Lower-Dose vs High-Dose Oral Estradiol Therapy of Hormone Receptor-Positive, Aromatase Inhibitor-Resistant Advanced Breast Cancer A Phase 2 Randomized Study

Context Estrogen deprivation therapy with aromatase inhibitors has been hypothesized to paradoxically sensitize hormone-receptor-positive breast cancer tumor cells to low-dose estradiol therapy. Objective To determine whether 6 mg of estradiol (daily) is a viable therapy for postmenopausal women with advanced aromatase inhibitor-resistant hormone receptor-positive breast cancer. Design, Setting, and Patients A phase 2 randomized trial of 6 mg vs 30 mg of oral estradiol used daily (April 2004-February 2008 [enrollment closed]). Eligible patients (66 randomized) had metastatic breast cancer treated with an aromatase inhibitor with progression-free survival (>= 24 wk) or relapse (after >= 2 y) of adjuvant aromatase inhibitor use. Patients at high risk of estradiol-related adverse events were excluded. Patients were examined after 1 and 2 weeks for clinical and laboratory toxicities and flare reactions and thereafter every 4 weeks. Tumor radiological assessment occurred every 12 weeks. At least 1 measurable lesion or 4 measurable lesions (bone-only disease) were evaluated for tumor response. Intervention Randomization to receive 1 oral 2-mg generic estradiol tablet 3 times daily or five 2-mg tablets 3 times daily. Main Outcome Measures Primary end point: clinical benefit rate (response plus stable disease at 24 weeks). Secondary outcomes: toxicity, progression-free survival, time to treatment failure, quality of life, and the predictive properties of the metabolic flare reaction detected by positron emission tomography/computed tomography with fluorodeoxyglucose F 18. Results The adverse event rate (> grade 3) in the 30-mg group (11/32 [34%]; 95% confidence interval [CI], 23%-47%) was higher than in the 6-mg group (4/34 [18%]; 95% CI, 5%-22%; P=.03). Clinical benefit rates were 9 of 32 (28%; 95% CI, 18%-41%) in the 30-mg group and 10 of 34 (29%; 95% CI, 19%-42%) in the 6-mg group. An estradiol-stimulated increase in fluorodeoxyglucose F 18 uptake (>= 12% prospectively defined) was predictive of response ( positive predictive value, 80%; 95% CI, 61%-92%). Seven patients with estradiol-sensitive disease were re-treated with aromatase inhibitors at estradiol progression, among which 2 had partial response and 1 had stable disease, suggesting resensitization to estrogen deprivation. Conclusions In women with advanced breast cancer and acquired resistance to aromatase inhibitors, a daily dose of 6 mg of estradiol provided a similar clinical benefit rate as 30 mg, with fewer serious adverse events. The efficacy of treatment with the lower dose should be further examined in phase 3 clinical trials. Trial Registration clinicaltrials.gov Identifier: NCT00324259 JAMA. 2009; 302(7):774-780 www.jama.com