of patients with ER+ disease, nearly all patients eventually experience disease progression and develop resistance to the therapeutic effects of estrogen. Clinical observations suggest that some cancers that progressed on estrogen therapy are re-sensitized to anti-estrogen treatment. We therefore examined whether resistance to estrogen therapy could be prevented by preemptively cycling estrogen therapy with estrogen deprivation in mice. Discontinuous scheduling of E2 and estrogen deprivation was tested with either 1 or 4 weeks on E2 treatment, followed by estrogen deprivation until tumors re-grew to baseline volume, then E2 treatment was repeated. In the WHIM16 tumor model, the 4-week E2 treatment cycle nearly doubled time to recurrence compared to mice treated continuously with E2. Surprisingly, there was no difference in time to recurrence between groups treated with the 1-week cycle vs. continuous E2. However, tumors that re-grew on continuous E2 were sensitized to estrogen deprivation. These collective findings warrant clinical testing of schedules of alternating estrogen and anti-estrogen therapies.
Citation Format: Traphagen NA, Hosford SR, Miller TW. Enhancing response to estrogen therapy in ER+ breast cancer with novel scheduling and dosing regimens [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-04-15.