Estradiol in Breast Cancer Treatment

Abstract

DESPITE A DECLINING INCIDENCE, BREAST CANCER REmains the most common cancer among women in the United States. More than two-thirds of all patients with breast cancer present with tumors that express estrogen receptors, progesterone receptors, or both, and the modulation of estrogen receptor signaling has been one of the most successful strategies for these patients. In recent years, the most commonly used forms of endocrine therapy have included the competitive inhibition of the estrogen receptors with an antiestrogen (selective estrogen receptor modulators [SERMs], eg, tamoxifen, or selective estrogen–receptor down-regulators, [SERDs], eg, fulvestrant) and the decrease in estrogen production from precursor steroid hormones using an aromatase inhibitor. In this issue of JAMA, Ellis and colleagues describe the findings of a preliminary phase 2 randomized study, evaluating the efficacy of 2 daily doses of oral estradiol (30 mg vs 6 mg). The study included 66 postmenopausal women with hormone receptor–positive metastatic breast cancer, who had received prior therapy with an aromatase inhibitor for at least 24 weeks for metastatic disease or for at least 2 years as adjuvant therapy. The authors reported a clinical benefit for 29% of patients (10/34) treated with the low-dose (6 mg) therapy and for 28% of those (9/32) treated with high-dose (30 mg) therapy. Grade 3 and 4 toxicities were significantly more common in patients receiving the higher dose of estradiol. The adverse effects associated with the 30-mg dose of estradiol led to treatment discontinuation in 4 of 32 patients and required a dose reduction in 4 patients, whereas only 1 patient withdrew from therapy at the lower dose for personal reasons. Estradiol-related pharmacodynamic end points, including changes in the fluorodeoxyglucose–positron-emission tomography/computed tomography (FDG-PET/CT) uptake over 24 hours after estradiol initiation and a decrease in the expression of insulinlike growth factor (IGF-1), were observed in both groups. The increase in the specific uptake value by FDGPET/CT in predefined tumor sites appeared predictive of response, although data were available for only 70% (46) of the patients. Based on the promising efficacy data and the acceptable toxicity profile observed with the low-dose estradiol, the authors suggest that further studies exploring this intervention should be pursued in larger randomized phase 3 trials. Synthetic estrogens were an integral part in the armamentarium of breast cancer for several decades. First synthesized in 1938, diethylstilbestrol (DES) was approved as a synthetic estrogen by the US Food and Drug Administration in 1941, and recommended as a treatment for breast cancer for postmenopausal women in 1960. Very high doses of estrogen were further tested in premenopausal women, albeit with more limited success. The use of estrogens for the treatment of breast cancer was largely empirical and perhaps counterintuitive because the benefits of estrogen withdrawal by oophorectomy, adrenalectomy, and hypophysectomy were well-recognized by that time as a treatment for breast cancer in both premenopausal and postmenopausal women by that time. Furthermore, formal testing of estrogen receptor expression was not yet available. High doses of estrogens remained one of the few nonsurgical options for breast cancer treatment until the introduction of the antiestrogen tamoxifen in 1971. A small randomized phase 2 trial evaluating 2 doses of tamoxifen in postmenopausal women with advanced breast cancer and prior exposure to hormonal manipulations showed sustained activity with acceptable toxicity with this agent, which had been unsuccessfully developed as a contraceptive. Further studies comparing tamoxifen with DES showed that DES and tamoxifen elicited similar results in terms of response rates and time to tumor progression; however, tamoxifen treatment led to far fewer adverse effects and treatment discontinuations. The subsequent introduction of thirdgeneration aromatase inhibitors and the approval of the SERD fulvestrant rendered synthetic estrogens a less desirable alternative, and high-dose estrogens have been rarely used in recent years. Furthermore, changes in practice patterns have shifted the use of chemotherapy more to the foreground, even for women with hormone receptor–positive tumors. The interest in estrogens as therapy for metastatic breast cancer was rekindled when Lonning et al reported a ben-