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A Phase 2 Randomized Study

Matthew J. Ellis, MB, BChir, PhD; Feng Gao, PhD; Farrokh Dehdashti, MD; Donna B. Jeffe, PhD; P. Kelly Marcom, MD; Lisa A. Carey, MD; Maura N. Dickler, MD; Paula Silverman, MD; Gini F. Fleming, MD; Aruna Kommareddy, MB BS; S. Jamalabadi-Majidi, DMD, MPH; Robert Crowder, PhD; Barry A. Siegel, MD

JAMA. 2009;302(7):774-780.

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

Author Affiliations: Department of Medicine, Division of Oncology (Drs Ellis, Kommareddy, Jamalabadi-Majidi, and Crowder), Siteman Comprehensive Cancer Center (Drs Ellis, Gao, Dehdashti, Jeffe, and Siegel), Division of Biostatistics (Dr Gao), Mallinckrodt Institute of Radiology (Drs Dehdashti and Siegel), and Division of Health Behavior Research (Dr Jeffe), Washington University, St Louis, Missouri; Duke Comprehensive Cancer Center, Durham, North Carolina (Dr Marcom); Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill (Dr Carey); Memorial Sloan-Kettering Cancer Center, New York, New York (Dr Dickler); Case Comprehensive Cancer Center, Cleveland, Ohio (Dr Silverman); and University of Chicago Cancer Research Center, Chicago, Illinois (Dr Fleming).

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