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):774-80. doi: 10.1001/jama.2009.1204.

Abstract

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.

Publication types

  • Clinical Trial, Phase II
  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Antineoplastic Agents, Hormonal / therapeutic use*
  • Aromatase Inhibitors / therapeutic use*
  • Biomarkers / metabolism
  • Breast Neoplasms / diagnostic imaging
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / mortality
  • Drug Resistance, Neoplasm
  • Estradiol / administration & dosage*
  • Estradiol / therapeutic use
  • Estrogens / administration & dosage*
  • Estrogens / therapeutic use
  • Female
  • Fluorodeoxyglucose F18
  • Humans
  • Insulin-Like Growth Factor I / metabolism
  • Middle Aged
  • Positron-Emission Tomography
  • Postmenopause
  • Predictive Value of Tests
  • Quality of Life
  • Radiopharmaceuticals
  • Receptors, Estrogen / metabolism*
  • Survival Analysis

Substances

  • Antineoplastic Agents, Hormonal
  • Aromatase Inhibitors
  • Biomarkers
  • Estrogens
  • Radiopharmaceuticals
  • Receptors, Estrogen
  • Fluorodeoxyglucose F18
  • Estradiol
  • Insulin-Like Growth Factor I

Associated data

  • ClinicalTrials.gov/NCT00324259