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Lower-dose vs high-dose oral estradiol therapy of hormone receptor-positive, aromatase inhibitor-resistant advanced breast cancer: a phase 2 randomized study.

Publication ,  Journal Article
Ellis, MJ; Gao, F; Dehdashti, F; Jeffe, DB; Marcom, PK; Carey, LA; Dickler, MN; Silverman, P; Fleming, GF; Kommareddy, A; Jamalabadi-Majidi, S ...
Published in: JAMA
August 19, 2009

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 (> or = 24 wk) or relapse (after > or = 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 (> or = 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 (> or = 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.

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Published In

JAMA

DOI

EISSN

1538-3598

Publication Date

August 19, 2009

Volume

302

Issue

7

Start / End Page

774 / 780

Location

United States

Related Subject Headings

  • Survival Analysis
  • Receptors, Estrogen
  • Radiopharmaceuticals
  • Quality of Life
  • Predictive Value of Tests
  • Postmenopause
  • Positron-Emission Tomography
  • Middle Aged
  • Insulin-Like Growth Factor I
  • Humans
 

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Ellis, M. J., Gao, F., Dehdashti, F., Jeffe, D. B., Marcom, P. K., Carey, L. A., … Siegel, B. A. (2009). Lower-dose vs high-dose oral estradiol therapy of hormone receptor-positive, aromatase inhibitor-resistant advanced breast cancer: a phase 2 randomized study. JAMA, 302(7), 774–780. https://doi.org/10.1001/jama.2009.1204
Ellis, Matthew J., Feng Gao, Farrokh Dehdashti, Donna B. Jeffe, P Kelly Marcom, Lisa A. Carey, Maura N. Dickler, et al. “Lower-dose vs high-dose oral estradiol therapy of hormone receptor-positive, aromatase inhibitor-resistant advanced breast cancer: a phase 2 randomized study.JAMA 302, no. 7 (August 19, 2009): 774–80. https://doi.org/10.1001/jama.2009.1204.
Ellis, Matthew J., et al. “Lower-dose vs high-dose oral estradiol therapy of hormone receptor-positive, aromatase inhibitor-resistant advanced breast cancer: a phase 2 randomized study.JAMA, vol. 302, no. 7, Aug. 2009, pp. 774–80. Pubmed, doi:10.1001/jama.2009.1204.
Ellis MJ, Gao F, Dehdashti F, Jeffe DB, Marcom PK, Carey LA, Dickler MN, Silverman P, Fleming GF, Kommareddy A, Jamalabadi-Majidi S, Crowder R, Siegel BA. Lower-dose vs high-dose oral estradiol therapy of hormone receptor-positive, aromatase inhibitor-resistant advanced breast cancer: a phase 2 randomized study. JAMA. 2009 Aug 19;302(7):774–780.
Journal cover image

Published In

JAMA

DOI

EISSN

1538-3598

Publication Date

August 19, 2009

Volume

302

Issue

7

Start / End Page

774 / 780

Location

United States

Related Subject Headings

  • Survival Analysis
  • Receptors, Estrogen
  • Radiopharmaceuticals
  • Quality of Life
  • Predictive Value of Tests
  • Postmenopause
  • Positron-Emission Tomography
  • Middle Aged
  • Insulin-Like Growth Factor I
  • Humans